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[(before)-487.7(performing)-487.1(any)-481.5(baseline)-493.1(study-specic)-486.7(evaluations.)-485.9(The)]TJ 0 -1.2266 TD [(investigator/study)-347.6(site)-344.8(retained)-349.1(the)-346.4(original)-348.3(signed)-346.1(informed)-352.7(con-)]TJ 0 -1.2203 TD [(sent)-245.9(document)-248.8(and)-247.5(provided)-245.4(one)-247.5(copy)-247.1(of)-248.2(the)-245.2(document)-248.8(to)-249.6(all)-249.3(study)]TJ T* (participants.)Tj /F12 1 Tf 0 -2.5987 TD (Participants)Tj /F6 1 Tf 1.1128 -1.8336 TD [(Eligible)-197.8(study)-198.8(participants)-204.6(were)-198.5(healthy)-199.1(subjects)-207.4(between)-200.9(18)-195(and)]TJ -1.1128 -1.2203 TD [(55)-289.9(years)-290.7(of)-292.5(age)-287.9(\(inclusive\))-296.1(at)-290(screening.)-291.8(They)-291.1(included)-293.5(males)-289.3(and)]TJ 0 -1.2266 TD [(nonpregnant,)-224(nonbreastfeeding)-231.3(females)-230.2(and)-228.6(had)-222.3(a)-229.5(body)-225.7(mass)-227.7(index)]TJ 0 -1.2203 TD [(between)-276.7(18)-270.9(and)-272.8(32)-169.7(kg/m)]TJ 6.7246 0 0 5.9768 399.0613 403.7101 Tm (2)Tj 8.9663 0 0 8.9663 404.9007 399.7416 Tm [(\(inclusive\))-277.2(and)-272.8(body)-269.9(weight)-276.4(between)-276.7(50)]TJ -10.4897 -1.2203 TD [(and)-279.2(100)-169.3(kg.)]TJ 1.1128 -1.2266 TD [(Exclusion)-203.1(criteria)-210.3(included)-205(a)-210.6(history)-204.4(or)-204(the)-207.3(presence)-211.9(of)-204(clinically)]TJ -1.1128 -1.2203 TD [(signicant)-233.1(cardiovascular,)-237.6(pulmonary,)-232.4(hepatic,)-236.1(renal,)-233.2(hematologic,)]TJ T* [(gastrointestinal,)-581.6(endocrine,)-575.1(immunologic,)-581.8(dermatologic,)-578.9(neuro-)]TJ 0 -1.2266 TD [(logic,)-308.1(oncologic,)-314.9(or)-311.5(psychiatric)-314.9(disease,)-310.3(among)-313.3(other)-310.1(factors.)-311.9(The)]TJ 0 -1.2203 TD [(complete)-286.8(list)-289.5(of)-286.2(inclusion)-283.2(and)-285.5(exclusion)-287.9(criteria)-292.5(is)-288.8(provided)-283.3(in)-287.6(the)]TJ T* [(Supplementary)-279.2(Data)-282.1(S1.)]TJ /F12 1 Tf 0 -2.5987 TD [(SDX/d-MPH)-333.5(capsules)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(Study)-537.6(subjects)-542.5(received)-543.5(SDX/d-MPH)-547.5(capsules)-540.9(containing)-543.1(a)]TJ -1.1128 -1.2203 TD [(70:30)-330.4(molar)-338.9(ratio)-333.1(of)-336.7(SDX)-332.5(and)-336.1(d-MPH,)-334.5(in)-331.8(the)-333.8(following)-336(dosages:)]TJ 0 -1.2266 TD [(Treatment)-225.5(A,)-227(26.1)-165.8(mg)-223.9(of)-222.9(SDX)-225(and)-228.6(5.2)-166.3(mg)-223.9(of)-222.9(d-MPH;)-227.6(Treatment)-225.5(B,)]TJ 0 -1.2203 TD [(39.2)-165.8(mg)-476.8(of)-482.2(SDX)-477.9(and)-481.5(7.8)-166.3(mg)-483.1(of)-475.8(d-MPH;)-480.5(Treatments)-485.4(C)-478.4(and)-481.5(D,)]TJ T* [(52.3)-165.8(mg)-280.8(of)-286.2(SDX)-281.9(and)-285.5(10.4)-165.8(mg)-287.1(of)-279.8(d-MPH.)-283.9(The)-285.3(total)-283.9(dose)-286.2(for)-288.3(Treat-)]TJ T* [(ments)-204.7(A,)-201.7(B,)-203.2(and)-209.6(C/D)-200.3(was)-207.8(equimolar)-204.3(to)-205.4(20,)-204.3(30,)-204.3(and)-203.3(40)-169.7(mg)-204.9(of)-204(d-MPH)]TJ 0 -1.2266 TD [(HCl,)-279.1(respectively.)]TJ /F12 1 Tf 0 -2.5987 TD [(Study)-332.3(design)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(The)-519.2(study)-521.2(was)-523.9(an)-526.2(open-label,)-521.8(randomized)-524.7(crossover)-526.5(design)]TJ -1.1128 -1.2203 TD [(consisting)-201.7(of)-204(single-dose)-202.2(and)-203.3(multiple-dose)-198.9(phases.)-203.2(Study)-202.5(drug)-203(was)]TJ T* [(administered)-343.2(orally)-345.2(to)-344.5(study)-344.2(participants)-343.7(under)-344(fasted)-344.8(conditions.)]TJ T* [(For)-233.7(the)-238.9(single-dose)-240.1(treatment)-236(phase,)-240.4(all)-236.6(study)-236.7(participants)-242.6(received)]TJ 0 -1.2266 TD [(T)13.3(r)0(e)21.3(a)0(t)19.8(m)0(e)20.3(n)13.1(t)-167.9(A)-173.5(\(S)25.1(DX)19.7(/d)22.3(-M)23(PH)-159(26)20(.1)22.9(/5)22.2(.2)-141.5(mg)16.4(\),)-156.8(T)13.3(r)0(e)21.2(a)0(t)19.8(m)0(e)20.3(n)13.1(t)-167.9(B)-174.9(\(S)25.1(DX)19.7(/d)22.2(-M)23(PH)]TJ 0 -1.2203 TD [(3)13.1(9)13.1(.)0(2)22.9(/)0(7)15.9(.)16(8)-157.6(m)0(g)22.7(\))0(,)-517.2(a)0(n)17.5(d)-530.6(T)13.3(r)0(e)21.2(a)0(t)19.8(m)0(e)20.3(n)13.1(t)-528.3(C)-529(\(S)18.8(DX)19.7(/)15.4(d)0(-)17.3(M)12.4(P)14.5(H)-533.9(5)13.1(2)13.1(.)0(3)16.5(/)15.4(10)20(.4)-141.5(mg)22.7(\))-533.2(ac-)]TJ T* [(cording)-302.8(to)-306.5(a)-305.4(randomization)-303.6(schedule)-305.7(in)-306.5(a)-305.4(crossover)-305.2(manner.)-301.8(Each)]TJ 0 -1.2266 TD [(treatment)-274(was)-277.3(separated)-278.7(by)-270.9(a)-273.8(96-hour)-273.7(washout)-273.1(period)-278(and)-272.8(was)-277.3(ad-)]TJ 0 -1.2203 TD [(ministered)-240.6(on)-239.3(days)-241.9(1,)-242.7(5,)-236.4(and)-241.2(9.)-242.7(After)-240.1(completion)-243.2(of)-241.9(the)-238.9(single-dose)]TJ T* [(treatment)-337.2(phase)-338.7(plus)-332.1(another)-336.8(96-hour)-336.9(washout)-336.3(period,)-337.8(all)-337.8(partici-)]TJ 0 -1.2266 TD [(pants)-251.8(received)-259(multiple)-252.1(doses)-255.3(of)-248.2(Treatment)-257.1(D)-255.7(every)-251.6(24)-251.9(hours)-254.3(for)-250.3(4)]TJ 0 -1.2203 TD [(consecutive)-285.4(days)-279.9(\(dose)-282(14\).)]TJ /F4 1 Tf -28.0042 77.228 TD [(PHARMACOKINETICS)-343.5(OF)-331.2(SDX/)]TJ 6.4556 0 0 6.4556 193.6629 749.7069 Tm (D)Tj 8.9663 0 0 8.9663 198.3117 749.7069 Tm (-MPH)Tj 37.5581 0 TD (289)Tj ET endstream endobj 40 0 obj <>stream /GS1 gs BT /F12 1 Tf 8.9663 0 0 8.9663 62.022 725.7825 Tm 0 0 0 rg 0 Tc 0 Tw [(Blood)-336.9(sampling)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(A)-205.1(total)-201.7(of)-204(86)-201.4(blood)-203.9(samples)-207.4(were)-204.8(collected)-207(from)-202.8(each)-201.3(participant)]TJ -1.1128 -1.2203 TD [(during)-534.8(the)-536.1(study.)-530.5(During)-531.8(single-dose)-537.3(treatment)-539.5(periods,)-534.5(blood)]TJ 0 -1.2266 TD [(sampling)-283.2(occurred)-286.8(predose)-283.4(and)-279.2(at)-283.7(0.5,)-283.1(1,)-280.6(1.5,)-283.1(2,)-280.6(2.5,)-276.7(3,)-287(5,)-280.6(7,)-280.6(9,)-280.6(12,)]TJ 0 -1.2203 TD [(13,)-400.3(24,)-394(36,)-400.3(48,)-394(60,)-400.3(and)-399.3(72)-397.4(hours)-399.7(postdose)-396.9(for)-395.8(each)-403.6(of)-393.6(the)-403.3(three)]TJ T* [(dosage)-363.5(strengths)-371.5(of)-362(SDX/d-MPH.)-367(In)-362(the)-365.4(multiple-dose)-363.3(treatment)]TJ 0 -1.2266 TD [(period,)-299.9(blood)-292.4(sampling)-295.8(was)-302.6(conducted)-297.7(on)-296.2(day)-291.8(1)-296.7(a)0(t)-296.3(predose)-302.4(and)-291.8(at)]TJ 0 -1.2203 TD [(0.5,)-200.9(1,)-198.4(1.5,)-200.9(2,)-198.4(2.5,)-200.9(3,)-198.4(5,)-198.4(7,)-198.4(9,)-198.4(12,)-197.9(13,)-198(and)-203.3(24)-201.4(hours)-197.4(postdose;)-204.5(on)-195(days)-204(2)]TJ T* [(and)-260.2(3)-258.8(a)0(t)-264.7(2)0(,)-261.7(8)0(,)-255.3(and)-260.2(24)-264.6(hours)-260.6(postdose;)-261.4(and)-260.2(on)-258.3(day)-260.2(4)-258.7(a)0(t)-264.7(0.5,)-257.8(1,)-261.7(1.5,)-257.8(2,)]TJ T* [(2.5,)-384.2(3,)-388.1(5,)-381.8(7,)-388.1(9,)-381.8(12,)-387.6(13,)-381.3(24,)-387.6(36,)-381.3(48,)-387.6(60,)-381.3(and)-386.7(72)-384.7(hours)]TJ /F7 1 Tf 22.0543 0 TD ()Tj /F6 1 Tf .5501 0 TD [(5)-385.2(minutes)]TJ -22.6044 -1.2266 TD [(postdose.)-305(All)-300.7(24-hour)-299(blood)-305.1(sample)-301.5(collections)-303.7(on)-302.5(days)-305.2(13)-302(were)]TJ 0 -1.2203 TD [(performed)-283.7(before)-279(administration)-284.7(of)-279.8(the)-283.2(next)-282.7(dose)-279.9(of)-279.8(the)-276.9(drug.)]TJ /F12 1 Tf 0 -3.3638 TD [(Bioanalytical)-339.3(assay)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(SDX)-395.7(was)-391.1(extracted)-395.3(from)-392.5(100)]TJ /F11 1 Tf 12.4119 0 TD (l)Tj /F6 1 Tf .5501 0 TD [(L)-397.7(o)0(f)-393.6(plasma)-390(using)-394.8(solid-phase)]TJ -14.0748 -1.2203 TD [(extraction)-282.6(\(SPE\))-284.3(with)-281.3(an)-286(Oasis)-281.6(HLB)-284.6(96-well)-284.8(plate)-282.3(and)-279.2(SDX-)]TJ /F8 1 Tf 24.6783 0 TD (d)Tj /F6 1 Tf 6.7246 0 0 5.9768 287.7732 540.7369 Tm (6)Tj 8.9663 0 0 8.9663 293.6692 542.2109 Tm (as)Tj -25.8354 -1.2203 TD [(internal)-344.4(standard.)-346.8(The)-342.2(analysis)-346.5(was)-346.9(performed)-346.9(by)-340.5(liquid)-344.2(chroma-)]TJ 0 -1.2266 TD [(tography)-251.7(with)-256(positive)-252(ion)-255.5(electrospray)-252.2(tandem)-256.1(mass)-253(spectrometry)]TJ 0 -1.2203 TD [(\(LC-MS/MS\).)-398.7(Monitored)-401.4(mass)-392.1(transitions)-403.8(for)-395.8(SDX)-395.7(and)-399.3(SDX-)]TJ /F8 1 Tf 25.7912 0 TD (d)Tj /F6 1 Tf 6.7246 0 0 5.9768 297.7511 507.855 Tm (6)Tj 8.9663 0 0 8.9663 62.022 498.3873 Tm (were)Tj /F8 1 Tf 2.2257 0 TD (m)Tj /F6 1 Tf .7208 0 TD (/)Tj /F8 1 Tf .2845 0 TD (z)Tj /F6 1 Tf .6639 0 TD (500.2)Tj /F13 1 Tf 2.4154 0 TD (/)Tj /F6 1 Tf 1.3594 0 TD [(142.1)-279.2(and)]TJ /F8 1 Tf 4.2616 0 TD (m)Tj /F6 1 Tf .7145 0 TD (/)Tj /F8 1 Tf .2845 0 TD (z)Tj /F6 1 Tf .6639 0 TD (506.2)Tj /F13 1 Tf 2.4153 0 TD (/)Tj /F6 1 Tf 1.3657 0 TD [(266.1,)-275.8(respectively.)]TJ -16.2625 -1.2266 TD [(Th)13.8(e)-488.8(m)0(a)14(i)0(n)-483.6(c)0(h)17.5(rom)20.6(at)13.5(og)13.6(ra)14.9(p)13.1(hic)-479.2(con)24.3(di)15.9(tio)18.7(ns)-480.7(we)14.2(re)-484.6(as)-483.2(fol)20.1(lo)15.9(ws)15.5(:)-490.4(P)0(h)15(e)0(-)]TJ -1.1128 -1.2203 TD [(no)13.6(me)14(n)13.1(e)0(x)-355.5(K)0(i)18.9(net)20.3(ex)-349.2(C1)15.2(8)-359.9(2)0(.)16.5(6)]TJ /F11 1 Tf 10.8754 0 TD (l)Tj /F6 1 Tf .5438 0 TD [(m,)-353.7(5)13.1(0)]TJ /F7 1 Tf 2.5355 0 TD ()Tj /F6 1 Tf .7082 0 TD [(2.)16.5(1)-157.6(m)0(m)-353.8(h)13.1(igh)22.7(-pe)21.7(rf)14.7(orm)20.6(an)17.5(ce)-351.6(LC)]TJ -14.6628 -1.2203 TD [(col)20.3(um)16.4(n,)-242.7(1)-157.6(m)0(M)-243.5(a)0(m)14(mon)23.2(iu)15.9(m)-256(t)0(r)13.3(i)0()17.3(u)0(o)13.6(r)0(o)17.3(a)0(c)15.1(e)0(t)13.5(a)0(t)13.5(e)-248.5(in)-249.6(wa)14.2(te)19.8(r)-255(a)0(s)-242.9(aqu)18(eo)17.5(us)-246.8(mo)16.4(-)]TJ T* [(bi)15.9(le)-315.3(ph)13.6(as)16.3(e,)-314.7(ace)19.5(to)15.9(ni)15.9(tr)13.3(ile)22.6(/f)13.3(or)17.3(mi)12.4(c)-324.4(a)0(c)15.1(i)0(d)-312.9(\()0(1)17.3(0)0(0)13.6(0)0(:)15.9(1)0(\))-317.8(a)0(s)-312.4(org)24.2(ani)20.3(c)-324.4(p)0(h)13.6(a)0(s)16.3(e)0(,)-314.7(and)]TJ 0 -1.2266 TD [(gr)17.3(adi)20.3(ent)-314.8(el)13.5(ut)15.9(io)15.9(n.)-324.9(De)14.2(te)13.5(ct)13.5(io)15.9(n)-328.3(w)0(a)14.2(s)-335.8(pe)17.5(rf)14.7(or)17.3(me)14(d)-334.6(w)0(i)12.6(t)0(h)-319.2(a)-330.7(Sc)12.6(ie)13.5(x)-328.3(API)-319.2(50)13.6(00)]TJ 0 -1.2203 TD [(Tri)20.3(pl)15.9(e)-324.4(Q)0(u)16.6(a)0(d)-317.6(L)0(C)15.4(-)0(M)16.6(S)0(/)17.3(M)0(S)14.3(.)-325.4(Th)13.8(e)-324.4(v)13.1(al)13.5(id)15.9(at)13.5(io)15.9(n)-322(r)0(a)14.9(n)0(g)13.6(e)-324.4(of)-317.8(th)15.9(e)-324.4(m)0(e)14(t)0(h)15.9(o)13.1(d)-328.3(w)0(a)14.2(s)]TJ T* [(0.)16.5(10)13.6(0)13.6(1)13.1(0)0(0)-150.8(n)0(g)13.6(/)0(m)12.4(L)-460.9(wi)18.9(th)-458.3(a)-457.2(l)0(o)15.9(w)0(e)14.2(r)-463.7(li)18.2(mi)12.4(t)-458.8(o)0(f)-456.9(q)13.1(uan)18(ti)18.2(ta)13.5(tio)25(n)-461.1(\(LL)18.2(OQ)19.7(\))-463.7(o)0(f)]TJ 0 -1.2266 TD [(0.)16.5(10)13.6(0)-157.6(n)0(g)13.6(/)0(m)18.7(L)0(.)-248.8(T)0(h)13.8(e)-254.8(in)15.9(tr)13.3(a-)-244.3(and)-241.2(in)15.9(te)13.5(r-)14.7(ru)17.3(n)-258.8(p)0(r)17.3(e)0(c)15.1(i)0(s)14.7(i)0(o)15.9(n)-258.7(\(c)14.9(oe)17.5(f)12.4(ci)13.5(en)17.5(t)-256.4(o)0(f)-248.2(v)0(a)17.5(r)0(i)13.3(-)]TJ 0 -1.2203 TD [(anc)21.9(e)-185.3([)0(C)18.9(V)0(])14(\))-179.2(was)]TJ /F7 1 Tf 6.2534 0 TD (<)Tj /F6 1 Tf .5438 0 TD [(7.)16.5(4%)-178.2(an)17.5(d)]TJ /F7 1 Tf 3.857 0 TD (<)Tj /F6 1 Tf .5438 0 TD [(6.)16.5(2%)17.8(,)-180(r)0(e)14.9(s)0(p)12.4(e)0(c)15.1(tiv)18.7(el)19.8(y.)-173.1(Th)13.8(e)-185.3(i)0(n)15.9(t)0(r)19.6(a)0(-)-174.8(and)-171.7(in)15.9(te)19.8(r-)]TJ -11.1979 -1.2203 TD [(ru)17.3(n)-246.1(a)0(c)15.1(c)0(u)17.5(r)0(a)14.9(c)0(y)-235.4(w)0(a)14.2(s)-247.3(9)13.1(6.4)23.3(%1)18.3(0)13.1(7.5)23.4(%)-241.9(and)-228.6(99)13.6(.0)16.5(%)17.8(10)13.6(2.)16.5(8%)17.8(,)-243.2(r)0(e)14.9(s)0(p)12.4(e)0(c)15.1(tiv)25(el)13.5(y.)]TJ 1.1128 -1.2266 TD [(SPE)-280(with)-275(an)-279.6(Oasis)-281.6(HLB)-284.6(96-well)-278.5(plate)-282.3(and)-279.2(racemic)-282(d,l-MPH-)]TJ /F8 1 Tf 24.6783 0 TD (d)Tj /F6 1 Tf 6.7246 0 0 5.9768 297.7511 376.3275 Tm (3)Tj 8.9663 0 0 8.9663 62.022 366.8597 Tm [(as)-331.4(internal)-331.7(standard)-337.5(was)-327.9(used)-336.8(to)-325.5(extract)-337(d-MPH)-331.5(and)-329.7(l-MPH)-335.6(from)]TJ 0 -1.2203 TD (50)Tj /F11 1 Tf 1.1697 0 TD (l)Tj /F6 1 Tf .5501 0 TD [(L)-486.2(o)0(f)-482.2(plasma.)-481.5(The)-487.6(analysis)-485.6(was)-486(performed)-486(by)-485.9(LC-MS/MS.)]TJ -1.7198 -1.2266 TD [(Monitored)-603.7(mass)-600.7(transitions)-599.8(for)-598.1(MPH)-601.8(and)-601.6(MPH-)]TJ /F8 1 Tf 21.2576 0 TD (d)Tj /F6 1 Tf 6.7246 0 0 5.9768 257.159 343.4456 Tm (3)Tj 8.9663 0 0 8.9663 265.8897 344.9196 Tm (were)Tj /F8 1 Tf 2.5481 0 TD (m)Tj /F6 1 Tf .7145 0 TD (/)Tj /F8 1 Tf .2845 0 TD (z)Tj /F6 1 Tf -26.2843 -1.2203 TD (234.3)Tj /F13 1 Tf 2.4154 0 TD (/)Tj /F6 1 Tf 1.3657 0 TD [(84.1)-279.7(and)]TJ /F8 1 Tf 3.7558 0 TD (m)Tj /F6 1 Tf .7208 0 TD (/)Tj /F8 1 Tf .2782 0 TD (z)Tj /F6 1 Tf .6639 0 TD (237.3)Tj /F13 1 Tf 2.4217 0 TD (/)Tj /F6 1 Tf 1.3594 0 TD [(84.1,)-282.6(respectively.)]TJ -11.8681 -1.2203 TD [(The)-519.2(main)-520.2(chromatographic)-518.6(conditions)-522.9(were)-520.9(Supelco)-522.5(CHIR-)]TJ -1.1128 -1.2203 TD [(OBIOTIC)-656.3(5)]TJ /F11 1 Tf 5.3745 0 TD (l)Tj /F6 1 Tf .5501 0 TD [(m,)-657.2(2.1)]TJ /F7 1 Tf 3.1045 0 TD ()Tj /F6 1 Tf .7145 0 TD [(150)-169.3(mm)-657.3(high-performance)-658.4(LC)-654.8(column,)]TJ -9.7436 -1.2266 TD [(me)20.3(th)22.2(an)23.9(ol)22.2(/e)19.8(th)22.2(an)17.5(o)13.1(l)0(/)24.6(a)0(m)20.3(m)0(o)22.7(n)0(i)22.2(u)0(m)-280.8(t)0(r)26(i)0()17.3(u)13.1(o)13.1(r)0(o)17.3(a)0(c)21.4(e)0(t)19.8(a)0(t)26.2(e)-292.8(\(6)23.7(0)13.1(0)0(:)22.2(4)0(0)19.9(0)13.1(:0)22.2(.1)16.5(,)-287.4(v)13.1(o)13.1(l)0(/)18.2(v)13.1(o)13.1(l)0(/)]TJ 0 -1.2203 TD [(wt\))-185.5(as)-186(mobile)-181.8(phase,)-183.5(and)-184.3(isocratic)-189.4(elution.)-184.7(Detection)-188.9(was)-182.5(performed)]TJ T* [(with)-376.1(a)-375(Sciex)-378(API)-376.1(5000)-377.4(Triple)-376.7(Quad)-376.8(LC-MS/MS.)-375.5(The)-380.1(validation)]TJ 0 -1.2266 TD [(range)-504.5(of)-494.8(the)-504.5(method)-500.2(was)-498.6(0.200200)-163.4(ng/mL)-504.4(with)-496.3(an)-500.9(LLOQ)-503.8(of)]TJ 0 -1.2203 TD [(0.200)-165.4(ng/mL.)-418.8(The)-411.8(intra-)-417.4(and)-418.3(inter-run)-412.2(precision)-416.9(was)]TJ /F7 1 Tf 22.1681 0 TD (<)Tj /F6 1 Tf .5564 0 TD [(4.1%)-414.6(and)]TJ /F7 1 Tf -22.7245 -1.2203 TD (<)Tj /F6 1 Tf .5501 0 TD [(6.5%,)-695.7(respectively.)-699.1(The)-696.3(intra-)-695.6(and)-696.5(inter-run)-690.4(accuracy)-700(was)]TJ -.5501 -1.2267 TD [(100.3%117.1%)-282.9(and)-279.2(94.7%108.5%,)-280(respectively.)]TJ /F12 1 Tf 0 -3.3575 TD [(PK)-337.3(analysis)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(Plasma)-439.2(concentrations)-448.7(of)-437.9(SDX)-440(and)-443.6(d-MPH)-439(were)-445.1(determined)]TJ -1.1128 -1.2266 TD [(after)-296.2(each)-296.2(treatment.)-302.2(Values)-294.9(obtained)-293.5(were)-299.6(used)-292.5(to)-293.9(derive)-299.4(the)-295.8(fol-)]TJ 0 -1.2203 TD [(lowing)-387.8(PK)-386.6(parameters)-391.8(for)-383.1(SDX)-389.4(and)-386.7(d-MPH:)-385.7(maximum)-386.7(concen-)]TJ T* [(tration)-405.7(in)-407.7(plasma)-409(\()]TJ /F8 1 Tf 7.8025 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 137.9338 154.3747 Tm (max)Tj 8.9663 0 0 8.9663 149.6125 155.9055 Tm [(\),)-403.4(time)-404.1(to)-407.7(reach)-412.1(maximum)-405.6(concentration)]TJ -9.7689 -1.2203 TD (\()Tj /F8 1 Tf .3351 0 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 69.959 143.433 Tm (max)Tj 8.9663 0 0 8.9663 81.6378 144.9638 Tm [(\),)-694.2(terminal)-702(half-life)-703.2(\()]TJ /F8 1 Tf 9.6045 0 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 172.6866 143.433 Tm (1/2)Tj 8.9663 0 0 8.9663 181.3039 144.9638 Tm [(\),)-700.6(weight-normalized)-699.7(clearance)]TJ -13.3034 -1.2266 TD (\(CL/)Tj /F8 1 Tf 1.8969 0 TD (F)Tj /F6 1 Tf .6133 0 TD (/)Tj /F8 1 Tf .2845 0 TD (W)Tj /F6 1 Tf .8283 0 TD [(,)-426.6(with)]TJ /F8 1 Tf 2.8832 0 TD (W)Tj /F7 1 Tf .999 0 TD (=)Tj /F6 1 Tf .7208 0 TD [(body)-428(weight\),)-426.9(weight-normalized)-427.8(volume)-430.7(of)]TJ -8.2261 -1.2203 TD [(distribution)-574.5(\()]TJ /F8 1 Tf 5.5325 0 TD (V)Tj 6.7246 0 0 5.9768 117.1275 121.5496 Tm (z)Tj /F6 1 Tf 8.9663 0 0 8.9663 119.7354 123.0236 Tm (/)Tj /F8 1 Tf .2782 0 TD (F)Tj /F6 1 Tf .6133 0 TD (/)Tj /F8 1 Tf .2845 0 TD (W)Tj /F6 1 Tf .8346 0 TD [(\),)-567.8(and)-576.3(areas)-571.3(under)-578(the)-567.7(concentrationtime)]TJ -8.4474 -1.2203 TD [(curve)-245.3(from)-240.7(time-zero)-240.9(to)-243.3(24)-239.3(hours)-241.6(postdose)-245.2(\(AUC)]TJ 6.7246 0 0 5.9768 238.2235 110.5512 Tm (024h)Tj 8.9663 0 0 8.9663 255.0613 112.0819 Tm [(\),)-245.3(from)-240.7(time-)]TJ -21.5295 -1.2266 TD [(zero)-296.3(to)-293.9(the)-295.8(time)-296.6(of)-298.8(the)-289.5(last)-300.5(quantiable)-297.1(concentration)-296.2(\(AUC)]TJ 6.7246 0 0 5.9768 279.7794 99.6094 Tm (0last)Tj 8.9663 0 0 8.9663 295.8802 101.0834 Tm (\),)Tj -26.082 -1.2203 TD [(and)-323.4(time-zero)-323.1(extrapolated)-322(to)-325.5(innity)-317.1(\(AUC)]TJ 6.7246 0 0 5.9768 223.3133 88.6677 Tm (0inf)Tj 8.9663 0 0 8.9663 237.5432 90.1417 Tm [(\).)-321.2(Concentration)]TJ -19.5757 -1.2203 TD [(time)-429.3(data)-430.5(for)-433.7(SDX)-427.4(and)-430.9(d-MPH)-432.7(in)-426.7(plasma)-434.3(were)-432.4(analyzed)-433.4(using)]TJ 0 -1.2266 TD [(noncompartmental)-440.9(methods)-444(in)-433(Phoenix)]TJ /F7 1 Tf 16.3005 0 TD ()Tj /F6 1 Tf 1.3278 0 TD (WinNonlin)Tj /F7 1 Tf 6.7246 0 0 5.9768 260.5038 72.2267 Tm ()Tj /F6 1 Tf 8.9663 0 0 8.9663 269.7448 68.2015 Tm (\(Version)Tj -23.1671 -1.2203 TD [(6.3;)-283.7(Certara,)-279.9(Inc.\).)]TJ /F12 1 Tf 27.9978 42.3762 TD [(Statistical)-342.4(analysis)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(Parametric)-285.7(and)-285.5(nonparametric)-279.3(descriptive)-289.6(statistics)-282.9(were)-280.7(calcu-)]TJ -1.1128 -1.2203 TD [(lated)-295(for)-288.3(demographic)-296.6(characteristics)-296.4(\(e.g.,)-290.5(age,)-290.8(sex,)-289.6(race)-292.4(and)-291.8(eth-)]TJ 0 -1.2266 TD [(nicity\),)-433.9(baseline)-423.6(characteristics)-435.5(\(e.g.,)-429.6(body)-421.7(weight,)-431.1(height,)-427.8(body)]TJ 0 -1.2203 TD [(mass)-354.1(index\),)-356.8(and)-348.7(each)-359.4(PK)-348.7(parameter.)-356.1(Parametric)-361.6(descriptive)-352.9(sta-)]TJ T* [(tistics)-384.2(included)-375.7(the)-378(number)-378.7(of)-374.7(subjects)-378.1(\()]TJ /F8 1 Tf 16.7494 0 TD (n)Tj /F6 1 Tf .4995 0 TD [(\),)-378.1(arithmetic)-378.7(mean)-379.5(and)]TJ -17.2489 -1.2266 TD [(standard)-445(deviation,)-445.4(percent)-446.7(coefcient)-450.3(of)-437.9(variation)-445.1(\(%CV\),)-445.8(and)]TJ 0 -1.2203 TD [(95%)-190.3(condence)-193.5(intervals)-187(\(CI\))-193.9(around)-185.5(the)-188.3(mean.)-192.7(The)-190.5(PK)-184.3(parameters)]TJ T* [(for)-263(each)-264.5(dose)-267.2(of)-260.9(SDX/d-MPH)-262.9(were)-268(normalized)-263.1(to)-262.3(the)-264.2(39.2/7.8-mg)]TJ 0 -1.2266 TD [(dose)-235.6(by)-226.6(multiplying)-233.2(the)-232.6(values)-234.7(for)-231.4(the)-226.3(26.1/5.2-mg)-232.9(dose)-229.3(by)-233(1.5)-229.6(and)]TJ 0 -1.2203 TD [(the)-283.2(values)-285.3(for)-275.6(the)-283.2(52.3/10.4-mg)-283(dose)-279.9(by)-277.2(0.75.)]TJ ET 313.058 720.113 239.131 .22681 re f 313.058 481.379 239.131 .28348 re f 313.058 701.405 239.131 .28345 re f BT /F10 1 Tf 8.9663 0 0 8.9663 324.7369 725.7825 Tm (Table)Tj /F6 1 Tf 2.9971 0 TD (1.)Tj /F10 1 Tf 1.2519 0 TD [(Demographic)-333.5(and)-336.9(Baseline)-333.2(Characteristics)]TJ /F8 1 Tf -5.5515 -2.0233 TD [(Parameter)-9367.9(Statistic)-1448.3(All)-328.9(subjects)-340.1(\()]TJ /F6 1 Tf 23.7299 0 TD (N)Tj /F7 1 Tf .8852 0 TD (=)Tj /F8 1 Tf .7208 0 TD (24\))Tj /F6 1 Tf -25.3359 -2.0802 TD [(Age)-339.4(at)-334.3(screening)-333.1(\(years\))-3627.1(Mean)-5700.5(37.2)]TJ 13.6448 -1.1128 TD [(SD)-6709.5(10.0)]TJ T* [(Median)-4919.5(36.0)]TJ T* [(Range)-5046.5(2053)]TJ -13.6448 -1.1065 TD (Gender)Tj 1.0053 -1.1128 TD (Male)Tj /F14 1 Tf 12.6395 0 TD (N)Tj /F6 1 Tf .999 0 TD [(\(%\))-4482.5(18)-334.1(\(75.0\))]TJ -13.6385 -1.1128 TD (Female)Tj /F14 1 Tf 12.6395 0 TD (N)Tj /F6 1 Tf .999 0 TD [(\(%\))-5007.3(6)-334.6(\(25.0\))]TJ -14.6439 -1.4416 TD (Race)Tj 1.0053 -1.1128 TD (White)Tj /F14 1 Tf 12.6395 0 TD (N)Tj /F6 1 Tf .999 0 TD [(\(%\))-4482.5(11)-334.1(\(45.8\))]TJ -13.6385 -1.1128 TD 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[(BMI,)-327.2(body)-326(mass)-335.1(index;)-322(SD,)-336.5(standar)12.2(d)-332.2(deviation.)]TJ ET q 1 i 313.625 297.694 m 551.565 297.694 l 551.565 133.795 l 313.625 133.795 l W n q 238.023 0 0 163.899 313.625 133.795 cm /Im2 Do Q Q BT /F9 1 Tf 8.9663 0 0 8.9663 313.0582 117.0141 Tm [(FIG.)-391.7(1.)]TJ /F6 1 Tf 4.1668 0 TD [(Plasma)-394.9(concentrationtime)-389.9(curve)-384.4(\(mean)]TJ /F7 1 Tf 16.7241 0 TD ()Tj /F6 1 Tf .7145 0 TD [(standard)-388.1(de-)]TJ -21.6054 -1.1065 TD [(viation\))-367.3(for)-364.2(d-MPH)-369.5(after)-365.7(Treatments)-365.3(A,)-366.1(B,)-361.2(and)-367.7(C.)-361.2(Treatment)-370.9(A:)]TJ 0 -1.1128 TD [(SDX/d-MPH)-477.9(26.1/5.2)-165(mg;)-467.7(total)-473.6(equivalent)-469.7(d-MPH)-470.6(HCl,)-468.7(20)-169.7(mg.)]TJ T* [(Treatment)-396.2(B:)-393.5(SDX/d-MPH)-395.7(39.2/7.8)-165(mg;)-391.8(total)-391.4(equivalent)-393.8(d-MPH)]TJ 0 -1.1065 TD [(HCl,)-740.6(30)-163.4(mg.)-738.9(Treatment)-737.7(C:)-734.9(SDX/d-MPH)-737.1(52.3/10.4)-164.5(mg;)-739.5(total)]TJ 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[(were)-236.4(analyzed)-231.1(using)-224.1(analysis)-232.6(of)-229.2(variance)-233.7(for)-225(a)-229.6(three-way)-236.7(crossover)]TJ 0 -1.2203 TD [(design.)-285.8(The)-279(model)-279.4(was)-283.7(applied)-281.3(to)-274.9(the)-283.2(natural)-283.9(log)-274.4(\(ln\)-transformed)]TJ T* [(data)-310.4(with)-300.2(sequence,)-307(period,)-306.2(and)-304.5(treatment)-305.6(as)-306.1(the)-302.1(xed)-308.9(effects)-305.1(and)]TJ 0 -1.2266 TD [(subject)-269.9(within)-265.4(sequence)-266.2(as)-261.9(a)-267.5(random)-264.9(effect.)-263.1(Treatment)-269.8(differences)]TJ 0 -1.2203 TD (in)Tj /F8 1 Tf 1.2014 0 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 75.4582 423.666 Tm (max)Tj 8.9663 0 0 8.9663 90.822 425.14 Tm (and)Tj /F8 1 Tf 1.8653 0 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 112.4787 423.666 Tm (1/2)Tj 8.9663 0 0 8.9663 124.8378 425.14 Tm [(for)-414.7(SDX)-414.7(and)-418.3(d-MPH)-413.7(were)-419.8(analyzed)-414.4(using)-420.1(the)]TJ -7.2587 -1.2203 TD [(Wilcoxon)-286.7(signed)-276.6(rank)-281.3(nonparametric)-285.7(test.)]TJ 1.1128 -1.2266 TD [(Do)16.6(se)-179.7(pr)17.3(o)13.1(p)0(o)19.9(r)0(t)19.6(i)0(o)15.9(n)13.1(al)19.8(it)18.2(y)-195.5(o)13.1(f)-191.8(C)]TJ 6.7246 0 0 5.9768 159.0236 401.7259 Tm [(ma)22.4(x)]TJ 8.9663 0 0 8.9663 170.4189 403.1999 Tm .1926 Tc [(,A)192.6(U)212.3(C)]TJ 6.7246 0 0 5.9768 192.9826 401.7259 Tm 0 Tc (0)Tj /F7 1 Tf .489 0 TD (-)Tj /F6 1 Tf .5396 0 TD [(la)28.3(st)]TJ 8.9663 0 0 8.9663 208.9133 403.1999 Tm .1926 Tc [(,A)192.6(U)205.9(C)]TJ 6.7246 0 0 5.9768 231.4771 401.7259 Tm 0 Tc [(0)22(24)22(h)]TJ 8.9663 0 0 8.9663 247.918 403.1999 Tm [(,)-192.6(a)0(n)23.9(d)-195.5(AU)19.7(C)]TJ 6.7246 0 0 5.9768 284.9952 401.7259 Tm [(0)22(i)19.7(n)0(f)]TJ 8.9663 0 0 8.9663 59.7543 392.2581 Tm [(for)-402.1(d-MPH)-407.4(and)-399.3(SDX)-402.1(was)-403.8(assessed)-406.4(using)-401.1(a)-400.3(power)-404.2(analysis)-403.4(with)]TJ 0 -1.2203 TD [(mixed)-380.6(effects)-381(\(Smith)-376.6(et)-378.5(al.)-375.1(2000\).)-376.1(The)-380.1(power)-378.9(model)-374.3(equation)-375.7(is)]TJ /F8 1 Tf T* (Y)Tj /F7 1 Tf .7208 0 TD (=)Tj /F11 1 Tf .7208 0 TD (a)Tj /F7 1 Tf .6639 0 TD ()Tj /F6 1 Tf .7208 0 TD (\(dose\))Tj /F11 1 Tf 6.7246 0 0 5.9768 107.4897 374.3432 Tm (b)Tj /F6 1 Tf 8.9663 0 0 8.9663 115.0299 370.3747 Tm (where)Tj /F8 1 Tf 2.8706 0 TD (Y)Tj /F6 1 Tf .9801 0 TD [(is)-421.5(the)-428.6(PK)-424.5(parameter)-429(evaluated,)]TJ /F11 1 Tf 13.4109 0 TD (a)Tj /F6 1 Tf .9231 0 TD [(is)-427.9(the)]TJ -24.3495 -1.2266 TD [(expected)-186.8(value)-183.5(of)]TJ /F8 1 Tf 7.1322 0 TD (Y)Tj /F6 1 Tf .7335 0 TD [(for)-180.8(a)-185.3(reference)-186.2(dose,)-181.6(and)]TJ /F11 1 Tf 9.7879 0 TD (b)Tj /F6 1 Tf .7398 0 TD [(is)-181.3(the)-182(proportionality)]TJ -18.3933 -1.2203 TD [(exponent.)-336.7(A)-331.6(mixed-effects)-340(model,)-332.9(allowing)-336.3(for)-332.5(random)-328.1(between-)]TJ T* [(subject)-402.7(variability)-401.5(in)]TJ /F11 1 Tf 8.9596 0 TD (a)Tj /F6 1 Tf .8979 0 TD (and)Tj /F11 1 Tf 1.8463 0 TD (b)Tj /F6 1 Tf .5564 0 TD [(,)-394.9(was)-403.8(implemented)-400.4(to)-401.4(estimate)-405.8(the)]TJ -12.2601 -1.2266 TD [(proportionality)-279.6(constant)-275.7(and)-279.2(its)-273.3(90%)-278.9(CI.)-274.8(Dose)-276.8(proportionality)-273.3(was)]TJ 0 -1.2203 TD [(declared)-290.6(if)-283.9(the)-283.2(calculated)-291.1(90%)-285.2(CI)-284.6(lay)-283.2(within)-284.3(the)-283.2(acceptance)-287.9(range)]TJ T* ([1)Tj /F7 1 Tf 1.0243 0 TD (+)Tj /F6 1 Tf .7398 0 TD (log\()Tj /F15 1 Tf 1.6123 0 TD (Y)Tj /F6 1 Tf 6.7246 0 0 5.9768 97.3984 303.0802 Tm (L)Tj 8.9663 0 0 8.9663 101.537 304.6109 Tm [(\)/log\(R\),)-190.3(1)]TJ /F7 1 Tf 4.3565 0 TD (+)Tj /F6 1 Tf .7398 0 TD (log\()Tj /F15 1 Tf 1.6123 0 TD (Y)Tj /F6 1 Tf 6.7246 0 0 5.9768 169.0582 303.0802 Tm (H)Tj 8.9663 0 0 8.9663 173.9338 304.6109 Tm [(\)/log\(R\)],)-186.1(where)]TJ /F15 1 Tf 6.6327 0 TD (Y)Tj /F6 1 Tf 6.7246 0 0 5.9768 240.7747 303.0802 Tm (L)Tj 8.9663 0 0 8.9663 246.6141 304.6109 Tm (and)Tj /F15 1 Tf 1.6313 0 TD (Y)Tj /F6 1 Tf 6.7246 0 0 5.9768 268.611 303.0802 Tm (H)Tj 8.9663 0 0 8.9663 275.1873 304.6109 Tm [(are)-189.3(the)]TJ 3.9771 20.7771 TD [(lower)-250.2(and)-247.5(upper)-249.2(limits)-245.5(of)-248.2(the)-251.6(CI)-246.6(\(0.8)-250.7(and)-247.5(1.25,)-244.6(respectively\))-255.7(and)-247.5(R)]TJ 0 -1.2203 TD [(is)-219.2(the)-226.3(ratio)-225.6(between)-226.1(the)-220(highest)-223.2(and)-228.6(lowest)-220.7(doses)-223.7(in)-224.3(the)-226.3(study)-217.8(\()]TJ /F8 1 Tf 24.6657 0 TD (R)Tj /F7 1 Tf .784 0 TD (=)Tj /F6 1 Tf .7145 0 TD (2)Tj -26.1642 -1.2266 TD [(in)-281.3(this)-279.2(study\).)]TJ 1.1128 -1.2203 TD [(Sta)21.7(tist)20.3(ica)11.6(l)-243.8(com)14.5(par)15.4(iso)15.2(n)-246.1(o)0(f)-241.9(the)-238.9(d-M)17.1(PH)-247.5(PK)-241.2(par)15.4(am)14(ete)11.6(rs)-243.1(of)-241.9(exp)18(os)12.4(ure)]TJ -1.1128 -1.2203 TD (\()Tj /F8 1 Tf .3288 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 319.6913 445.5495 Tm (max)Tj 8.9663 0 0 8.9663 331.1999 447.0802 Tm (,)Tj /F8 1 Tf .4236 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 340.9511 445.5495 Tm (min)Tj 8.9663 0 0 8.9663 351.3259 447.0802 Tm .18 Tc [(,A)180(U)193.3(C)]TJ 6.7246 0 0 5.9768 373.8896 445.5495 Tm 0 Tc [(02)24.6(4h)]TJ 8.9663 0 0 8.9663 390.444 447.0802 Tm .18 Tc [(,A)180(U)193.3(C)]TJ 6.7246 0 0 5.9768 413.0078 445.5495 Tm 0 Tc (03h)Tj 8.9663 0 0 8.9663 426.2739 447.0802 Tm .18 Tc [(,A)180(U)193.3(C)]TJ 6.7246 0 0 5.9768 448.8377 445.5495 Tm 0 Tc [(37)24.6(h)]TJ 8.9663 0 0 8.9663 462.1038 447.0802 Tm [(,)-173.6(and)-165.3(AUC)]TJ 6.7246 0 0 5.9768 499.0676 445.5495 Tm [(712)18.8(h)]TJ 8.9663 0 0 8.9663 515.6786 447.0802 Tm [(\))-179.2(bet)14(we)14.2(en)]TJ -22.8447 -1.2266 TD [(the)-371.7(r)12.4(st)-383.6(and)-374(la)13.5(st)-383.6(do)13.6(ses)-376.4(of)-381(the)-371.7(mul)12.9(tip)18.7(le-)17.7(dos)12.9(e)-387.6(t)0(r)13.3(eat)17.9(men)14.5(t)-389.2(p)0(h)13.6(ase)-377.6(wa)14.2(s)]TJ 0 -1.2203 TD [(per)15.4(for)15.2(me)14(d)-265.1(u)0(s)12.4(ing)-255.5(ana)15.6(lys)15.2(is)-257.1(of)-260.9(var)15.4(ia)13.5(nce)-256.3(on)-258.3(the)-257.9(ln-)20.1(tra)11.4(ns)12.4(for)15.2(me)14(d)-265.1(dat)14(a.)]TJ /F4 1 Tf 0 -3.6673 TD (Results)Tj /F12 1 Tf 0 -1.8336 TD [(Subjects)-333.2(and)-335.7(demographics)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(A)-268.4(total)-265(of)-273.5(24)-264.6(participants)-274.2(enrolled)-270.8(in)-268.6(the)-270.5(study,)-271.3(and)-266.5(23)-270.9(received)]TJ -1.1128 -1.2203 TD [(the)-276.9(single-dose)-284.4(and)-279.2(multiple-dose)-281.1(treatments.)-283.9(One)-276.1(participant)-286.1(was)]TJ 0 -1.2266 TD [(withdrawn)-419.9(early)-420(after)-416.3(administration)-423.8(of)-412.6(Treatment)-421.5(B)-421.5(b)0(y)-416.3(the)-416(in-)]TJ 0 -1.2203 TD [(vestigator,)-410.7(because)-418.4(of)-406.3(the)-416(adverse)-412.3(event)-411.1(\(AE\))-411(ventricular)-417.5(extra-)]TJ T* [(systoles.)-468.3(The)-462.3(AE)-470(was)-467(grade)-466.6(1)-467.4(i)0(n)-464.6(severity,)-470.9(considered)-465.4(possibly)]TJ T* [(related)-292.7(to)-300.2(study)-293.6(medication,)-292.8(and)-298.1(resolved)-293.3(within)-297(5)-296.7(hours)-292.2(of)-292.5(onset.)]TJ ET 59.754 710.135 490.167 .22681 re f 59.754 585.071 490.167 .22681 re f 255.175 691.256 294.746 .22681 re f 59.754 673.568 490.167 .22675 re f BT /F10 1 Tf 8.9663 0 0 8.9663 106.2425 725.7825 Tm (Table)Tj /F6 1 Tf 2.9971 0 TD (2.)Tj /F10 1 Tf 1.2519 0 TD [(Plasma)-333.8(Pharmacokinetic)-333.1(Parameters)-331.9(for)-334.7(Dexmethylphenidate)-340.9(After)-332.1(Single)-333.2(Oral)-335.1(Dose)]TJ 8.0996 -1.1128 TD [(Administration)-338.6(of)-335.1(Treatments)-334.4(A,)-334.5(B,)-329.6(and)-336.9(C)]TJ /F8 1 Tf 18.6399 -2.0233 TD (Treatment)Tj -11.9946 -1.9917 TD 13.132 Tc [(AB)25.3(C)]TJ /F14 1 Tf -24.1788 -2.0866 TD 0 Tc (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 65.7637 659.6218 Tm (max)Tj 8.9663 0 0 8.9663 80.3905 661.0959 Tm [(\(ng/mL\))-17150.6(7.1)]TJ /F7 1 Tf 21.9089 0 TD ()Tj /F6 1 Tf .7208 0 TD [(2.1)-10358.9(9.8)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7208 0 TD [(2.8)-9859.4(13.8)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7145 0 TD (3.8)Tj /F14 1 Tf -52.4169 -1.1065 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 64.7433 649.6439 Tm (max)Tj 8.9663 0 0 8.9663 79.37 651.1746 Tm [(\(hours\))-16792.9(2.0)-330.7(\(1.59.0\))-8499.3(2.0)-330.7(\(1.59.0\))-8493(2.0)-337.1(\(1.07.0\))]TJ /F14 1 Tf -2.1877 -1.1128 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 64.7433 639.7227 Tm (1/2)Tj 8.9663 0 0 8.9663 76.3653 641.1967 Tm [(\(hours\))-18057.5(9.7)]TJ /F7 1 Tf 22.3578 0 TD ()Tj /F6 1 Tf .7208 0 TD [(3.3)-9859.4(10.3)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7208 0 TD [(3.6)-9859.4(10.8)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7145 0 TD (3.0)Tj -52.4169 -1.1128 TD (AUC)Tj 6.7246 0 0 5.9768 78.633 629.7448 Tm (0last)Tj 8.9663 0 0 8.9663 97.7952 631.2188 Tm [(\(h*ng/mL\))-13709.9(97.2)]TJ /F7 1 Tf 19.9678 0 TD ()Tj /F6 1 Tf .7208 0 TD [(28.8)-8859.9(142.5)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7208 0 TD [(41.2)-8859.9(199.8)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7145 0 TD (57.2)Tj -52.4169 -1.1065 TD (AUC)Tj 6.7246 0 0 5.9768 78.633 619.7668 Tm (024h)Tj 8.9663 0 0 8.9663 98.4756 621.2975 Tm [(\(h*ng/mL\))-13634.1(79.2)]TJ /F7 1 Tf 19.8919 0 TD ()Tj /F6 1 Tf .7208 0 TD [(23.4)-8859.9(113.4)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7208 0 TD [(32.8)-8859.9(153.2)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7145 0 TD (47.9)Tj -52.4169 -1.1128 TD (AUC)Tj 6.7246 0 0 5.9768 78.633 609.7888 Tm (0inf)Tj 8.9663 0 0 8.9663 95.8677 611.3195 Tm [(\(h*ng/mL\))-13425.4(102.4)]TJ /F7 1 Tf 20.1827 0 TD ()Tj /F6 1 Tf .7208 0 TD [(27.8)-8859.9(148.6)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7208 0 TD [(40.9)-8859.9(206.0)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7145 0 TD (57.2)Tj -52.4169 -1.1128 TD [(Clearance)-341.5(\(CL/L/kg\))-13816.1(2.62)]TJ /F7 1 Tf 24.2104 0 TD ()Tj /F6 1 Tf .7208 0 TD [(0.83)-9359.4(2.71)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7208 0 TD [(0.84)-9359.4(2.61)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7145 0 TD (0.80)Tj -52.4169 -1.1128 TD [(Volume)-339.1(of)-330.4(distribution)-334.2(\()]TJ /F14 1 Tf 10.0218 0 TD (V)Tj 6.7246 0 0 5.9768 155.1118 589.8896 Tm (z)Tj /F6 1 Tf 8.9663 0 0 8.9663 157.7196 591.3636 Tm (/)Tj /F14 1 Tf .2782 0 TD (F)Tj /F6 1 Tf .6196 0 TD [(/kg\))-8357.2(38.89)]TJ /F7 1 Tf 12.3866 0 TD ()Tj /F6 1 Tf .7208 0 TD [(25.06)-8359.9(41.92)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7208 0 TD [(24.61)-8359.9(41.93)]TJ /F7 1 Tf 13.0252 0 TD ()Tj /F6 1 Tf .7145 0 TD (20.51)Tj 7.9702 0 0 7.9702 67.748 573.2219 Tm [(Parameters)-241.7(presente)11(d)-246.9(a)0(s)-249.2(mean)]TJ /F7 1 Tf 12.1848 0 TD ()Tj /F6 1 Tf .7184 0 TD [(SD)-245.1(with)-240.1(the)-244.4(exception)-236.9(of)]TJ /F8 1 Tf 10.2287 0 TD (T)Tj /F6 1 Tf 5.9774 0 0 5.3127 256.4787 571.918 Tm (max)Tj 7.9702 0 0 7.9702 266.7968 573.2219 Tm [(,)-247.9(which)-242.8(is)-244.5(presente)11(d)-246.9(a)0(s)-249.2(median)-237.8(\(range\).)-242.9(Descriptiv)11.8(e)-250.1(statistic)10.3(s)-248.1(for)-242.4(Treatments)-242.7(A,)-241.2(B,)-243.4(and)-245.9(C.)]TJ -25.9772 -1.1239 TD [(Treatment)-464.1(A:)-473.4(SDX/d-MP)15(H)-469.9(26.1/5.2)-161.8(mg;)-465.3(total)-464.9(equivalent)-460.9(d-MPH,)-468(20)-159.4(mg.)-467.8(Treatment)-464.1(B:)-468.5(SDX/d-MPH)-462(39.2/7.8)-154.7(mg;)-465.3(total)-472(equivalen)12.1(t)-473(d-MPH,)-460.9(30)-166.6(mg.)]TJ T* [(Treatment)-329(C:)-333.4(SDX/d-MP)15(H)-334.7(52.3/10.4)-152.6(mg;)-330.1(total)-329.7(equivalent)-325.8(d-MPH,)-325.7(40)-166.6(mg)-326.6(\()]TJ /F8 1 Tf 30.4442 0 TD (n)Tj /F7 1 Tf .6615 0 TD (=)Tj /F6 1 Tf .7184 0 TD (23\).)Tj -30.8212 -1.1239 TD (AUC)Tj 5.9774 0 0 5.3127 84.4724 545.0455 Tm (024h)Tj 7.9702 0 0 7.9702 99.3826 546.3495 Tm [(,)-397.3(area)-395.9(under)-387.4(the)-400.9(concentr)12.2(ationtime)-388.6(curve)-397.8(from)-386.1(time-zero)-396.6(to)-392.7(24)-394.2(hours)-392.5(postdose)12.5(;)-401.9(AUC)]TJ 5.9774 0 0 5.3127 384.6613 545.0455 Tm (0last)Tj 7.9702 0 0 7.9702 398.9479 546.3495 Tm [(,)-397.3(AUC)-387.6(from)-393.2(time-zero)-389.4(to)-399.8(the)-393.8(time)-393.7(of)-390.5(the)-400.9(last)]TJ -42.5579 -1.1239 TD [(quantiable)-812.3(concentrati)11.2(on;)-817.4(AUC)]TJ 5.9774 0 0 5.3127 172.9133 536.0314 Tm (0inf)Tj 7.9702 0 0 7.9702 185.5558 537.392 Tm [(,)-817(AUC)-814.4(from)-820(time-zero)-809.1(extrapolate)11.2(d)-823(t)0(o)-819.5(innity)14.2(;)]TJ /F8 1 Tf 22.7691 0 TD (C)Tj /F6 1 Tf 5.9774 0 0 5.3127 372.3589 536.0314 Tm (max)Tj 7.9702 0 0 7.9702 382.6771 537.392 Tm [(,)-817(maximum)-808.6(concentrati)11.2(on)-821(in)-819.5(plasma;)-811.6(d-MPH,)]TJ -40.5164 -1.1239 TD [(dexmethylpheni)13.4(date;)-334.4(SD,)-329.4(standard)-320.1(of)-333.6(deviation;)-328.1(SDX,)-322.7(serdexmethyl)10.2(phenidate;)]TJ /F8 1 Tf 32.2794 0 TD (T)Tj /F6 1 Tf 5.9774 0 0 5.3127 321.4487 527.0739 Tm (max)Tj 7.9702 0 0 7.9702 331.7668 528.4345 Tm [(,)-326.2(time)-329.7(to)-335.8(reach)-329.8(maximum)-324.9(concentr)12.2(ation;)]TJ /F8 1 Tf 16.7799 0 TD (T)Tj /F6 1 Tf 5.9774 0 0 5.3127 469.8707 527.0739 Tm (1/2)Tj 7.9702 0 0 7.9702 477.5243 528.4345 Tm [(,)-333.3(termina)11.3(l)-337.8(half-life.)]TJ ET 59.754 252.283 490.167 .28348 re f 59.754 132.151 490.167 .22681 re f 59.754 223.653 490.167 .22676 re f BT /F10 1 Tf 8.9663 0 0 8.9663 96.548 267.9307 Tm (Table)Tj /F6 1 Tf 3.0034 0 TD (3.)Tj /F10 1 Tf 1.2456 0 TD [(Statistical)-334.7(Analysis)-337.9(of)-335.1(the)-333.5(Dose-Normalized)-333.5(Natural)-332(Log-Transformed)-337.4(Systemic)-332(Exposure)]TJ -5.9182 -1.1128 TD [(of)-335.1(Dexmethylphenidate)-334.6(Comparing)-335.8(Single-Dose)-336.4(Administration)-332.3(of)-335.1(Treatments)-334.4(A)-337.9(and)-330.6(C)]TJ /F6 1 Tf 40.7512 0 TD (Versus)Tj /F10 1 Tf 3.1046 0 TD [(Treatment)-333.7(B)]TJ /F8 1 Tf -46.29 -2.017 TD [(Test)-339.4(versus)]TJ 0 -1.1128 TD (Ref)Tj 9.3769 1.1128 TD (Dependent)Tj .4995 -1.1128 TD (variable)Tj 8.6118 1.1128 TD (GeoMean)Tj /F6 1 Tf 6.7246 0 0 5.9768 260.9007 243.8361 Tm (a)Tj /F8 1 Tf 8.9663 0 0 8.9663 238.4503 229.8897 Tm (test)Tj 7.0627 1.1128 TD (GeoMean)Tj /F6 1 Tf 6.7246 0 0 5.9768 337.1526 243.8361 Tm (a)Tj /F8 1 Tf 8.9663 0 0 8.9663 314.9857 229.8897 Tm (Ref)Tj 7.0374 1.1128 TD [(Ratio)-334.2(\(%\))]TJ /F6 1 Tf 6.7246 0 0 5.9768 414.0282 243.8361 Tm (b)Tj /F8 1 Tf 8.9663 0 0 8.9663 380.8629 229.8897 Tm [(\(test/Ref)-83.4(\))]TJ 8.302 1.1128 TD [(90%)-329.4(CI)]TJ .4426 -1.1128 TD (lower)Tj 6.9489 1.1128 TD [(90%)-329.4(CI)]TJ .411 -1.1128 TD (upper)Tj /F6 1 Tf -51.9174 -2.0866 TD [(A)-337.9(versus)-333.3(B)-4227.9(ln\()]TJ /F14 1 Tf 9.9459 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 154.885 209.707 Tm (max)Tj 8.9663 0 0 8.9663 166.5637 211.181 Tm [(\))-7007.9(10.1338)-5760.2(9.4181)-5305.4(107.60)-5254.8(101.80)-4635.2(113.73)]TJ -3.0793 -1.1065 TD (ln\(AUC)Tj 6.7246 0 0 5.9768 167.811 199.729 Tm (024h)Tj 8.9663 0 0 8.9663 184.6488 201.2598 Tm [(\))-4491.4(112.1968)-4754.3(107.4592)-5310.7(104.41)-5254.8(100.77)-4635.2(108.18)]TJ -5.0963 -1.1128 TD (ln\(AUC)Tj 6.7246 0 0 5.9768 167.811 189.8078 Tm (0last)Tj 8.9663 0 0 8.9663 183.9118 191.2818 Tm [(\))-4573.6(138.3565)-4754.3(135.7108)-5310.7(101.95)-5754.3(98.40)-4635.7(105.63)]TJ -5.0141 -1.1128 TD (ln\(AUC)Tj 6.7246 0 0 5.9768 167.811 179.8298 Tm (0inf)Tj 8.9663 0 0 8.9663 182.0409 181.3039 Tm [(\))-4782.2(147.0757)-4754.3(142.2095)-5310.7(103.42)-5254.8(100.13)-4635.2(106.82)]TJ -13.6385 -1.4416 TD [(C)-339.3(versus)-333.3(B)-4278.5(ln\()]TJ /F14 1 Tf 9.9459 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 154.885 166.8472 Tm (max)Tj 8.9663 0 0 8.9663 166.5637 168.3779 Tm [(\))-7507.4(9.9278)-5760.6(9.4181)-5305.4(105.41)-5754.3(99.73)-4635.7(111.42)]TJ -3.0793 -1.1128 TD (ln\(AUC)Tj 6.7246 0 0 5.9768 167.811 156.926 Tm (024h)Tj 8.9663 0 0 8.9663 184.6488 158.3999 Tm [(\))-4491.4(108.0530)-4754.3(107.4592)-5310.7(100.55)-5754.3(97.05)-4635.7(104.18)]TJ -5.0963 -1.1128 TD (ln\(AUC)Tj 6.7246 0 0 5.9768 167.811 146.948 Tm (0last)Tj 8.9663 0 0 8.9663 183.9118 148.422 Tm [(\))-4573.6(142.9778)-4754.3(135.7108)-5310.7(105.35)-5254.8(101.69)-4635.2(109.15)]TJ -5.0141 -1.1065 TD (ln\(AUC)Tj 6.7246 0 0 5.9768 167.811 136.97 Tm (0inf)Tj 8.9663 0 0 8.9663 182.0409 138.5007 Tm [(\))-4782.2(147.9301)-4754.3(142.2095)-5310.7(104.02)-5254.8(100.71)-4635.2(107.44)]TJ 7.9702 0 0 7.9702 67.748 120.359 Tm [(Treatment)-393(A:)-402.3(SDX/d-MPH)-398(26.1/5.2)-154.7(mg;)-401.2(total)-400.9(equivalen)12.1(t)-409(d-MPH,)-396.8(20)-159.4(mg.)-403.8(Treatment)-393(B:)-404.5(SDX/d-MPH)-390.9(39.2/7.8)-154.7(mg;)-401.2(total)-400.9(equivalent)-396.9(d-MPH,)-396.8(30)-166.6(mg.)]TJ -1.003 -1.1239 TD [(Treatment)-329(C:)-333.4(SDX/d-MP)15(H)-334.7(52.3/10.4)-152.6(mg;)-330.1(total)-329.7(equivalent)-325.8(d-MPH,)-325.7(40)-166.6(mg.)]TJ 5.9774 0 0 5.3127 67.748 105.959 Tm (a)Tj 7.9702 0 0 7.9702 70.4126 102.3874 Tm [(Geometric)-324.5(mean)-328.8(based)-331.5(on)-330.2(least-squares)-327.5(mean)-328.8(of)-326.4(log-transformed)-317.7(parameter)-330.1(values.)]TJ 5.9774 0 0 5.3127 67.748 97.0016 Tm (b)Tj 7.9702 0 0 7.9702 70.7527 93.4299 Tm [(Ratio)-328.8(\(%\))]TJ /F7 1 Tf 4.1612 0 TD (=)Tj /F6 1 Tf .7184 0 TD [(Geometric)-324.5(Mean)-331.5(\(Test\)/Geom)12.7(etric)-330.7(Mean)-331.5(\(Ref)-77.5(\).)]TJ -5.2566 -1.1239 TD (AUC)Tj 5.9774 0 0 5.3127 84.4724 83.1685 Tm (024h)Tj 7.9702 0 0 7.9702 99.3826 84.4724 Tm [(,)-397.3(area)-395.9(under)-387.4(the)-400.9(concentr)12.2(ationtime)-388.6(curve)-397.8(from)-386.1(time-zero)-396.6(to)-392.7(24)-394.2(hours)-392.5(postdose)12.5(;)-401.9(AUC)]TJ 5.9774 0 0 5.3127 384.6613 83.1685 Tm (0last)Tj 7.9702 0 0 7.9702 398.9479 84.4724 Tm [(,)-397.3(AUC)-387.6(from)-393.2(time-zero)-389.4(to)-399.8(the)-393.8(time)-393.7(of)-390.5(the)-400.9(last)]TJ -42.5579 -1.1239 TD [(quantiable)-328.6(concentra)11.1(tion;)-333.6(AUC)]TJ 5.9774 0 0 5.3127 165.2031 74.211 Tm (0inf)Tj 7.9702 0 0 7.9702 177.7889 75.5149 Tm [(,)-340.4(AUC)-330.7(from)-329.2(time-zero)-325.4(extrapolate)11.2(d)-339.4(t)0(o)-328.7(innity;)-330.8(CI,)-330.1(condence)-326.2(interval;)]TJ /F8 1 Tf 29.3061 0 TD (C)Tj /F6 1 Tf .6615 0 TD [(max,)-333.8(maximum)-324.9(concentrati)11.2(on)-337.3(in)-328.7(plasma;)]TJ -44.7772 -1.1239 TD [(d-MPH,)-361.3(dexmeth)13.2(ylphenidate;)-355.7(GeoMean,)-358.4(geometric)-357.6(mean;)-353.7(Ref,)-359.7(reference;)-359.6(SDX,)-358.3(serdexmethyl)10.2(phenidate;)]TJ /F8 1 Tf 43.0558 0 TD (T)Tj /F6 1 Tf 5.9774 0 0 5.3127 407.3385 65.1968 Tm (max)Tj 7.9702 0 0 7.9702 417.6566 66.5575 Tm [(,)-361.7(time)-358.2(to)-364.2(reach)-358.3(maximum)-353.4(concentration;)]TJ /F8 1 Tf -44.9052 -1.1239 TD (T)Tj /F6 1 Tf 5.9774 0 0 5.3127 64.1763 56.2393 Tm (1/2)Tj 7.9702 0 0 7.9702 71.8299 57.6 Tm [(,)-333.3(termina)11.3(l)-337.8(half-life.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PHARMACOKINETICS)-343.5(OF)-331.2(SDX/)]TJ 6.4556 0 0 6.4556 193.6629 749.7069 Tm (D)Tj 8.9663 0 0 8.9663 198.3117 749.7069 Tm (-MPH)Tj 37.5581 0 TD (291)Tj ET endstream endobj 57 0 obj <>stream /GS1 gs BT /F6 1 Tf 8.9663 0 0 8.9663 62.022 525.2597 Tm 0 0 0 rg 0 Tc 0 Tw [(Table)-455.2(1)-448.4(shows)-452.2(the)-447.6(demographic)-454.6(and)-449.9(baseline)-448.9(characteristics)-460.8(of)]TJ 0 -1.2203 TD [(the)-327.4(intent-to-treat)-329(population.)-328.7(Median)-329.1(age)-325.8(of)-324.1(the)-327.4(participants)-331.1(was)]TJ 0 -1.2266 TD [(36)-283.6(years)-278.1(\(range,)-281.9(2053)-282.1(years\),)-283.1(and)-279.2(most)-278.7(were)-280.7(men)-282.7(\(75%\).)]TJ /F12 1 Tf 0 -2.5481 TD [(PK)-337.3(properties)-329.8(of)-336.7(SDX/d-MPH)-333.5(in)-336.5(the)-334.8(single-dose)-331.4(study)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(The)-297.9(PK)-291.8(prole)-301.9(of)-292.5(SDX/d-MPH)-300.9(exhibited)-297(a)-299.1(single)-293.2(d-MPH)-299.9(con-)]TJ -1.1128 -1.2203 TD [(centration)-263.6(peak)-262.1(at)-264.7(about)-263.2(2)-258.7(hours)-260.6(postadministration,)-265.6(followed)-259.1(by)-264.6(a)]TJ 0 -1.2266 TD [(gradual)-336.8(elimination)-332.9(through)-332(the)-333.8(remainder)-338.1(of)-330.4(the)-333.8(72-hour)-330.6(assess-)]TJ 0 -1.2203 TD [(ment)-279.9(period.)]TJ 1.1128 -1.2203 TD [(The)-184.1(following)-190.6(results)-182.7(represent)-190.3(mean)]TJ /F7 1 Tf 14.8336 0 TD ()Tj /F6 1 Tf .7145 0 TD [(standard)-192.1(deviation)-183.2(unless)]TJ -16.6609 -1.2266 TD [(stated)-447.4(otherwise.)-442.1(After)-442.5(each)-447.9(single)-445(dose)-437.9(of)-444.2(SDX/d-MPH)-446.3(\(26.1/)]TJ 0 -1.2203 TD [(5.2)-166.3(mg,)-441.8(9.2/7.8)-165.5(mg,)-441.8(or)-444.2(52.3/10.4)-164.5(mg\),)-437.5(d-MPH)-445.4(peak)-439.2(plasma)-446.9(con-)]TJ T* [(centrations)-390.8(were)-394.5(7.1)]TJ /F7 1 Tf 8.5486 0 TD ()Tj /F6 1 Tf .7208 0 TD [(2.1,)-390.6(9.8)]TJ /F7 1 Tf 3.3069 0 TD ()Tj /F6 1 Tf .7145 0 TD [(2.8,)-390.6(or)-387.3(13.8)]TJ /F7 1 Tf 5.033 0 TD ()Tj /F6 1 Tf .7145 0 TD [(3.8)-166.3(ng/mL,)-393.5(respec-)]TJ -19.0383 -1.2203 TD [(tively,)-292.7(followed)-290.7(by)-289.9(a)-292.8(gradual)-292.6(decline)-290.1(in)-287.6(concentration)-296.2(through)-287.7(the)]TJ 0 -1.2266 TD [(last)-250(time)-246(point)-252.2(\(72)-247.7(hours\).)-246.7(The)-247.4(same)-247.9(doses)-248.9(yielded)-249.7(an)-248(AUC)]TJ 6.7246 0 0 5.9768 274.6204 363.9117 Tm (024h)Tj 8.9663 0 0 8.9663 293.6692 365.3857 Tm (of)Tj -25.8354 -1.2203 TD (79.2)Tj /F7 1 Tf 1.9158 0 TD ()Tj /F6 1 Tf .7208 0 TD [(23.4,)-358.5(113.4)]TJ /F7 1 Tf 4.7738 0 TD ()Tj /F6 1 Tf .7145 0 TD [(32.8,)-358.5(and)-361.4(153.2)]TJ /F7 1 Tf 6.5822 0 TD ()Tj /F6 1 Tf .7145 0 TD [(47.9)-361.9(h*ng/mL,)-354.6(respectively)]TJ -15.4216 -1.2203 TD [(\(Fig.)-278.1(1;)-281.3(Table)-284.4(2\).)]TJ 1.1128 -1.2266 TD .0114 Tc [(At)-498(13)-493.9(hou)11.4(r)-9.2(s)-495.1(po)11.4(s)-7.8(t)1.5(do)11.4(s)-7.8(e)3.2(,)-497.3(p)-.8(lasma)-496.4(d)-.8(-MPH)-497.2(concen)11.4(tration)11.4(s)-507.3(were)]TJ -1.1128 -1.2203 TD .0107 Tc (2.9)Tj /F7 1 Tf 1.4543 0 TD 0 Tc ()Tj /F6 1 Tf .7335 0 TD .0115 Tc [(1)11.5(.)-3.6(0,)-478.3(4.4)]TJ /F7 1 Tf 3.4776 0 TD 0 Tc ()Tj /F6 1 Tf .7271 0 TD .0105 Tc [(1.5)10.5(,)-491.4(and)-482.2(5)10.5(.)-10.9(7)]TJ /F7 1 Tf 5.4377 0 TD 0 Tc ()Tj /F6 1 Tf .7271 0 TD [(2)-12.2(.)-9.2(4)-176.6(n)-12.2(g/)-22(m)-9.4(L)-492.5(a)-8.2(f)-8.4(t)-9.9(e)-14.6(r)-489(a)-495.1(s)-13.3(i)-9.9(ng)-18(l)-9.8(e)-495.1(do)-18(s)-13.3(e)-488.8(o)-12.2(f)]TJ -12.5573 -1.2203 TD .0113 Tc [(SDX/d-MPH)-351.9(26.1)11.3(/)-4.4(5.2,)-352(39)11.3(.)-10.1(2)11.3(/7.8,)-352(a)3.1(nd)-354.9(52)11.3(.3/10)11.3(.)-3.8(4)-165.2(m)-4.4(g)11.3(,)-364.2(resp)11.3(e)-9.1(c)3.1(tively.)]TJ 0 -1.2266 TD .0104 Tc [(Median)-488.6(d-MPH)]TJ /F8 1 Tf 7.1449 0 TD 0 Tc (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 131.074 298.1479 Tm .0183 Tc (max)Tj 8.9663 0 0 8.9663 147.4015 299.6219 Tm .0116 Tc [(occu)11.6(r)-9(r)3.2(ed)-487.4(at)-485.1(2.00)-487.4(ho)11.6(u)-6.4(r)3.2(s)-488.6(pos)4.6(tdo)11.6(s)-7.6(e)-489.8(f)3.2(or)-490(all)]TJ 18.4755 25.1652 TD .0096 Tc [(t)-6.6(r)1.2(ea)-5(tments,)-341.1(a)-5(n)9.6(d)-349.8(median)-337.7(d-MPH)]TJ /F8 1 Tf 13.4425 0 TD 0 Tc (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 438.633 523.7857 Tm .0142 Tc (1/2)Tj 8.9663 0 0 8.9663 450.5385 525.2597 Tm .0105 Tc [(values)-344.3(rang)10.5(e)-9.9(d)-336.8(fro)10.5(m)-346.1(8.59)-336.8(to)]TJ -15.3331 -1.2203 TD .011 Tc [(10.54)-298.3(hou)11(rs,)-301.7(w)1.9(ith)-298.3(n)-1.2(o)-304.7(s)4(ignicant)-302.4(d)-1.2(ifferen)11(c)-9.4(es)-305.8(o)11(b)-7(s)4(e)-3.6(rved)-304.7(among)-298.3(t)1.1(he)]TJ 0 -1.2266 TD .0097 Tc [(t)-6.5(r)1.3(ea)-4.9(tment)-683(g)-2.5(ro)9.7(u)-8.3(p)-2.5(s)-680.2(\()-5.1(T)9.7(a)-10.5(b)9.7(l)-6(e)-687.7(2)-2.5(\).)-682.4(Mean)-685.3(bo)9.7(d)-8.3(y)-685.3(weight-no)9.7(r)-4.6(m)-6(a)1.5(liz)-4.9(ed)]TJ 0 -1.2203 TD .0108 Tc [(clearance)-357.9(a)2.5(nd)-349.1(volu)10.8(m)-10.7(e-of-distribu)10.8(t)-4.9(ion)-355.4(v)10.8(a)-9.6(l).9(u)10.8(e)-9.6(s)-350.3(f)-4(o)10.8(r)-357.6(d-MPH)-352.4(d)-1.4(id)-349.1(not)]TJ T* .0102 Tc [(differ)-352.3(acro)10.2(s)-9(s)-344.6(t)-6(h)10.2(e)-358(t).3(h)10.2(r)-10.4(ee)-352.1(treatments.)-346.8(W)2.4(eig)10.2(h)-7.8(t-normal)-6(ized)-349.7(clearance)]TJ 0 -1.2266 TD .0108 Tc [(valu)10.8(e)-9.6(s)-318.7(\(CL/F/weight\))-313.8(f)-4(o)10.8(r)-325.9(d-M)10.8(P)-6.5(H)-320.8(r)2.4(an)10.8(g)-7.2(e)2.5(d)-317.5(f)-4(rom)-314.7(2)-1.4(.6)]TJ /F7 1 Tf 20.9225 0 TD 0 Tc ()Tj /F6 1 Tf .7334 0 TD [(0.)-15.1(8)-176.6(L)-12(/)-9.9([)-14.8(h)]TJ /F16 1 Tf 3.212 0 TD ($)Tj /F6 1 Tf .4489 0 TD .0122 Tc [(kg)12.2(])]TJ -25.3169 -1.2203 TD .0124 Tc [(\(SDX/d-MPH)-395.1(5).2(2)12.4(.)-2.7(3/10)12.4(.4)-164.2(mg)12.4(\))-406.5(t)2.5(o)-398.1(2)12.4(.7)]TJ /F7 1 Tf 14.8336 0 TD 0 Tc ()Tj /F6 1 Tf .7271 0 TD .0099 Tc [(0.8)-166.6(L)-2.1(/[h)]TJ /F16 1 Tf 3.2184 0 TD 0 Tc ($)Tj /F6 1 Tf .4426 0 TD .0117 Tc [(kg])-395.1(\(S)11.7(D)-8.2(X)2.6(/d-M)11.7(P)-5.6(H)]TJ -19.2216 -1.2203 TD .0106 Tc [(39.2/7)10.6(.)-4.5(8)-166(m)1.2(g\),)-890.2(a)2.4(nd)-886.8(weig)10.6(h)-7.4(t).7(-normali)]TJ 15.0106 0 TD .0107 Tc [(zed)-886.7(volu)10.7(m)-4.5(e-of-dist)-5.5(r)2.3(ibu)10.7(t)-5(ion)]TJ -15.0106 -1.2203 TD .0117 Tc [(valu)11.7(e)-8.7(s)-469.5(\()]TJ /F8 1 Tf 3.446 0 TD 0 Tc (V)Tj 6.7246 0 0 5.9768 349.5117 436.0818 Tm (z)Tj /F6 1 Tf 8.9663 0 0 8.9663 352.233 437.6125 Tm (/)Tj /F8 1 Tf .2909 0 TD (F)Tj /F6 1 Tf .626 0 TD .011 Tc [(/weight\))-471.7(f)2.6(or)-471.7(d-MPH)-472.4(r)2.6(ang)11(e)-9.4(d)-469(f)-3.8(rom)-472.6(3)-1.2(8)11(.)-4.1(8)]TJ /F7 1 Tf 16.7747 0 TD 0 Tc ()Tj /F6 1 Tf .7271 0 TD .0126 Tc [(25)12.6(.0)-163.9(L/kg)]TJ -22.7878 -1.2267 TD .0106 Tc [(\(SDX/d-MPH)-681.4(2)10.6(6)-7.4(.)1.4(1/5.2)-165.9(m)1.2(g)10.6(\))-692.9(to)-684.4(4)10.6(1)-7.4(.9)]TJ /F7 1 Tf 15.6808 0 TD 0 Tc ()Tj /F6 1 Tf .7335 0 TD [(20)-18(.)-9.2(5)-176.6(L)-12(/)-9.9(k)-12.2(g)-688.7(\()-14.8(S)0(D)-19.9(X)-9.1(/)-9.9(d)-12.2(-)-8.4(M)0(P)-17.3(H)]TJ -16.4143 -1.2203 TD [(5)-12.2(2)-12.2(.)-9.2(3)-12.2(/)-9.9(10)-18(.)-9.2(4)-176.6(m)-9.4(g)-12.2(\))-286.6(\()-14.8(Ta)-20.2(bl)-15.7(e)-292.8(2)-12.2(\))-8.4(.)]TJ 1.1128 -1.2203 TD [(Do)16.6(se)22.7(-n)17.3(o)13.1(r)0(m)13.8(a)0(l)19.8(i)0(z)19.8(e)0(d)-260.7(m)0(e)20.3(a)0(n)-260.7(m)0(a)14(x)13.1(im)18.7(u)13.1(m)-274.9(an)23.8(d)-271.4(t)0(o)15.9(t)0(a)19.8(l)-269.1(d-)17.3(M)12.4(P)0(H)-260.1(e)0(x)17.5(p)0(o)20(s)0(u)18.8(r)0(e)21.2(,)-274.8(as)]TJ -1.1128 -1.2266 TD [(me)14(as)22.7(ur)17.3(ed)-437.7(by)]TJ /F8 1 Tf 5.6653 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 369.6944 392.2581 Tm [(ma)22.4(x)]TJ 8.9663 0 0 8.9663 381.0897 393.7322 Tm .4518 Tc [(,A)451.8(U)471.5(C)]TJ 6.7246 0 0 5.9768 405.9778 392.2581 Tm 0 Tc [(0)30.5(la)19.8(st)]TJ 8.9663 0 0 8.9663 421.5684 393.7322 Tm [(,)-445.5(a)0(n)17.5(d)-448.4(AU)19.7(C)]TJ 6.7246 0 0 5.9768 463.2377 392.2581 Tm [(0)22(in)30.7(f)]TJ 8.9663 0 0 8.9663 477.0707 393.7322 Tm [(,)-445.5(w)0(e)20.5(r)0(e)-440.3(s)0(i)21.1(m)0(i)18.7(l)0(a)19.8(r)-451(wh)16.6(en)]TJ -18.2922 -1.2203 TD [(co)17.5(mp)16.4(ar)21.3(in)22.3(g)-182.9(S)0(D)18.1(X)0(/)18.9(d)13.1(-M)16.6(PH)-171.6(2)13.1(6)0(.)16.5(1)13.1(/5)15.9(.)16(2)-157.6(mg)-173.3(an)17.5(d)-176.6(S)0(D)18.1(X)0(/)18.9(d)13.1(-M)16.6(PH)-171.6(5)13.1(2)0(.)16.5(3)13.1(/1)15.9(0)13.1(.)0(4)-147.9(m)0(g)]TJ T* [(wi)18.9(th)-262.3(SD)18.1(X/)18.9(d)13.1(-)0(M)16.6(P)0(H)-260.1(3)13.1(9.)16.5(2)13.1(/)0(7)15.9(.)0(8)-147.9(m)0(g)-255.5(\()0(T)17.5(a)0(b)17.5(l)0(e)-258.4(3)0(\))17.3(.)]TJ /F12 1 Tf 0 -2.5545 TD [(Dose)-340(proportionality)-336.2(of)-330.4(PK)-337.2(parameters)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(Aft)16.8(er)-541.5(a)-539.4(sin)15.2(gle)14(-do)17.8(se)-540.1(adm)14.5(in)15.9(istr)21.7(atio)16.8(n)-543.3(o)0(f)-532.7(SDX)15.2(/d-)13.8(MP)14.3(H)-546.6(2)0(6)13.6(.1/)19.3(5.2)17(,)]TJ -1.1128 -1.2203 TD [(39.2)17.5(/7)15.9(.8,)-397.4(a)17(n)19.5(d)-397.9(5)19.5(2)19.5(.)22.4(3)19.5(/)15.4(1)19.5(0)19.5(.)22.4(4)-151.3(m)22.3(g)19.5(,)-394.9(d)19.5(-)16.9(M)18.8(P)20.9(H)]TJ /F8 1 Tf 14.6692 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 450.4251 320.0881 Tm -.0239 Tc (max)Tj 8.9663 0 0 8.9663 465.2786 321.5621 Tm -.022 Tc [(and)-419.9(A)-5.8(UC)]TJ 6.7246 0 0 5.9768 499.8046 320.0881 Tm -.0279 Tc [(0i)-8.2(nf)]TJ 8.9663 0 0 8.9663 516.8691 321.5621 Tm -.0199 Tc [(values)-418.9(in-)]TJ -22.7309 -1.2203 TD -.0188 Tc [(creased)-555.8(proportionally)-549.4(w)-2.6(ith)-555.8(t)3(he)]TJ 13.4488 0 TD [(SDX/d-MPH)-552.7(dose)-558.2(\()4.4(Fig.)-552.9(2A,)-552.8(B)2.3(;)]TJ -13.4488 -1.2266 TD -.0181 Tc [(Supplementary)-213.6(Table)-216(S)2.8(1\).)-217(D)]TJ 10.9386 0 TD -.0192 Tc [(ose)-217.1(p).3(roportion)-6.1(ality)-214.7(o).3(f)]TJ /F8 1 Tf 8.4537 0 TD 0 Tc (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 492.7747 298.1479 Tm -.0239 Tc (max)Tj 8.9663 0 0 8.9663 505.8707 299.6219 Tm -.0183 Tc [(and)-213.8(A)-2.1(U)4.2(C)]TJ 6.7246 0 0 5.9768 538.6392 298.1479 Tm -.028 Tc [(0)-8.6(inf)]TJ ET q 360.926 0 0 127.105 126.822 605.14 cm /Im3 Do Q BT /F9 1 Tf 8.9663 0 0 8.9663 62.022 588.3589 Tm 0 Tc [(FIG.)-492.9(2.)]TJ /F6 1 Tf 4.2743 0 TD [(Power)-497.7(model)-494.4(regression)-492.1(analysis)-498.2(of)-494.8(total)-492.6(equivalent)-495(d-MPH)-495.9(dose)-494.8(versus)-497.7(plasma)-497.5(d-MPH)]TJ /F9 1 Tf 38.3421 0 TD (\(A\))Tj /F8 1 Tf 1.8842 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 466.9794 586.8282 Tm (max)Tj 8.9663 0 0 8.9663 483.0235 588.3589 Tm (and)Tj /F9 1 Tf 1.9411 0 TD (\(B\))Tj /F6 1 Tf 1.8273 0 TD (AUC)Tj 6.7246 0 0 5.9768 535.6912 586.8282 Tm (0inf)Tj 8.9663 0 0 8.9663 549.9211 588.3589 Tm (.)Tj /F9 1 Tf -54.415 -1.1128 TD (\(A\))Tj /F6 1 Tf 1.6629 0 TD (Intercept)Tj /F7 1 Tf 3.7368 0 TD .1688 Tc (=-)Tj /F6 1 Tf 1.2709 0 TD 0 Tc [(0.9812;)-275.9(slope)]TJ /F7 1 Tf 5.5895 0 TD (=)Tj /F6 1 Tf .7208 0 TD (0.9625.)Tj /F9 1 Tf 3.2753 0 TD (\(B\))Tj /F6 1 Tf 1.606 0 TD (Intercept)Tj /F7 1 Tf 3.7432 0 TD (=)Tj /F6 1 Tf .7145 0 TD [(1.5806;)-275.9(slope)]TJ /F7 1 Tf 5.5894 0 TD (=)Tj /F6 1 Tf .7208 0 TD [(1.0021.)-275.3(Treatment)-276.1(A:)-278.2(SDX/d-MPH)-281.9(26.1/5.2)-165(mg;)-278(total)-277.6(equivalent)]TJ -28.6301 -1.1128 TD [(d-MPH)-559.2(HCl,)-557.3(20)-163.4(mg.)-561.9(Treatment)-554.3(B:)-557.9(SDX/d-MPH)-560.1(39.2/7.8)-165(mg;)-556.2(total)-562.1(equivalent)-558.2(d-MPH)-559.2(HCl,)-557.3(30)-163.4(mg.)-555.6(Treatment)-560.6(C:)-557.9(SDX/d-MPH)]TJ T* [(52.3/10.4)-164.5(mg;)-379.1(total)-385.1(equivalent)-381.2(d-MPH)-375.8(HCl,)-380.2(40)-169.7(mg.)]TJ /F8 1 Tf 21.3651 0 TD (n)Tj /F7 1 Tf .6639 0 TD (=)Tj /F6 1 Tf .7208 0 TD [(23.)-375(AUC)]TJ 6.7246 0 0 5.9768 299.4519 556.951 Tm (0inf)Tj 8.9663 0 0 8.9663 313.6818 558.425 Tm [(,)-382.3(area)-381(under)-375.6(the)-384.4(concentrationtime)-383.6(curve)-378.1(from)-379.8(time-zero)-380(extra-)]TJ -28.0674 -1.1065 TD [(polated)-338.3(to)-331.8(innity;)]TJ /F8 1 Tf 7.9163 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 138.9543 546.9731 Tm (max)Tj 8.9663 0 0 8.9663 150.633 548.5038 Tm [(,)-331.7(maximum)-336.1(concentration)-334.1(in)-338.2(plasma;)-330.3(d-MPH,)-334.5(dexmethylphenidate;)-342.6(SDX,)-329.1(serdexmethylphenidate.)]TJ ET q 420.92 0 0 200.693 96.775 84.019 cm /Im4 Do Q BT /F9 1 Tf 8.9663 0 0 8.9663 62.022 67.2378 Tm [(FIG.)-296.8(3.)]TJ /F6 1 Tf 4.0783 0 TD [(Plasma)-300.1(concentrationtime)-301.4(curve)-302.2(\(mean)]TJ /F7 1 Tf 16.4522 0 TD ()Tj /F6 1 Tf .7208 0 TD [(standard)-299.6(deviation\))-299.2(for)]TJ /F9 1 Tf 9.5223 0 TD (\(A\))Tj /F6 1 Tf 1.6819 0 TD [(d-MPH)-299.9(and)]TJ /F9 1 Tf 5.033 0 TD (\(B\))Tj /F6 1 Tf 1.6313 0 TD [(SDX)-300.9(after)-296.2(1)-296.7(and)-298.1(4)-296.7(doses)-299.5(of)-298.8(Treatment)]TJ -39.1199 -1.1128 TD [(D:)-290.9(52.3/10.4)-170.8(mg)-287.1(SDX/d-MPH,)-297.5(40)-163.4(mg)-293.4(total)-290.2(equivalent)-299(d-MPH)-293.6(HCl.)]TJ /F8 1 Tf 27.4035 0 TD (n)Tj /F7 1 Tf .6639 0 TD (=)Tj /F6 1 Tf .7208 0 TD [(23.)-292.8(d-MPH,)-290.2(dexmethylphenidate;)-298.3(SDX,)-291.2(serdexmethylphenidate.)]TJ /F4 1 Tf -28.7882 77.2217 TD (292)Tj 44.5765 0 TD [(BRAECKMAN)-335.4(ET)-338.7(AL.)]TJ ET endstream endobj 59 0 obj <>stream AdobedC         s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjz?Zu֡v;[8CcK6~OOy_6-mmcM1EjІl #=76lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l=:~firJ- =.c jrI?K&$󤺅Zmt_̋OƜ o" w-'1%ƯYk0M[zKoV|qM[ǩLF"r`T2=ڨX'<;5טנow?/ ~^I-Yg$o"3NػzSC˚ffkmEuRhp6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lh;<*A%8%q5C v8˟qyz)5+[7($^%LT=:Wƛg&u/ߖ^iBA 0=3M6lٳfO@5FmĒeg@CUVvvVD[8`*Դ;S6][C đ1וt.Ο 8aЫ /hS\ݚT~?d;";^Lݠ_&@TYO?Ȭj~ m#[[_J[ jx1K=#L FED2Ȩ#-@ ͛6lٳf͛6lٳf͛6lٳf͜oWK]{iф~ZN(B}<8kygSӴ/ifuo$vW۪43T JӶ?h|=қ)LVC#z#?ц揑i{KSGmq fy5ʡ7nBZ插4v] OҐ4I4ZNPчxbt^J+͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͜+[s·o*_ͣ[-˺ȷN#XR!#z䧛,΍;>3+]G#+*:³R| 7S|{]:/LJ#ZIU݋a2bRNo͟%y^2O[^6<+ 5K;?o*.ݜmvwUŻOЅm&v|jǮW:W"wz| CNsIΌXdxyZm-Zdiԥ0W5)ԭ bkMfE0pe#F?6ߥi+Zͤ uy '9> Ue _Iu=7\Y]50,vrK rw`#Pub)iϦX_:lZtEsi՜]+S=Jm?ݰbZoKgZ2I&^j$TH8bd+ByrR:1K+6˧R]JF{VZj cR\(ZfXڥ̈́7{b]Z,a'tI8 vש//t/]ZjZJ^5Y."<%<=ep|pO͚ލ]jo,6R4!E#lOO:Vu zv-Mnl$QZѾ(^@JPW'f͛6lٳf͛6lٳf͛6lٳf͜O͞doOV:1,pg ynik2&dUyQЮ</y?5G!W D 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[(tio)12.4(nal)20.3(ity)-373.3(for)-370.5(SDX)15.2(/d-)13.8(MP)14.3(H)-382.2(wit)15.4(h)-385.2(res)14.2(pec)15.6(t)-382.9(t)0(o)-376.1(d-M)17.1(PH)-374(expo)18.5(su)12.4(re)-377.1(par)15.4(a-)]TJ T* [(mete)14.9(rs)-312.6(\()]TJ /F15 1 Tf 3.3006 0 TD (*)Tj /F6 1 Tf .9927 0 TD [(6.5)17(-fo)15.2(ld)-312.9([)]TJ /F8 1 Tf 3.8064 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 138.274 333.1842 Tm (max)Tj 8.9663 0 0 8.9663 149.7826 334.6582 Tm [(])-318.3(t)0(o)-312.9(82.)17(7-f)15.2(old)-312.4([A)14(UC)]TJ 6.7246 0 0 5.9768 222.6897 333.1842 Tm [(0in)19(f)]TJ 8.9663 0 0 8.9663 236.6928 334.6582 Tm [(];)-315.5(Sup)15.5(ple)14(me)14(nta)14(ry)]TJ -19.7338 -1.2203 TD [(Tab)11.9(le)-264.7(S1\))12.9(.)-274.8(Sim)20.6(ila)16.3(r)-274(nd)15.5(ing)16.4(s)-272.6(wer)12.1(e)-273.8(o)0(b)13.6(ser)14.2(ved)-260.2(for)-263(the)-264.2(ove)18(ral)11.4(l)-275.4(exp)18(os)12.4(ure)]TJ 0 -1.2266 TD [(par)15.4(ame)12.1(te)13.5(rs)-274.7(AU)13.3(C)]TJ 6.7246 0 0 5.9768 120.0189 311.244 Tm [(02)24.6(4)]TJ 8.9663 0 0 8.9663 135.7795 312.718 Tm [(and)-266.5(AU)13.3(C)]TJ 6.7246 0 0 5.9768 169.8519 311.244 Tm [(0l)24.8(ast)]TJ 8.9663 0 0 8.9663 185.6692 312.718 Tm (.)Tj /F12 1 Tf -14.0432 -2.2889 TD [(PK)-261.4(pr)18.8(op)16.5(e)14.6(r)0(t)19.6(i)0(e)17.6(s)-271.4(of)-260.9(SD)18.2(X)14.7(/)0(d)17.3(-)0(M)21.6(P)0(H)-266.3(i)0(n)-260.6(t)0(h)23.7(e)-270(mu)19.2(lt)18.5(ip)17.6(le)17.6(-d)25.1(os)15(e)-270(s)13.1(tu)17.3(d)14.6(y)]TJ /F2 1 Tf 1.1128 -1.6882 TD (Dexmethylphenidate.)Tj /F6 1 Tf 10.4644 0 TD [(M)12.4(e)17(an)-159.5(p)19.5(l)15.4(as)29(ma)-156.7(co)23.9(n)19.5(c)0(e)27.8(n)13.1(t)15.4(r)16.9(at)26.2(i)15.4(o)13.1(n)19.5(s)-171.4(o)13.1(f)-172.8(d)19.5(-)0(M)29.3(P)14.6(H)]TJ -11.5773 -1.2203 TD -.0156 Tc [(w)-15.6(e)11.3(re)-314.7(highe)-15.6(r)-297.9(a)-15.6(f)12(te)-15.6(r)-297.8(m).3(ultiple)-314.7(dos)-15.6(e)13.4(s)-313.5(o)3.9(f)-314.9(S)-1(DX/)-15.6(d)13(-)-15.6(M)13.7(P)-1(H)-315.6(5)3.9(2.3/10.)-15.6(4)-157.1(mg)-312.3(tha)-15.6(n)]TJ T* -.0153 Tc [(a)-15.3(f)12.3(te)-15.3(r)-272.3(a)-282.8(s)-15.3(i)12.1(ngle)-282.8(dose)-289.1(o)4.2(f)-283(S)-.7(D)-15.3(X)10.7(/d-MPH)-283.7(52.3/10.)-15.3(4)-156.8(m).6(g)-280.4(\()-15.3(F)16.1(i)-15.3(g)13.3(.)-283.8(3A;)-284.4(T)-2(able)-282.8(4\).)]TJ T* -.015 Tc [(Mea)-15(n)-503.3(ma)-15(x)8.9(i).4(mum)-511.2(\()]TJ /F8 1 Tf 7.5432 0 TD 0 Tc (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 133.2283 242.7023 Tm -.0222 Tc [(ma)-5.2(x)]TJ 8.9663 0 0 8.9663 144.4535 244.233 Tm 0 Tc [(\),)-485.6(mi)25(n)19.5(i)15.4(mu)29.1(m)-502.5(\()]TJ /F8 1 Tf 5.7096 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 201.4866 242.7023 Tm -.021 Tc (min)Tj 8.9663 0 0 8.9663 211.5779 244.233 Tm -.0163 Tc [(\),)-518.7(a)-16.3(n)13.9(d)-521.6(t)-.9(otal)-519.3(\(A)-16.3(U)9.7(C)]TJ 6.7246 0 0 5.9768 279.7227 242.7023 Tm -.0195 Tc (024h)Tj 8.9663 0 0 8.9663 295.8802 244.233 Tm 0 Tc (\))Tj -26.3349 -1.2266 TD -.0146 Tc [(d-MPH)-301.9(e)2.4(xpo)4.9(s)-14.6(u)10.5(re)-301.1(a)-14.6(f)13(ter)-301.2(m)-14.6(u)14.5(lti)-14.6(p)14(l).8(e)-301.1(dos)3.7(e)-14.6(s)-289.1(of)-301.2(SDX/d-MPH)-301.9(5)4.9(2.3/10)4.9(.)-14.6(4)-156.1(mg)]TJ 0 -1.2203 TD 0 Tc [(we)26.9(r)16.9(e)]TJ /F15 1 Tf 2.1624 0 TD (*)Tj /F6 1 Tf .9864 0 TD -.0151 Tc [(35%,)-277.3(1)4.4(2%,)-277.3(a)-15.1(n)15.1(d)-273.8(36%)-276(h)4.4(i)-15.1(g)13.5(h)-2(er)-15.1(,)-260.4(r)-15.1(e)12.5(s)-15.1(p)10(ect)-15.1(i)9.5(v)4.4(e)-15.1(l)11.1(y,)-270.9(tha)-15.1(n)-263.1(af)-15.1(t)10.9(e)1.9(r)-276.5(a)-276.3(s)-15.1(i)12.3(n)4.4(g)-2(le)]TJ -3.1488 -1.2203 TD -.0142 Tc [(dos)4.1(e)-14.2(,)-347.8(indica)-14.2(t)12(i)1.2(ve)-357.6(of)-357.8(m)-14.2(o)14.9(de)-14.2(s)14.8(t)-359.2(a)-14.2(c)13.6(c)-14.2(u)16(m)-14.2(u)14.9(la)-14.2(t)12(i)1.2(on)-361.5(o)5.3(f)-364.1(d-MPH.)-358.6(Mea)-14.2(n)-350.8(d)5.3(-)-14.2(M)15.1(P).4(H)]TJ 0 -1.2266 TD 0 Tc [(ex)23.9(p)19.5(o)13.1(s)18.3(u)13.1(re)-193.7(fr)27.4(o)13.1(m)-205.4(0)-208.2(t)15.4(o)-214.5(3)-208.2(h)19.5(o)13.1(u)13.1(r)16.9(s)-209.4(\()16.9(AU)26(C)]TJ 6.7246 0 0 5.9768 176.0314 198.8787 Tm -.0195 Tc (03h)Tj 8.9663 0 0 8.9663 188.9574 200.3527 Tm .2082 Tc [(\))225.1(,)-3.4(3t)223.6(o7h)221.3(o)221.3(u)227.7(r)208.2(s)9.4(\()225.1(A)224.4(U)208.2(C)]TJ 6.7246 0 0 5.9768 259.9369 198.8787 Tm -.0195 Tc (37h)Tj 8.9663 0 0 8.9663 272.8629 200.3527 Tm -.016 Tc [(\),)-227.6(and)-224.2(7)]TJ -23.7678 -1.2203 TD -.0143 Tc [(to)-361.6(12)-361.6(hou)5.2(r)-14.3(s)-345.9(\()-14.3(A)12.4(UC)]TJ 6.7246 0 0 5.9768 125.4614 187.9369 Tm -.0195 Tc [(712)-19.5(h)]TJ 8.9663 0 0 8.9663 141.6756 189.411 Tm -.0152 Tc [(\))-358.7(a)-15.2(f)12.4(t).2(e)-15.2(r)-348(multiple)-364.9(dos)-15.2(e)13.8(s)-363.7(o)-2.1(f)-358.7(S)-.6(D)-15.2(X)10.8(/d-MPH)-359.4(52.3/)]TJ -9.1366 -1.2203 TD -.0149 Tc [(10.4-mg)-216.7(w)-14.9(a)12(s)]TJ /F15 1 Tf 5.2038 0 TD 0 Tc (*)Tj /F6 1 Tf .9864 0 TD -.0148 Tc [(59)4.7(%)-14.8(,)-202.7(43%,)-220(a)2.2(nd)-216.6(38)4.7(%)-218.8(h)-1.7(igh)4.7(e)-14.8(r)12.8(,)-220(re)-14.8(s)14.2(p)-1.7(ec)-14.8(t)11.4(i).6(vely,)-220(t).6(h)4.7(a)-14.8(n)-205.9(a)2.2(f)-14.8(t)11.2(er)-219.2(a)]TJ -6.1901 -1.2266 TD -.0145 Tc [(s)-14.5(i)12.9(ng)5(l)-14.5(e)11.7(-dos)3.8(e)-471.7(a)2.5(dminis)-14.5(t)12.9(r)2.4(a)-14.5(t)11.7(io)5(n.)-466.3(Ste)-14.5(a)13.3(dy-s)-14.5(t)12.9(ate)-471.7(c)2.5(once)-14.5(n)15.7(tr)-14.5(a)13.1(tions)-470.4(o)5(f)-471.9(d)5(-)-14.5(M)14.8(P).1(H)]TJ 0 -1.2203 TD -.0152 Tc [(w)-15.2(e)11.7(re)-402.8(re)-15.2(a)12.6(c)-15.2(h)15(e)-15.2(d)-389.7(b)4.3(e)-15.2(f)12.4(ore)-402.8(t).2(h)4.3(e)-402.8(adminis)-15.2(t)12.2(ra)-15.2(t)11(i).2(on)-394.1(of)-396.7(t)-15.2(h)13.4(e)-402.8(t).2(hird)-400.4(d)4.3(o)-2.1(s)-15.2(e)-384.6(\()-15.2(S)9.9(u)4.3(pple-)]TJ T* 0 Tc [(me)26.6(n)13.1(t)15.4(a)17(r)0(y)-254.5(T)19.6(ab)23.9(l)15.4(e)-261.2(S)14.6(2)13.1(\))16.9(.)]TJ /F2 1 Tf 1.1128 -2.5165 TD (Serdexmethylphenidate.)Tj /F6 1 Tf 11.8491 0 TD [(Mean)-737(SDX)-730.9(prodrug)-735.3(maximum)]TJ -12.962 -1.2203 TD [(concentrations)-240(\()]TJ /F8 1 Tf 6.4241 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 123.3637 110.5512 Tm (max)Tj 8.9663 0 0 8.9663 134.9858 112.0819 Tm [(\))-236.1(were)-236.4(similar)-239.7(after)-239.2(a)-235.9(single)-236.3(dose)-235.6(and)-241.2(multiple)]TJ -8.3905 -1.2266 TD [(doses)-337.5(of)-330.4(SDX/d-MPH)-338.8(52.3/10.4)-164.5(mg)-331.3(\(Fig.)-335(3B;)-329.7(Table)-335(4\).)-333.3(Accumu-)]TJ 0 -1.2203 TD [(lation)-416.2(ratios)-416(for)-414.7(SDX)-408.4(prodrug)]TJ /F8 1 Tf 12.9051 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 181.474 88.6677 Tm (max)Tj 8.9663 0 0 8.9663 193.096 90.1417 Tm (,)Tj /F8 1 Tf .6639 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 205.0582 88.6677 Tm (min)Tj 8.9663 0 0 8.9663 215.5464 90.1417 Tm [(,)-413.9(AUC)]TJ 6.7246 0 0 5.9768 240.3779 88.6677 Tm (024h)Tj 8.9663 0 0 8.9663 257.2157 90.1417 Tm [(,)-413.9(and)-411.9(elim-)]TJ -22.0227 -1.2203 TD [(ination)-327.2(rate)-325.7(constant)-326.3(\()]TJ /F8 1 Tf 8.9532 0 TD (k)Tj /F6 1 Tf 6.7246 0 0 5.9768 144.0566 77.6693 Tm (el)Tj 8.9663 0 0 8.9663 148.9322 79.2 Tm [(\))-324.6(were)-324.9(close)-330.1(to)-319.2(1)-328.3(\(1.004,)-322.1(0.9705,)-325.9(0.9169,)]TJ -9.9459 -1.2266 TD [(and)-234.9(1.060,)-225.2(respectively\),)-233.4(indicating)-237.3(no)-226.6(accumulation)-234.4(of)-229.2(SDX)-231.3(at)-233.1(the)]TJ 0 -1.2203 TD [(test)-281.6(dose)-286.2(during)-275.6(the)-283.2(multiple-dose)-281.1(regimen)-283.5(\(Table)-280.2(4\).)]TJ /F12 1 Tf 28.0042 45.6072 TD [(SDX/d-MPH)-333.5(composite)-335(PK)-337.2(prole)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(A)-268.4(composite)-278.8(PK)-272.8(prole)-276.6(was)-277.3(constructed)-279.3(to)-268.6(show)-280.7(the)-270.5(individual)]TJ -1.1128 -1.2266 TD [(contributions)-566(of)-570.7(SDX)-566.5(and)-570(d-MPH)-565.5(to)-565.8(the)-567.7(observed)-567.5(combined)]TJ 0 -1.2203 TD [(d-MPH)-382.1(plasma)-383.7(concentrations)-385.4(after)-384.7(oral)-380.1(administration)-385.8(of)-381(SDX/)]TJ T* [(d)13.1(-)0(M)23(P)0(H)18.1(.)-186.3(F)14.5(i)0(g)22.3(u)13.1(re)-181.1(4)-182.9(s)0(h)18.8(o)13.1(ws)-174.2(th)22.2(e)-185.3(P)0(K)-178(p)13.1(ro)23.7(l)17.3(e)-185.3(f)0(o)23.7(r)-185.5(im)18.7(m)15.9(e)0(d)17.5(i)0(a)19.8(t)15.4(e-)21.2(re)21.2(le)19.8(as)22.7(e)-191.6(d)13.1(-M)23(PH)]TJ 0 -1.2266 TD [(1)13.1(0)13.1(.)0(4)-147.9(m)0(g)22.7(,)-312.7(SD)18.1(X)-312.6(5)0(2)19.9(.)0(3)-141.5(m)0(g)16.4(,)-312.7(an)23.9(d)-315.7(S)0(D)18.1(X)0(/)25.3(d)0(-)17.3(M)12.4(P)14.6(H)-319(5)13.1(2)0(.)22.9(3)0(/)22.3(1)0(0)19.9(.)0(4)-147.9(m)15.9(g.)-305.9(M)12.4(e)0(a)21.4(n)-315.7(pl)22.2(a-)]TJ 0 -1.2203 TD [(sm)21.5(a)-330.7(c)0(o)17.5(n)13.1(ce)21.4(nt)22.2(ra)21.3(ti)18.2(o)13.1(n)13.1(s)-335.8(co)17.5(n)13.1(t)0(r)19.6(i)15.4(bu)19.9(te)19.8(d)-334.6(b)13.1(y)-334.6(a)-330.7(si)21.1(ng)19.9(le)19.8(-e)21.2(n)13.1(t)0(i)18.2(t)15.4(y)-334.6(d)0(-)23.7(M)0(P)20.7(H)-337.9(1)13.1(0)13.1(.)0(4)22.9(-)0(m)20.1(g)]TJ T* [(component)-754.1(was)-757.9(derived)-754.1(from)-759.2(data)-753(previously)-761.8(reported)-756.3(for)]TJ 0 -1.2266 TD [(immediate-release)-335.3(d-MPH)-325.2(\()-84.3(Midha)-333.5(et)-327.9(al.)-330.8(2001\).)-325.6(After)-328.7(administra-)]TJ 0 -1.2203 TD [(tion)-278(of)-286.2(single-entity)-281.6(SDX)-281.9(52.3)-165.8(mg,)-283.7(exposure)-282.9(to)-281.3(d-MPH)-287.3(was)-283.7(negli-)]TJ T* [(gible)-393.7(\()]TJ /F7 1 Tf 2.7378 0 TD (<)Tj /F6 1 Tf .5501 0 TD [(1)-170.2(ng/mL\))-392.7(for)-402.1(the)-397(rst)-396.5(23)-396.9(hours)-393.4(postdose.)-399.8(At)]TJ /F15 1 Tf 19.2659 0 TD (*)Tj /F6 1 Tf .999 0 TD [(3)-391.5(hours)]TJ ET 59.754 710.135 490.167 .22681 re f 59.754 545.216 490.167 .22681 re f 220.989 691.256 150.803 .22681 re f 412.611 691.256 137.31 .22681 re f 59.754 673.568 490.167 .22675 re f BT /F10 1 Tf 8.9663 0 0 8.9663 97.2283 725.7825 Tm (Table)Tj /F6 1 Tf 2.9971 0 TD (4.)Tj /F10 1 Tf 1.2519 0 TD [(Plasma)-333.8(Pharmacokinetic)-333.1(Parameters)-338.2(for)-328.3(Serdexmethylphenidate)-339.6(and)-330.6(Dexmethylphenidate)]TJ 5.248 -1.1128 TD [(After)-332.1(Multiple)-338.2(Oral)-335(Dose)-329.9(Administration)-338.6(of)-335.1(Treatment)-333.7(D)]TJ /F8 1 Tf 11.7986 -2.0233 TD [(SDX)-18205.3(d-MPH)]TJ -6.0447 -1.9917 TD [(Day)-333(1)-8181.4(Day)-333(4)-7934.8(Day)-333(1)-7435.3(Day)-339.4(4)]TJ /F14 1 Tf -19.4303 -2.0866 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 65.7637 659.6218 Tm (max)Tj 8.9663 0 0 8.9663 80.3905 661.0959 Tm [(\(ng/mL\))-12838.3(41.8)]TJ /F7 1 Tf 18.1025 0 TD ()Tj /F6 1 Tf .7145 0 TD [(23.5)-6052.5(41.7)]TJ /F7 1 Tf 9.7183 0 TD ()Tj /F6 1 Tf .7145 0 TD [(38.0)-6552(14.9)]TJ /F7 1 Tf 10.2178 0 TD ()Tj /F6 1 Tf .7145 0 TD [(3.9)-5553.5(20.0)]TJ /F7 1 Tf 8.7193 0 TD ()Tj /F6 1 Tf .7145 0 TD (4.7)Tj /F14 1 Tf -51.9174 -1.1065 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 64.7433 649.6439 Tm (max)Tj 8.9663 0 0 8.9663 79.37 651.1746 Tm [(\(h\))-15128.1(2.18)]TJ /F7 1 Tf 18.2163 0 TD ()Tj /F6 1 Tf .7145 0 TD [(1.0)-7052(1.8)]TJ /F7 1 Tf 9.7183 0 TD ()Tj /F6 1 Tf .7145 0 TD [(1.0)-7551.5(1.9)]TJ /F7 1 Tf 10.2178 0 TD ()Tj /F6 1 Tf .7145 0 TD [(0.5)-6053(1.8)]TJ /F7 1 Tf 8.7193 0 TD ()Tj /F6 1 Tf .7145 0 TD (0.4)Tj /F14 1 Tf -51.9174 -1.1128 TD (T)Tj /F6 1 Tf 6.7246 0 0 5.9768 64.7433 639.7227 Tm (1/2)Tj 8.9663 0 0 8.9663 76.3653 641.1967 Tm [(\(h\))-17157.8()-8244.1(5.5)]TJ /F7 1 Tf 28.9842 0 TD ()Tj /F6 1 Tf .7145 0 TD [(1.7)-8493.6()-7491.7(9.8)]TJ /F7 1 Tf 19.6516 0 TD ()Tj /F6 1 Tf .7145 0 TD (2.5)Tj -51.9174 -1.1128 TD (AUC)Tj 6.7246 0 0 5.9768 78.633 629.7448 Tm (024h)Tj 8.9663 0 0 8.9663 98.4756 631.2188 Tm [(\(h*ng/mL\))-9321.8(256.7)]TJ /F7 1 Tf 16.0855 0 TD ()Tj /F6 1 Tf .7145 0 TD [(108.5)-5046.6(241.2)]TJ /F7 1 Tf 9.7183 0 TD ()Tj /F6 1 Tf .7145 0 TD [(159.9)-5552.5(159.3)]TJ /F7 1 Tf 10.2178 0 TD ()Tj /F6 1 Tf .7145 0 TD [(38.3)-4553.9(215.4)]TJ /F7 1 Tf 8.7193 0 TD ()Tj /F6 1 Tf .7145 0 TD (49.4)Tj -51.9174 -1.1065 TD (AUC)Tj 6.7246 0 0 5.9768 78.633 619.7668 Tm (0last)Tj 8.9663 0 0 8.9663 97.7952 621.2975 Tm [(\(h*ng/mL\))-11591.8()-7238.8(246.9)]TJ /F7 1 Tf 26.5942 0 TD ()Tj /F6 1 Tf .7145 0 TD [(161.0)-7493.6()-6492.6(280.5)]TJ /F7 1 Tf 19.6516 0 TD ()Tj /F6 1 Tf .7145 0 TD (69.8)Tj -51.9174 -1.1128 TD (AUC)Tj 6.7246 0 0 5.9768 78.633 609.7888 Tm (0inf)Tj 8.9663 0 0 8.9663 95.8677 611.3195 Tm [(\(h*ng/mL\))-11806.7()-7238.8(248.6)]TJ /F7 1 Tf 26.8091 0 TD ()Tj /F6 1 Tf .7145 0 TD [(160.8)-7493.6()-6492.6(291.7)]TJ /F7 1 Tf 19.6516 0 TD ()Tj /F6 1 Tf .7145 0 TD (69.1)Tj -51.9174 -1.1128 TD [(Clearance)-341.5(\(CL/L/Kg\))-11479.9()-7238.8(36.67)]TJ /F7 1 Tf 30.8368 0 TD ()Tj /F6 1 Tf .7145 0 TD [(1.633)-7493.6()-6992.2(2.44)]TJ /F7 1 Tf 19.6516 0 TD ()Tj /F6 1 Tf .7145 0 TD (0.65)Tj 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)f4:oNlݭD&Dh²k͑/;Ě|ä~Юgi"Dun9+4,Yj")؜lS˫yGg/$*_F:/ȯ,C_GY UYZ*C}'oR^?5}U3ʐ_|q~H|t|qIy|׼}U3ʐ_|qTO_L<W2jf!WS7/̟Hy{dT*C}'ƯoR^?5}U3ʐ_|qTO_L<W2jf!WS7/̟Hy{dT*C}'ƯoR^?5}U3ʐ_|qTO_L<W2ja?%.Ak5Vђ9/WHy{dT*C}'ƯoR^?5}U3ʐ_|qTO_L<W2jf!WS7/̟SU][JѬ^iA/Z57") Ϙ08YUUz!WS7/̟Hy{dT*K@7}U2I?/oRz_q$+%? <z>.[QEƣkWfeʐ_|qߗ+mA5R.bHe5yG%]9y PHMQV-ŔבXY4d-)@np6lٳ@Or/+y̧[Vf͛6ٳ͛6ٳ͛6ٳyO2yԳ۲̴ܖe7▍TDpo*C Z8'~R˱4XԭDqmmwa -0SmLf͛6lٳf͛6lٳf͛6lٳd)?,3jamuO#ZlPG2[%]{oMסoXA j8P^J%K' 9&͛6lٳf͛6lٳf͛6lٳf͛6lX#oHx 8^v~lhߚe Ir%ATz|2g8e(YX$qhTO@0C󎉭\k&6pj*F[k zX͍֔ƫ{#2X,RMZ8&9ҒԌ6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfA>/Wb[{PGrjȫ'텷>Bk.۩/n|:\OIP2TKW>ɮj>Z/!&XZ[izm$56!}MzT`qmMt?J!󙕄xfvk:d_(I`#6( Xʑ #}/ZP\ʄF@C{@I_΍6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛66_ߧCNI_G!V~W~үدқctoGYUK?W~_I=:Suf͛6lٳf͛6lٳf͛6l endstream endobj 74 0 obj <>stream /GS1 gs BT /F6 1 Tf 8.9663 0 0 8.9663 62.022 582.7463 Tm 0 0 0 rg 0 Tc 0 Tw [(postdose,)-336.6(plasma)-339.4(d-MPH)-337.9(concentrations)-334.8(began)-337.5(to)-338.2(rise,)-333.7(with)-338.2(peak)]TJ 0 -1.2266 TD 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[(To)-308.7(achieve)-307.4(late-day)-311.2(efcacy,)-307.5(some)-308.7(extended-duration)-309.5(products)]TJ -1.1128 -1.2266 TD [(incorporate)-318.6(a)-311.7(second)-312.9(MPH)-317.3(peak,)-315.6(potentially)-310.4(increasing)-317.7(the)-314.8(likeli-)]TJ 0 -1.2203 TD [(hood)-421.7(of)-425.3(AEs)-420.2(later)-424(in)-420.4(the)-422.3(day,)-427.5(either)-423.5(from)-417.8(high)-425.7(exposure)-422(levels)]TJ 27.9978 58.6071 TD [(during)-427.3(the)-422.3(second)-426.7(peak)-426.5(or)-418.9(from)-424.1(a)-425.6(precipitous)-426.3(drop)-424.3(in)-420.4(exposure)]TJ 0 -1.2266 TD [(following)-253.8(the)-251.6(second)-256(peak.)-246.1(These)-256.3(symptoms)-249.8(can)-256.3(be)-248(severe)-254.7(enough)]TJ 0 -1.2203 TD [(to)-483.6(lead)-487.4(to)-477.3(treatment)-489(discontinuation)-480.4(in)-483.6(some)-485.7(patients.)-485(The)-481.3(PK)]TJ T* [(prole)-314.5(of)-317.8(SDX/d-MPH,)-316.4(which)-310.8(consists)-313.6(of)-317.8(a)-311.8(single)-312.2(peak)-312.7(and)-317.1(shal-)]TJ 0 -1.2267 TD [(lower)-408.2(decline)-410.2(in)-407.7(d-MPH)-407.4(plasma)-402.7(concentrations,)-413.6(may)-402.8(promote)-407.5(a)]TJ 0 -1.2203 TD [(more)-284.8(consistent)-280(drug)-285.2(effect)-279.1(throughout)-284(the)-276.9(day.)]TJ 1.1128 -1.2203 TD [(Determining)-394(the)-390.7(predictability)-393.9(of)-387.3(d-MPH)-394.8(exposure)-390.4(across)-392.6(the)]TJ -1.1128 -1.2203 TD [(clinical)-228.1(dose)-223(range)-220(is)-219.2(important)-224.9(for)-218.7(appropriate)-223.8(titration)-223.1(in)-218(patients.)]TJ 0 -1.2266 TD [(Accordingly,)-572.8(in)-559.5(the)-567.7(present)-565.6(study,)-568.4(a)-564.7(power)-562.3(model)-563.9(regression)]TJ 0 -1.2203 TD [(analysis)-308.5(showed)]TJ /F8 1 Tf 6.8857 0 TD (C)Tj /F6 1 Tf 6.7246 0 0 5.9768 380.8062 482.6266 Tm (max)Tj 8.9663 0 0 8.9663 395.1495 484.1007 Tm [(and)-304.5(AUC)]TJ 6.7246 0 0 5.9768 429.6755 482.6266 Tm [(0i)-8.9(nf)]TJ 8.9663 0 0 8.9663 446.6833 484.1007 Tm [(to)-300.2(be)-304.9(dose)-298.8(proportional)-304.7(at)-302.6(all)]TJ -14.9031 -1.2203 TD [(dosage)-376.1(strengths,)-368(indicating)-370.1(predictable)-373.1(exposure)-371.5(and)-367.7(the)-365.4(oppor-)]TJ 0 -1.2266 TD [(tunity)-281(for)-282(initial)-284.7(dose)-279.9(titration)-280(and)-279.2(ongoing)-285.1(dose)-279.9(adjustments.)]TJ 1.1128 -1.2203 TD [(Children)-292.1(receiving)-285.4(ADHD)-289.5(medications)-290.6(may)-282.7(experience)-292(uncon-)]TJ -1.1128 -1.2203 TD [(trolled)-222.3(symptoms)-218.2(in)-218(the)-220(early)-224(morning)-215.4(and)-215.9(the)-220(early)-224(evening)-220.4(hours,)]TJ 0 -1.2266 TD [(resulting)-475.4(in)-464.6(an)-469.3(increased)-474.7(burden)-463.7(for)-471.6(children)-473.1(and)-468.8(their)-465.9(parents)]TJ 0 -1.2203 TD [(\(Whalen)-408.3(et)-410.1(al.)-400.4(2006;)-406.3(Sallee)-409.3(2015\).)-401.4(Data)-408.5(from)-405.1(the)-403.3(present)-407.6(study)]TJ T* [(suggest)-233(that)-236.1(the)-232.6(PK)-228.5(characteristics)-239.5(of)-229.2(SDX/d-MPH)-231.3(may)-232.1(offer)-235.4(more)]TJ 0 -1.2266 TD [(desirable)-248.6(symptom)-242.8(management)-249.8(from)-240.7(early)-249.3(morning)-240.7(through)-243.5(early)]TJ 0 -1.2203 TD [(evening.)-191.7(Specically,)-193.5(the)-188.3(long)-191.8(half-life)-191(of)-191.3(d-MPH)-186.1(may)-194.2(delay)-189.8(loss)-187.8(of)]TJ T* [(efcacy)-285.6(near)-283.7(the)-283.2(end)-279.2(of)-279.8(the)-283.2(day)-279.2(without)-283.8(the)-283.2(need)-281.1(for)-282(additional)-281.6(or)]TJ T* [(higher)-322.3(doses,)-327.7(and)-317.1(attenuate)-327.2(potential)-326.3(rebound)-317.7(effects)-324.1(that)-324.7(may)-320.6(be)]TJ 0 -1.2266 TD [(engendered)-260.3(by)-251.9(faster)-258.9(elimination)-257(of)-254.5(d-MPH.)-252.3(In)-254.5(addition,)-253.8(the)-257.9(SDX/)]TJ 0 -1.2203 TD [(d-MPH)-344.2(PK)-342.3(attributes)-342.3(reported)-345.3(in)-338.2(the)-340.1(current)-345.8(study)-344.2(are)-341.1(consistent)]TJ T* [(with)-464.6(the)-460.2(efcacytime)-461.6(prole)-460(determined)-459.2(in)-458.3(a)-463.5(separate)-462.5(trial)-457.2(in)]TJ 0 -1.2266 TD [(children)-201.3(612)-200.4(years)-202.2(of)-197.6(age)-199.4(with)-199.1(ADHD)-201(who)-197.8(were)-198.5(treated)-204.2(with)-199.1(daily)]TJ 0 -1.2203 TD [(doses)-286.9(of)-279.8(SDX/d-MPH)-281.9(\(Kollins)-280.8(et)-277.3(al.)-286.6(2021\).)]TJ /F4 1 Tf 0 -2.3837 TD (Conclusions)Tj /F6 1 Tf 1.1128 -1.8273 TD [(The)-297.9(new)-295.1(treatment)-299.3(containing)-296.5(a)-292.8(coformulation)-297.5(of)-292.5(SDX/d-MPH)]TJ -1.1128 -1.2267 TD [(exhibits)-214.1(a)-210.6(single)-211(d-MPH)-211.4(plasma)-213(concentration)-214(peak)]TJ /F15 1 Tf 20.6886 0 TD (*)Tj /F6 1 Tf .999 0 TD [(2)-208.2(hours)-210(after)]TJ -21.6876 -1.2203 TD [(administration,)-230.7(followed)-221.1(by)-226.6(a)-223.2(gradual)-223(elimination)-225.4(phase)-224.9(dened)-228.1(by)]TJ T* [(a)-533.1(long)-526.9(half-life)-532.5(of)-526.4(10.8)-526.3(hours.)-529.1(The)-531.9(immediate-release)-531.3(d-MPH)]TJ 0 -1.2267 TD [(component)-286.2(accounts)-286.8(for)-288.3(the)-283.2(rapid)-284.8(increase)-291.8(in)-281.3(plasma)-288.9(d-MPH)-281(con-)]TJ 0 -1.2203 TD [(centrations,)-305.2(while)-302.2(the)-295.8(SDX)-300.9(component)-298.9(provides)-297.2(sustained)-301.7(plasma)]TJ T* [(d-MPH)-432.7(concentrations)-436(through)-426.8(the)-434.9(evening)-429.1(hours.)-427.9(SDX/d-MPH)]TJ 0 -1.2266 TD [(also)-321.8(exhibited)-316(dose)-317.8(proportionality)-317.6(across)-316.7(the)-314.8(dose)-317.8(range)-321.1(studied,)]TJ 0 -1.2203 TD [(thus)-426.9(providing)-423.6(predictable)-430(increases)-425.3(in)-420.4(d-MPH)-426.4(exposure)-428.4(during)]TJ T* [(dose)-260.9(titration)-254.7(or)-254.5(when)-256.7(making)-260(later)-253.3(dose)-260.9(adjustments.)-254.3(Upon)-254.3(repeat)]TJ 0 -1.2266 TD [(dosing)-299.5(of)-298.8(SDX/d-MPH,)-297.5(there)-299.9(was)-296.3(low)-296.7(to)-300.2(modest)-299.1(accumulation)-297.6(of)]TJ 0 -1.2203 TD [(d-MPH)-533.9(but)-533.7(not)-527.4(the)-529.8(intact)-532.4(prodrug,)-535.8(SDX.)-531.4(Steady-state)-530.4(plasma)]TJ T* [(concentrations)-284.3(were)-287(achieved)-281.7(before)-279(the)-283.2(third)-280.1(dose.)]TJ 1.1128 -1.2203 TD [(Together,)-187.3(these)-178.3(data)-183.9(indicate)-186.1(that)-185.6(SDX/d-MPH)-180.7(may)-181.5(offer)-184.8(a)-185.3(novel)]TJ -1.1128 -1.2267 TD [(treatment)-349.8(capable)-351.7(of)-343.1(addressing)-344.1(current)-345.8(unmet)-349(needs)-345(for)-345.2(patients)]TJ 0 -1.2203 TD [(with)-186.4(ADHD)-188.3(as)-179.7(they)-187.9(relate)-185.7(to)-180.1(symptom)-185.9(control)-180.4(during)-187.1(waking)-183.9(hours.)]TJ /F4 1 Tf 0 -2.447 TD [(Clinical)-341.3(Signicance)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(Current)-335.4(d-MPHbased)-341(treatments)-337.9(leave)-337.6(unmet)-336.3(needs)-332.4(for)-338.9(some)]TJ -1.1128 -1.2203 TD [(patients)-690.7(with)-685.9(ADHD)-687.8(and)-683.8(their)-687.2(families.)-693.5(The)-683.7(present)-685.8(study)]TJ ET 62.022 720.113 490.167 .22681 re f 62.022 634.847 490.167 .28351 re f 103.294 701.234 82.318 .22675 re f 194.967 701.234 82.261 .22675 re f 286.583 701.234 82.318 .22675 re f 378.255 701.234 82.261 .22675 re f 469.927 701.234 82.261 .22675 re f 62.022 673.568 490.167 .22675 re f BT /F10 1 Tf 8.9663 0 0 8.9663 130.4503 725.7825 Tm (Table)Tj /F6 1 Tf 3.0034 0 TD (5.)Tj /F10 1 Tf 1.2456 0 TD [(Summary)-336.7(of)-335.1(Treatment-Emergent)-334.8(Adverse)-333.4(Events)-337.9(in)-331.6(the)-333.5(Safety)-336.7(Population)]TJ /F8 1 Tf -7.0184 -2.0233 TD [(Treatment)-334(A)-334.4(\()]TJ /F6 1 Tf 5.7286 0 TD (N)Tj /F7 1 Tf .8852 0 TD (=)Tj /F8 1 Tf .7208 0 TD [(23\))-1556.6(Treatment)-334(B)-334.4(\()]TJ /F6 1 Tf 8.6118 0 TD (N)Tj /F7 1 Tf .8852 0 TD (=)Tj /F8 1 Tf .7208 0 TD [(24\))-1531.3(Treatment)-334(C)-333(\()]TJ /F6 1 Tf 8.6434 0 TD (N)Tj /F7 1 Tf .8852 0 TD (=)Tj /F8 1 Tf .7208 0 TD [(23\))-1474.4(Treatment)-340.4(D)-331.6(\()]TJ /F6 1 Tf 8.6434 0 TD (N)Tj /F7 1 Tf .8852 0 TD (=)Tj /F8 1 Tf .7145 0 TD [(23\))-2505(Overall)-336.4(\()]TJ /F6 1 Tf 7.5685 0 TD (N)Tj /F7 1 Tf .8852 0 TD (=)Tj /F8 1 Tf .7208 0 TD (24\))Tj -47.4787 -1.9917 TD (Participants,)Tj /F6 1 Tf 1.4416 -1.1128 TD (n)Tj /F8 1 Tf .8346 0 TD (\(%\))Tj 3.9771 1.1128 TD (Events,)Tj /F6 1 Tf 1.214 -1.1128 TD (n)Tj /F8 1 Tf 2.7568 1.1128 TD (Participants,)Tj /F6 1 Tf 1.4353 -1.1128 TD (n)Tj /F8 1 Tf .8346 0 TD (\(%\))Tj 3.9834 1.1128 TD (Events,)Tj /F6 1 Tf 1.214 -1.1128 TD (n)Tj /F8 1 Tf 2.7505 1.1128 TD (Participants,)Tj /F6 1 Tf 1.4416 -1.1128 TD (n)Tj /F8 1 Tf .8346 0 TD (\(%\))Tj 3.9771 1.1128 TD (Events,)Tj /F6 1 Tf 1.214 -1.1128 TD (n)Tj /F8 1 Tf 2.7568 1.1128 TD (Participants,)Tj /F6 1 Tf 1.4353 -1.1128 TD (n)Tj /F8 1 Tf .8346 0 TD (\(%\))Tj 3.9834 1.1128 TD (Events,)Tj /F6 1 Tf 1.214 -1.1128 TD (n)Tj /F8 1 Tf 2.7568 1.1128 TD (Participants,)Tj /F6 1 Tf 1.4353 -1.1128 TD (n)Tj /F8 1 Tf .8346 0 TD (\(%\))Tj 3.9771 1.1128 TD (Events,)Tj /F6 1 Tf 1.214 -1.1128 TD (n)Tj -52.9544 -2.0866 TD [(TEAE)-3023.1(3)-334.6(\(13.0\))-3236.7(3)-3236.8(5)-334.6(\(20.8\))-3236.7(5)-3230.5(6)-334.6(\(26.1\))-3236.7(8)-2983.9(1)0(5)-334.1(\(65.2\))-2737.2(39)-2736.8(19)-334.1(\(79.2\))-2737.2(55)]TJ 0 -1.1065 TD (Related)Tj .999 -1.1128 TD (TEAE)Tj 4.5841 1.1128 TD [(2)-334.6(\(8.7\))-3736.7(2)-3236.8(5)-334.6(\(20.8\))-3236.7(5)-3230.5(5)-334.6(\(21.7\))-3236.7(7)-2983.9(1)0(4)-334.1(\(60.9\))-2737.2(37)-2736.8(17)-334.1(\(70.8\))-2737.2(51)]TJ 7.9702 0 0 7.9702 70.0157 623.0549 Tm [(Treatment)-329(A:)-338.3(SDX/d-MPH)-326.8(26.1/5.2)-154.7(mg;)-337.2(total)-336.8(equivalent)-332.9(d-MPH)-326.7(HCl,)-339.9(20)-159.4(mg.)-339.8(Treatment)-329(B:)-340.5(SDX/d-MP)15(H)-341.9(39.2/7.8)-154.7(mg;)-337.2(total)-336.8(equivalen)12.1(t)-345(d-MPH)-326.7(HCl,)]TJ -1.003 -1.1239 TD [(30)-166.6(mg.)-325.5(Treatment)-329(C:)-326.3(SDX/d-MPH)-326.8(52.3/10.4)-152.6(mg;)-330.1(total)-329.7(equivalent)-325.8(d-MPH)-326.7(HCl,)-325.6(40)-166.6(mg.)]TJ 1.003 -1.1239 TD [(d-MPH,)-325.7(dexmeth)13.2(ylphenidate;)-327.2(SDX,)-329.9(serdexme)13.1(thylphenidate;)-321.5(TEAE,)-326.9(treatment-em)9.9(ergent)-330.2(adverse)-326.9(event.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (294)Tj 44.5765 0 TD [(BRAECKMAN)-335.4(ET)-338.7(AL.)]TJ ET endstream endobj 78 0 obj <>stream /GS1 gs BT /F6 1 Tf 8.9663 0 0 8.9663 59.7543 725.7825 Tm 0 0 0 rg 0 Tc 0 Tw [(demonstrated)-307.6(key)-298.1(PK)-298.1(characteristics)-302.7(of)-298.8(a)-299.1(novel)-301.2(prodrug)-299(coformu-)]TJ 0 -1.2203 TD [(lated)-370.8(with)-363.5(d-MPH)-369.5(that)-362.6(may)-364.9(address)-366.8(some)-371.9(of)-362(these)-368(unmet)-367.9(needs,)]TJ 0 -1.2266 TD [(namely,)-467.6(a)-457.2(rapid)-461.9(onset)-466.8(of)-456.9(d-MPH)-464.3(exposure)-460(followed)-461.4(by)-460.6(a)-463.5(very)]TJ 0 -1.2203 TD [(gradual)-254.6(decline)-252.1(until)-249.9(the)-251.6(next)-251.1(dose.)-251.2(This)-256(PK)-247.5(prole)-251.3(can)-256.3(potentially)]TJ T* [(treat)-379.8(ADHD)-378(symptoms)-376.3(consistently)-377.8(from)-379.8(early)-375.7(morning)-373.5(through)]TJ 0 -1.2266 TD [(early)-255.6(evening.)-255(Individual)-252.5(patient)-253.7(titration)-254.7(and)-253.9(potential)-256.8(subsequent)]TJ 0 -1.2203 TD [(dose)-229.3(changes)-226.3(are)-227.3(facilitated)-235.7(by)-220.3(consistent)-229.4(and)-228.6(predictable)-227.6(exposure)]TJ T* [(across)-285.1(the)-283.2(available)-282.9(dose)-279.9(range.)]TJ /F4 1 Tf 0 -2.5545 TD (Disclosures)Tj /F6 1 Tf 1.1128 -1.8336 TD [(All)-250.1(authors)-247.1(were)-255.4(responsible)-252.8(for)-244(the)-251.6(study)-249.4(design,)-247.9(data)-253.5(analysis,)]TJ -1.1128 -1.2266 TD [(and)-355(interpretation)-360.8(and)-355(provided)-352.9(critical)-357.1(review)-353.3(and)-355(editing)-352.5(of)-355.7(all)]TJ 0 -1.2203 TD [(drafts)-383(of)-374.7(the)-378(article.)-375.5(R.B.,)-377.6(A.B.,)-382.5(T.C.M.,)-375.8(S.G.,)-376.4(and)-374(A.S.)-379.8(are)-379(em-)]TJ T* [(ployees)-284.8(and)-279.2(shareholders)-284.9(of)-279.8(KemPharm,)-281(Inc.)-278.4(C.O.)-284.8(is)-276.1(an)-279.6(employee)]TJ 0 -1.2266 TD [(and)-285.5(shareholder)-277.9(of)-286.2(Ӱ,)-280.4(Inc.)]TJ /F4 1 Tf 0 -2.4406 TD [(Supplementary)-341.9(Material)]TJ /F6 1 Tf 1.1128 -1.8336 TD [(Supplementary)-285.6(Data)-282.1(S1)]TJ /F4 1 Tf -1.1128 -2.447 TD (References)Tj /F6 1 Tf 8.4682 0 0 8.4682 59.7543 489.5432 Tm [(Bra)13.3(eck)14.9(man)-407.6(R,)-416.3(Bar)13.3(ret)16.6(t)-422(A)0(,)-417.8(G)0(u)12.9(ent)16.2(her)-413.8(S,)-416.5(Mi)14.5(ckl)16.2(e)-423.3(TC,)-411.5(Co)14.5(rlis)21.4(s)-425.1(M)0(:)-414(Mas)16.5(s)]TJ 1.0042 -1.2385 TD [(bal)16.2(anc)14.9(e)-503.7(and)-494.5(met)16.1(abo)14.3(li)13(c)-503.7(pat)16.2(hway)-486.1(fol)16.1(low)12.8(ing)-493.1(or)16.2(al)-503.8(adm)20.8(ini)17.6(str)14.9(atio)22.7(n)-504.2(o)0(f)]TJ 0 -1.2318 TD [([1)16.2(4C)21.2(]-)16.6(se)21.9(rd)16.2(ex)16.4(me)22.9(th)17.8(yl)17.8(ph)22.6(en)16.4(i)13.2(d)0(a)16.4(t)13.2(e,)-213.5(a)-215.8(n)0(o)22.6(v)0(e)16.4(l)-221.1(pr)22.9(od)15.9(ru)22.9(g)-216.3(o)0(f)-211.4(d)0(-)22.9(m)0(e)16.2(t)13.2(hy)15.9(l)13.2(p)0(h)15.9(e)0(n)23.1(i)0(d)17.8(a)0(t)18.3(e)0(.)]TJ 0 -1.2385 TD 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