2010 - Berlin - Germany

PAGE 2010: Applications- Other topics
Chiara Piana

Once Daily Pharmacokinetics Of Lamivudine In HIV-Infected Children

C. Piana(1), K. Adkinson(2), M. Danhof(1), , O.E. Della Pasqua(1,3)

(1) Division of Pharmacology, Leiden/Amsterdam Centre for Drug Research, The Netherlands (2) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Research Triangle Park, USA (3) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK

Objectives: The use of antiretroviral (ARV) drugs in children imposes careful considerations regarding dosing frequency and patient compliance. There may be considerable benefits for both children and caregivers if dosing frequency can be reduced to once daily for all drugs used during the course of therapy. The objective of this investigation was to assess whether once daily dosing provides similar exposure to lamivudine (3TC), as compared to the recommended b.i.d. regimen in HIV-infected children between 3 months and 12 years old.

Methods: Simulation scenarios were explored using a pharmacokinetic one-compartment model previously developed to describe drug disposition in the paediatric population. In the model body weight was found to have an effect on clearance and volume of distribution. The simulated population consisted of a cohort of 180 patients, aged between 3 months and 12 years old. 500 replicates were simulated, in which the use of solution and tablets was considered taking into account the wide age range. To ensure appropriate representation of different age groups, the WHO weight-for-age tables were used as reference for the correlation between age and body weight. Systemic exposure (AUC) and maximum peak concentration (Cmax) were derived as primary parameters of interest. In addition to median and percentiles, parameter distributions were also presented and compared to previous clinical trial data following once daily dosing. NONMEM VI was used to perform the simulations and R was used for the graphical and statistical summary of the results.

Results: The simulations show that once daily dosing of lamivudine yields comparable exposure (AUC) to historical values observed in children on a twice daily regimen of lamivudine, as well as in adults receiving lamivudine once or twice daily, both for solution and tablet administration. Given the change in dose frequency, higher Cmax are observed, but the observed values do not exceed tolerability limits.

Conclusions: Administration of lamivudine according to a once daily dosing regimen provides appropriate exposure in children aged from 3 months to 12 years. Our findings strongly suggest that the reduction in the dosing frequency to once daily may represent an improvement in treatment acceptability and adherence. Increased adherence may result in increased efficacy particularly in resource limited settings.

Reference: PAGE 19 (2010) Abstr 1896 [www.page-meeting.org/?abstract=1896]
Poster: Applications- Other topics
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