Plasma Pharmacokinetics of Once- versus Twice-Daily Lamivudine and Abacavir: Simplification of Combination Treatment in HIV-1-Infected Children (Penta-13)

Background There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children. Methods Children aged 2–13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0–24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response. Results 24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1–12.8) years] had evaluable PK data for 3TC (n=19) and/or ABC (n=14). GMRs of 3TC and ABC AUC0–24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2–6 versus 6–13 years old (P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2–6 versus 6–13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24. Conclusion AUC0–24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.

[1]  C. Farthing,et al.  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. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  D. Hoelscher,et al.  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 , 2004, Antimicrobial Agents and Chemotherapy.

[3]  C. Giaquinto,et al.  Adherence to antiretroviral therapy and its determinants in children with human immunodeficiency virus infection: a multicentre, national study , 2003, Acta paediatrica.

[4]  E. Delaporte,et al.  Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal , 2003, AIDS.

[5]  D. Gibb,et al.  Adherence to prescribed antiretroviral therapy in human immunodeficiency virus-infected children in the PENTA 5 trial , 2003, The Pediatric infectious disease journal.

[6]  E. Dejesus,et al.  Lamivudine 300 mg QD Versus Continued Lamivudine 150 mg BID with Stavudine and a Protease Inhibitor in Suppressed Patients , 2002, HIV clinical trials.

[7]  J. Montaner,et al.  Intracellular carbovir triphosphate levels in patients taking abacavir once a day. , 2002, AIDS.

[8]  J. Bilello,et al.  Pharmacodynamics of Abacavir in an In Vitro Hollow-Fiber Model System , 2002, Antimicrobial Agents and Chemotherapy.

[9]  S. Khoo,et al.  Development of Enzymatic Assays for Quantification of Intracellular Lamivudine and Carbovir Triphosphate Levels in Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus-Infected Patients , 2002, Antimicrobial Agents and Chemotherapy.

[10]  G. Aldrovandi,et al.  Antiretroviral Pharmacokinetics in the Paediatric Population , 2002, Clinical pharmacokinetics.

[11]  C. Katlama,et al.  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 , 2001, Pharmacotherapy.

[12]  R. Maserati,et al.  Virological and Immunological Responses to a Once-a-Day Antiretroviral Regimen with Didanosine, Lamivudine and Efavirenz , 2000, Antiviral therapy.

[13]  R. Bruno,et al.  Comparison of the Plasma Pharmacokinetics of Lamivudine During Twice and Once Daily Administration in Patients with HIV , 2001, Clinical pharmacokinetics.

[14]  C. Fletcher,et al.  Zidovudine triphosphate and lamivudine triphosphate concentration–response relationships in HIV-infected persons , 2000, AIDS.

[15]  D. Stein,et al.  Multiple-Dose Pharmacokinetics and Pharmacodynamics of Abacavir Alone and in Combination with Zidovudine in Human Immunodeficiency Virus-Infected Adults , 2000, Antimicrobial Agents and Chemotherapy.

[16]  C. Perry,et al.  Abacavir , 2000, Drugs.

[17]  S. Weller,et al.  Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects , 2000, Antimicrobial Agents and Chemotherapy.

[18]  J. Bartlett,et al.  Population Pharmacokinetics of Lamivudine in Adult Human Immunodeficiency Virus-Infected Patients Enrolled in Two Phase III Clinical Trials , 1999, Antimicrobial Agents and Chemotherapy.

[19]  D. Back,et al.  The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1. , 1999, AIDS.

[20]  C. Fletcher,et al.  A Phase I Study of Abacavir (1592U89) Alone and in Combination With Other Antiretroviral Agents in Infants and Children With Human Immunodeficiency Virus Infection , 1999, Pediatrics.

[21]  S. Hetherington,et al.  Safety and Pharmacokinetics of Abacavir (1592U89) following Oral Administration of Escalating Single Doses in Human Immunodeficiency Virus Type 1-Infected Adults , 1999, Antimicrobial Agents and Chemotherapy.

[22]  R. Yogev,et al.  Safety and Single-Dose Pharmacokinetics of Abacavir (1592U89) in Human Immunodeficiency Virus Type 1-Infected Children , 1999, Antimicrobial Agents and Chemotherapy.

[23]  G. E. Pakes,et al.  Clinical Pharmacokinetics of Lamivudine , 1999, Clinical pharmacokinetics.

[24]  Steven G. Deeks,et al.  Safety, Pharmacokinetics, and Antiretroviral Activity of Intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a Novel Anti-Human Immunodeficiency Virus (HIV) Therapy, in HIV-Infected Adults , 1998, Antimicrobial Agents and Chemotherapy.

[25]  J. Church,et al.  Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group. , 1996, The Journal of infectious diseases.