Integrated Population Pharmacokinetic Model Development of Nevirapine for Mothers and Newborns including Healthy Male Volunteer Data
M. Frank (1), JS. Van der Walt (3,4), A. Kunz (5), G. Harms (5), C. Kloft (1, 2)
(1) Department of Clinical Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg, Halle, Germany; (2) Department of Clinical Pharmacy, Freie Universitaet Berlin, Berlin, Germany; (3) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (4) Department of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa; (5) Institute of Tropical Medicine, Charité – University Medicine Berlin, Germany.
Objectives: A population pharmacokinetic (PK) model of nevirapine (NVP) was developed to describe the population PK of NVP after single dose administration during prevention of mother-to-child (PMTCT) HIV transmission. . Autoinduction of CYP3A and CYP2B6 pathways limits the use of NVP models developed from steady-state data in PMTCT . Sparse data in pregnant women/mothers and newborns were supplemented with rich single dose data in healthy male volunteers.
Methods: In Uganda NVP-based prophylaxis consisted of 200 mg NVP tablets for women and 2 mg/kg NVP syrup for newborns. Healthy males received 200 mg NVP. The PK analysis was supported by 113 plasma data of mothers (N=62) and newborns (N=62) and 95 breast milk samples. In a first step an integrated PK model for mothers/newborns was developed using the NLME approach implemented in NONMEM VI (ADVAN6). Subsequently, 390 plasma samples of 26 healthy males were added to the analysis. Data were analysed with NONMEM VI (all FOCE INTER). Model fit and performance were guided by various diagnostic tools.
Results: Based on a previously published integrated PK model , further model development focused on mother and newborn plasma data only . In a subsequent step, milk data was included to incorporate breastfeeding. Due to sparse data the absorption rate constant (KA=1.34 1/h) was fixed (interindividual variabilitiy (IIV): 170% CV). The volume of distribution and clearance estimates for mothers were V/F=101 L (IIV: 31% CV), CL/F=1.4 L/h (IIV: 31% CV) and for newborns V/F=14.8 L and CL/F=0.2 L/h (IIV: 13% CV), respectively. NVP plasma/placental transfer was estimated to be 89 L/h and the partition coefficient was estimated to be 1.24. The precision of estimates was <35%, except IIV of newborn CL (53%).
In the final step healthy male plasma data were added to support the integrated PK model. KA was estimated to be 0.9 1/h (IIV: 128% CV) for mothers and healthy males. All other parameter estimates revealed similar values and good precision (RSE<29%), except IIV newborn CL (48%). Both integrated models presented adequate model fit and predictive performance.
Conclusions: A population PK model integrating single dose NVP data from pregnant women, newborns and healthy volunteers was developed to guide dosing regimens for newborns to assist MTCT strategies.
 The German HIV Practice Collection. Prevention of mother-to-child transmission of HIV in Kenya, Tanzania and Uganda, (2007). [www.charite.de/tropenmedizin/AIDS1.htm.
 Sabo JP, Lamson MJ, Leitz G, Young CL, MacGregor TR. Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection. AAPS PharmSci., 2: E1 (2000).
 Frank M, Kunz A, Harms G, J.S. Van der Walt, Kloft C. Population pharmacokinetic model building for mothers and newborns using additional information from a different nevirapine dataset. PAGE (2010). Abstr 1814 [www.page-meeting.org/?abstract=1814].
 von Kleist M, Frank M, Kunz A, Harms G, Schütte C, Kloft C. A Mathematical Modelling Framework to Assess the Impact of Nevirapine-based Prophylaxis on vertical HIV Transmission. Abstract submitted to PAGE (2011).