Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC.
Methods
Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV/r:3TC:ZDV(ABC) dose ratios were 2.67:1:2(2), respectively.
Results
Using WHO dosage, LPV efficacy target was reached in all weight bands. Given the recommended drug ratios, the dosage for the 4–5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [bid]) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg bid decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria.
Conclusions
This defined a flexible and simple FDC containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4–5.9 kg, 6–9.9 kg, 10–13.9 kg, 14–19.9 kg, 20–24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid.
NewellM-L, CoovadiaH., Cortina-BorjaM.Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis.Lancet2004; 364: 1236–1243.
3.
PuthanakitT., AurpibulL., OberdorferP.Hospitalization and mortality among HIV-infected children after receiving highly active antiretroviral therapy.Clin Infect Dis2007; 44: 599–604.
4.
SutcliffeC.G., van DijkJ.H., BoltonC., PersaudD., MossW.J.Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa.Lancet Infect Dis2008; 8: 477–489.
SalemA.H., ChiuY., ValdesJ., NiliusA., KleinC.Assessment of bioequivalence and food effect for a complete antiretroviral fixed-dose combination of lopinavir, ritonavir, lamivudine and zidovudine.Rev Antivir Ther Infect Dis2014; 4: 30. Poster presentation.
7.
SalemA.H., ChiuY., ValdesJ., NiliusA., KleinC.Lopinavir/ ritonavir/lamivudine as a fixed-dose combination tablet: assessment of bioequivalence and effect of food on bioavailability.Rev Antivir Ther Infect Dis2014; 4: 31. Poster presentation.
8.
FoissacF., UrienS., HirtD.Pharmacokinetics and virological efficacy after switch to once-daily lopinavir-ritonavir in treatment-experienced HIV-1-infected children.Antimicrob Agents Chemother2011; 55: 4320–4325.
9.
JullienV., UrienS., HirtD.Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years.Antimicrob Agents Chemother2006; 50: 3548–3555.
10.
NikanjamM., ChadwickE.G., RobbinsB.Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band-based dosing.Clin Pharmacol Ther2012; 91: 243–249.
11.
UrienS., FirtionG., AndersonS.T.Lopinavir/ritonavir population pharmacokinetics in neonates and infants.Br J Clin Pharmacol2011; 71: 956–960.
12.
BouazzaN., HirtD., BardinC.Is the recommended once-daily dose of lamivudine optimal in West African HIV-infected children?Antimicrob Agents Chemother2010; 54: 3280–3286.
13.
BouazzaN., HirtD., BlancheS.Developmental pharmacokinetics of lamivudine in 580 pediatric patients ranging from neonates to adolescents.Antimicrob Agents Chemother2011; 55: 3498–3504.
14.
TremouletA.H., NikanjamM., CresseyT.R.Developmental pharmacokinetic changes of lamivudine in infants and children.J Clin Pharmacol2012; 52: 1824–1832.
15.
BergshoeffA., BurgerD., VerweijC.Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13).Antivir Ther2005; 10: 239–246.
16.
JullienV., UrienS., ChappuyH.Abacavir pharmacokinetics in human immunodeficiency virus-infected children ranging in age from 1 month to 16 years: a population analysis.J Clin Pharmacol2005; 45: 257–264.
17.
KlineM.W., BlanchardS., FletcherC.V.A Phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection. AIDS Clinical Trials Group 330 Team.Pediatrics1999; 103: e47.
18.
SleasmanJ.W., RobbinsB.L., CrossS.J.Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults.Clin Pharmacol Ther2009; 85: 394–401.
19.
LuzuriagaK., McManusM., MofensonL.A trial of three antiretroviral regimens in HIV-1-infected children.N Engl J Med2004; 350: 2471–2480.
20.
CrossS.J., RodmanJ.H., LindseyJ.C.Abacavir and metabolite pharmacokinetics in HIV-1-infected children and adolescents.J Acquir Immune Defic Syndr2009; 51: 54–59.
21.
CapparelliE.V., EnglundJ.A., ConnorJ.D.Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children.J Clin Pharmacol2003; 43: 133–140.
22.
ChokephaibulkitK., CresseyT.R., CapparelliE.Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children.Antivir Ther2011; 16: 1287–1295.
23.
CapparelliE.V., MirochnickM., DanknerW.M.Pharmacokinetics and tolerance of zidovudine in preterm infants.J Pediatr2003; 142: 47–52.
24.
FauchetF., TreluyerJ-M, FrangeP.Population pharmacokinetics study of recommended zidovudine doses in HIV-1-infected children.Antimicrob Agents Chemother2013; 57: 4801–4808.
25.
HirtD., WarszawskiJ., FirtionG.High exposure to zidovudine during the first 2 weeks of life and concentration-toxicity relationships.J Acquir Immune Defic Syndr2013; 63: 555–562.
26.
McDowellJ.A., ChittickG.E., RavitchJ.R., PolkR.E., KerkeringT.M., SteinD.S.Pharmacokinetics of [(14)C] abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study.Antimicrob Agents Chemother1999; 43: 2855–2861.
27.
KuhnE., LavielleM.Maximum likelihood estimation in nonlinear mixed effects models.Comput Stat Data Anal2005; 49: 1020–1038.
28.
AndersonB.J., HolfordN.H.G.Mechanism-based concepts of size and maturity in pharmacokinetics.Annu Rev Pharmacol Toxicol2008; 48: 303–332.
29.
R Development Core Team.R: a language and environment for statistical computing.Vienna, Austria: R Foundation for Statistical Computing2009.
SolasC., Poizot-MartinI., DrogoulM-PTherapeutic drug monitoring of lopinavir/ritonavir given alone or with a non-nucleoside reverse transcriptase inhibitor.Br J Clin Pharmacol2004; 57: 436–440.
32.
la PorteC.J.L., BackD., BlaschkeT.Updated guideline to perform therapeutic drug monitoring for antiretroviral agents. (Accessed 16 July 2014.) Available from http://repository.ubn.ru.nl/handle/2066/50424.
CrémieuxA.C., KatlamaC., GillotinC.A comparison of the steady-state pharmacokinetics and safety of abacavir, lamivudine, and zidovudine taken as a triple combination tablet and as abacavir plus a lamivudine-zidovudine double combination tablet by HIV-1-infected adults.Pharmacotherapy2001; 21: 424–430.
37.
DumondJ.B., ReddyY.S., TroianiL.Differential extracellular and intracellular concentrations of zidovudine and lamivudine in semen and plasma of HIV-1-infected men.J Acquir Immune Defic Syndr2008; 48: 156–162.
38.
BalisF.M., PizzoP.A., MurphyR.F.The pharmacokinetics of zidovudine administered by continuous infusion in children.Ann Intern Med1989; 110: 279–285.
39.
ZhaoW., PianaC., DanhofM., BurgerD., Della PasquaO., Jacqz-AigrainE.Population pharmacokinetics of abacavir in infants, toddlers and children.Br J Clin Pharmacol2013; 75: 1525–1535.
BouazzaN., TréluyerJ-M, GhosnJ.Evaluation of impaired renal function on lamivudine pharmacokinetics.Br J Clin Pharmacol2014; 78: 847–854.
42.
ZhouX.J., SheinerL.B., D'AquilaR.T.Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators.Antimicrob Agents Chemother1999; 43: 121–128.
