2010 - Berlin - Germany

PAGE 2010: Applications- Anti-infectives
Monika Frank

Population Pharmacokinetic Model Building for Mothers and Newborns using Additional Information from a Different Nevirapine Dataset

M. Frank (1), A. Kunz (2), G. Harms (2), JS. Van der Walt (3,4), C. Kloft (1)

(1) Martin-Luther-Universitaet Halle-Wittenberg, Dept. Clinical Pharmacy, Halle, Germany; (2) Institute of Tropical Medicine, Charité – University Medicine Berlin, Germany;

Objectives: Risk of HIV transmission from mother to newborn could be reduced by prophylaxis of nevirapine (PMTCT). 62 HIV-1 mothers and newborns received nevirapine-based (NVP) PMTCT. Due to sparse data population pharmacokinetic (PK) analysis was performed to describe NVP PK in mothers and newborns. Data of NVP in healthy men from a clinical study were used to supplement the sparse data.

Methods: Medication was a single oral dose of 200 mg NVP tablet for pregnant women and healthy males and 2 mg/kg NVP syrup for newborns. For PK analysis 113 mother and newborn plasma and 95 breast milk samples were available. Investigation of PK in 26 men resulted in 15 plasma samples per subject. Firstly a combined population PK model for mothers/newborns was developed using NLME approach implemented in NONMEMTM VI (ADVAN6, TOL5, FOCE INTERACTION). Appropriateness of model fit and performance was guided by various diagnostic tools.

Results: First results demonstrated appropriateness of 1-compartment (CMT) models for separate analysis of maternal and newborn data, respectively [1]. These experiences were used to build a combined model for both groups. Due to sparse data in a first step, absorption rate constant (KA) was fixed to prior reported value[2]. NVP input through plasma/placental transfer before delivery was modelled with a rate constant to link mother and newborn data. For the change of situation before/after delivery time-dependency was introduced. First results assume sufficient model performance. A transit absorption model adequately described the highly variable absorption in healthy males. For disposition PK a 1-CMT model was adequate and provided PK parameters in the same range as for the adult female population (clearance 1.5 L/h (IIV: 21% CV), KA 3.3 h-1 (IIV: 155% CV) and V 99 L (IIV: 16% CV), MTT 1 h). In a subsequent step, knowledge from population PK analysis of healthy men will be implemented in the combined PK model especially for the absorption process.

Conclusions: A first combined PK model for maternal and newborn data was developed. Due to sparse data situation additional rich data of healthy men will be used to describe the complex absorption process of NVP more adequately. Final PK model could guide dosing regime for newborns to assist prevention strategies for HIV transmission from mother-to-child.

[1] Frank M, Kunz A, Harms G, Kloft C. Population pharmacokinetic model development and evaluation after nevirapine administration to mothers and newborns. PAGE 18 (2009) Abstr 1484 [www.page-meeting.org/?abstract=1484]
[2] Kappelhoff BS, van Leth F, MacGregor TR, et al. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Antivir. Ther., 10: 145-155 (2005)

Reference: PAGE 19 (2010) Abstr 1814 [www.page-meeting.org/?abstract=1814]
Poster: Applications- Anti-infectives