Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3–<36 months.
Methods
Children with stable HIV type-1 (HIV-1) RNA levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under the plasma concentration– time curve over 24 h (AUC0–24) and the maximum concentration (Cmax) were compared using geometric mean ratios (GMRs); 90% confidence intervals (CIs) within the range of 0.80–1.25 were considered bioequivalent.
Results
A total of 18 children (4, 6 and 8 in the 3–<12, 12–<24 and 24–<36 month age ranges, respectively) provided pharmacokinetic data for abacavir (17 for lamivudine). The GMR of AUC0–24, once-daily versus twice-daily, was 1.07 (90% CI 0.92–1.23) for abacavir and 0.91 (90% CI 0.79–1.06) for lamivudine. Cmax almost doubled on once-daily versus twice-daily dosing: abacavir and lamivudine GMRs were 2.04 (90% CI 1.73–2.42) and 1.78 (90% CI 1.52–2.09), respectively. At baseline, 12, 24 and 48 weeks, 89%, 94%, 100% and 89% of children had HIV-1 RNA<400 copies/ml, respectively.
Conclusions
Bioequivalence was demonstrated on AUC0–24 between twice-daily and once-daily abacavir; very similar AUC0–24 values were seen for twice-daily and once-daily lamivudine. Given that viral load suppression rates were maintained, these data suggest that once-daily abacavir and lamivudine might be an option for children aged 3–<36 months.
References
1.
MocroftA., LedergerberB., KatlamaC.Decline in the AIDS and death rates in the EuroSIDA study: an observational study.Lancet2003; 362: 22–29.
2.
MurphyE.L., CollierA.C., KalishL.A.Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease.Ann Intern Med2001; 135: 17–26.
3.
PatersonD.L., SwindellsS., MohrJ.Adherence to protease inhibitor therapy and outcomes in patients with HIV infection.Ann Intern Med2000; 133: 21–30.
4.
ChiB.H., CantrellR.A., ZuluI.Adherence to first-line antiretroviral therapy affects non-virologic outcomes among patients on treatment for more than 12 months in Lusaka, Zambia.Int J Epidemiol2009; 38: 746–756.
5.
MontanerJ.S., ReissP., CooperD.A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial.JAMA1998; 279: 930–937.
6.
GibbD.M., GoodallR.L., GiacometV., McGeeL., CompagnucciA., LyallH.Adherence to prescribed antiretroviral therapy in human immunodeficiency virus-infected children in the PENTA 5 trial.Pediatr Infect Dis J2003; 22: 56–62.
7.
PontaliE.Facilitating adherence to highly active antiretroviral therapy in children with HIV infection: what are the issues and what can be done?Paediatr Drugs2005; 7: 137–149.
8.
ReddingtonC., CohenJ., BaldilloA.Adherence to medication regimens among children with human immunodeficiency virus infection.Pediatr Infect Dis J2000; 19: 1148–1153.
9.
StoneV.E., JordanJ., TolsonJ., MillerR., PilonT.Perspectives on adherence and simplicity for HIV-infected patients on antiretroviral therapy: self-report of the relative importance of multiple attributes of highly active antiretroviral therapy (HAART) regimens in predicting adherence.J Acquir Immune Defic Syndr2004; 36: 808–816.
10.
MaitlandD., JacksonA., OsorioJ., MandaliaS., GazzardB.G., MoyleG.J.Switching from twice-daily abacavir and lamivudine to the once-daily fixed-dose combination tablet of abacavir and lamivudine improves patient adherence and satisfaction with therapy.HIV Med2008; 9: 667–672.
11.
MolinaJ.M.Efficacy and safety of once-daily regimens in the treatment of HIV infection.Drugs2008; 68: 567–578.
12.
MaggioloF., RipamontiD., AriciC.Simpler regimens may enhance adherence to antiretrovirals in HIV-infected patients.HIV Clin Trials2002; 3: 371–378.
13.
PortsmouthS.D., OsorioJ., McCormickK., GazzardB.G., MoyleG.J.Better maintained adherence on switching from twice-daily to once-daily therapy for HIV: a 24-week randomized trial of treatment simplification using stavudine prolonged-release capsules.HIV Med2005; 6: 185–190.
14.
LePrevostM., GreenH., FlynnJ.Adherence and acceptability of once daily lmivudine and abacavir in human immunodeficiency virus type-1 infected children.Pediatr Infect Dis J2006; 25: 533–537.
15.
MoyleG.J., DeJesusE., CahnP.Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study.J Acquir Immune Defic Syndr2005; 38: 417–425.
16.
DeJesusE., McCartyD., FarthingC.F.Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial.Clin Infect Dis2004; 39: 411–418.
17.
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.
18.
KingJ.R., KimberlinD.W., AldrovandiG.M., AcostaE.P.Antiretroviral pharmacokinetics in the paediatric population: a review.Clin Pharmacokinet2002; 41: 1115–1133.
YuenG.J., WellerS., PakesG.E.A review of the pharmacokinetics of abacavir.Clin Pharmacokinet2008; 47: 351–371.
21.
Verweij-van WissenC.P., AarnoutseR.E., BurgerD.M.Simultaneous determination of the HIV nucleoside analogue reverse transcriptase inhibitors lamivudine, didanosine, stavudine, zidovudine and abacavir in human plasma by reversed phase high performance liquid chromatography.J Chromatogr B Analyt Technol Biomed Life Sci2005; 816: 121–129.
22.
MoyleG., BoffitoM., FletcherC.Steady-state pharmacokinetics of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-infected subjects.Antimicrob Agents Chemother2009; 53: 1532–1538.
23.
YuenG.J., LouY., BumgarnerN.F.Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily.Antimicrob Agents Chemother2004; 48: 176–182.
24.
JohnsonV.A., Brun-VezinetF., ClotetB.Update of the drug resistance mutations in HIV-1: spring 2008.Top HIV Med2008; 16: 62–68.
25.
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.
26.
JullienV., TreluyerJ.M., ChappuyH.Weight related differences in the pharmacokinetics of abacavir in HIV-infected patients.Br J Clin Pharmacol2005; 59: 183–188.
27.
BurgerD.M., VerweelG., RakhmaninaN.Age-dependent pharmacokinetics of lamivudine in HIV-infected children.Clin Pharmacol Ther2007; 81: 517–520.
28.
TremouletA.H., CapparelliE.V., PatelP.Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants.Antimicrob Agents Chemother2007; 51: 4297–4302.
29.
MusiimeV., FerrierA., KitakaS.B.Pharmacokinetics of once versus twice daily lamivudine and abacavir in HIV-1 infected Ugandan children in the ARROW trial.5th IAS Conference on HIV Pathogenesis. 19–22 July 2009, Cape Town, South Africa. Abstract WEPEB271.
30.
ViolariA., CottonM.F., GibbD.M.Early antiretroviral therapy and mortality among HIV-infected infants.N Engl J Med2008; 359: 2233–2244.
31.
PENTA Steering Committee.PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection.HIV Med2009; 10: 591–613.
32.
Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children.Guidelines for the use of antiretroviral agents in pediatric HIV infection.US Department of Health and Human Services (Updated 23 February 2009. Accessed 17 June 2009.) Available from http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf.
