Esther J.H. Janssen* (1), Diane E.T. Bastiaans* (2), Pyry A.J. Välitalo (1), Annemarie MC van Rossum (3), Diana M Gibb (4,5), Evelyne Jacqz-Agrain (6,7), Hermione Lyall (8), Catherijne A.J. Knibbe (1,9), David M. Burger (2)
(1) Division of Pharmacology, LACDR, Leiden University, Leiden, the Netherlands, (2) Department of Pharmacy, Radboud University Medical Center, , Nijmegen, the Netherlands, (3) Division of Pediatric Infectious Diseases and Immunology, Erasmus MC/Sophia, Rotterdam, the Netherlands, (4) Medical Research Council/Clinical Trials Unit, London UK, (5) Department of Pediatrics, Great Ormond Street Hospital, London, UK, (6) Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Université Paris VII, Paris, France, (7) Clinical Investigation Center CIC9202, INSERM, Paris, France, (8) Department of Pediatrics, St Mary’s hospital, London, UK, (9) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: Lamivudine is a nucleoside reverse transcriptase inhibitor and used as part of antiretroviral therapy in HIV-infected children. A population pharmacokinetic analysis was performed to explore the impact of covariates on lamivudine pharmacokinetics.
Methods: Population pharmacokinetic modelling was performed in NONMEM 7.3 using data from four different studies[1-5], of which two were used for model building[1] and two for model validation[2-5]. Children (n=180) were aged 0.4-18 years (median age 6.6 years) and received a daily oral lamivudine dose of 60-300 mg. A median of 12 samples per individual was available. Different absorption models and different covariates were investigated. For the covariate analysis, different functions (e.g. power function, exponent function, maturation function) were evaluated. The model was validated internally and externally[6].
Results: A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution was 13.2 L/h and 39.0 L for a median individual of 16.6 kg, respectively. Bodyweight was identified as the most significant covariate on both apparent clearance and the apparent volume of distribution, which was implemented with a power function for both parameters. The external validation confirmed the predictive ability of the final model.
Conclusions: In this study, bodyweight alone was able to explain 19% of variation in apparent clearance and 14% of variation in apparent volume of distribution. As these covariate functions may reflect not only the development of clearance and distribution volume, but also age-dependent changes in bioavailability, further analysis, which includes intravenously administered lamivudine, is warranted in order to get insight in these age-dependent changes in parameters.
References:
[1] L’homme, R. F. A. et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS 22, 557–65 (2008).
[2] Lee, M. van der, Verweel, G., de Groot, R. & Burger, D. Pharmacokinetics of a once-daily regimen of lopinavir/ritonavir in HIV-1-infected children. Antivir. Ther. 11, 439–45 (2006).
[3] Bergshoeff, A., Burger, D., Verweij, C. & Farrelly, L. Plasma pharmacokinetics of once-versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir. Ther. 10, 239–246 (2005).
[4] Paediatric European Network for the Treatment of AIDS (PENTA). Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months. Antivir. Ther. 15, 297–305 (2010).
[5] Musiime, V. et al. Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial. Antivir. Ther. 15, 1115–24 (2010).
[6] Krekels, E. H. J., van Hasselt, J. G. C., Tibboel, D., Danhof, M. & Knibbe, C. A. J. Systematic evaluation of the descriptive and predictive performance of paediatric morphine population models. Pharm. Res. 28, 797–811 (2011).
Reference: PAGE 24 () Abstr 3395 [www.page-meeting.org/?abstract=3395]
Poster: Drug/Disease modeling - Paediatrics