Apr, 2010

A Model-based approach to dose selection in early pediatric development


Authors: Cella M, Gorter de Vries F, Burger D, Danhof M, Della Pasqua O.

Published in: Clinical Pharmacology and Therapeutics, 2010, 87(3):294-302.

Abstract The establishment of a rationale for determining dosing regimens in pediatric patients remains a challenge in drug development. In this investigation, we explored several methodologies to support bridging studies and evaluated the best descriptor of developmental changes that can be used as a covariate for dose adjustment in children. The proposed approach is illustrated for the antiviral drug abacavir. Using data from six pharmacokinetic studies in adults and one study in children, a model-based analysis was applied in order to characterize differences in parameter distributions and their implications for systemic exposure to abacavir. Simulations were subsequently performed to define the appropriate dosing regimen in children. Although body weight was identified as a covariate for clearance and volume, dosing recommendations calculated on the basis of mg/kg cannot be linearly applied across all weight ranges. Our analysis shows the consequences of empirical dose adjustment and the importance of priors from historical data to support dose selection in children.


Apr, 2006

Adherence and acceptability of once daily lamivudine and abacavir in HIV-1 infected children


Authors: LeProvost M, Green H, Flynn J, et al; on behalf of the PENTA 13 study group.

Published in: Pediatr Infect Dis J. 2006;25(6):533-7

Background Data on adherence to and acceptability of once daily lamivudine and abacavir are few.

Methods Twenty-four U.K. human immunodeficiency virus type-1 infected children 2-13 years of age participated in the Pediatric European Network for the Treatment of AIDS (PENTA) 13 single arm, open label pharmacokinetic study of twice (every 12 hours) versus once (every 24 hours) daily lamivudine and abacavir. Caregivers were asked to complete an adherence questionnaire at screening, week 0 (switch once daily to twice daily) and weeks 4, 12 and 24. Acceptability was also assessed at screening and week 24.

Results Fifteen children were taking lamivudine and abacavir as part of their regimens, 8 lamivudine only and 1 abacavir only. After switching to lamivudine/abacavir every 24 hours, 7 (29%) received once daily regimens for all drugs. Twenty-three (96%) caregivers thought that switching to once daily lamivudine/abacavir would make things a lot/a little easier for their child: 17 (71%) thought it was actually easier after switching. Six mothers with children taking a mixture of twice/once daily drugs changed their mind, whereas all mothers of children on once daily regimens agreed that it was a lot easier. Nonadherence (missing doses in the last 3 days) was reported for 8 of 118 (7%) completed questionnaires; missed doses were reported for every drug in the regimen with reasons such as “not at home,” “forgot” or “routine different from normal.” However, viral loads in all these children remained <100 copies/mL.

Conclusion Adherence to once daily abacavir/lamivudine was good with no evidence of an association between nonadherence and virologic rebound. Acceptability of once daily drugs was best when the whole regimen was dosed once daily.


Jul, 2005

Adherence and acceptability of once daily lamivudine and abacavir in HIV-1 infected children


Authors: LeProvost M, Green H, Flynn J, et al: on behalf of the PENTA 13 study group.

Published in: 3rd IAS Conference on HIV Pathogenesis and Treatment, 24-27 July 2005, Rio de Janerio. Poster MoPe9.2C03


Apr, 2005

Pharmacokinetics of once versus twice daily lamivudine and abacavir. Simplification of combination treatment in HIV-1 infected children (Penta 13)


Authors: Bergshoeff A, Burger D, Verweij C, et al; on behalf of the PENTA 13 study group

Published in: Antivir Ther. 2005; 10:239-246

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.

Conclusions 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.



Feb, 2004

Pharmacokinetics (PK) of once daily versus twice daily Lamivudine and Abacavir in HIV-1 infected children: PENTA 13


Authors: Bergshoeff A, Burger D, Verweij C, Farrelly L, Flynn J, LeProvost M, Walker AS, Novelli V, Lyall H, Gibb DM.

Published in: 11th Conference of Retroviruses and Opportunistic Infections, San Francisco, 8-11 February 2004. Poster 934.