Nevirapine - Population pharmacokinetic model building and simulation for mothers and newborns
M. Frank (1), A. Kunz (2), G. Harms (2), 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: Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, is used as single-dose prophylaxis (mother: 200 mg tablet during labor, newborn: 2 mg/kg syrup within 3 d after birth) to reduce the risk of HIV intrapartum transmission in resource-limited areas. A population pharmacokinetic (PK) model was to be developed describing the sparse data situation in different matrices from Ugandan mothers and children as well as to assess the maintenance period of NVP concentrations in different individuals.
Methods: For model development 62 mothers (113 plasma, 95 breast milk samples) and 62 newborns (113 plasma samples) were available. Population PK analyses for mother and child data were separately performed using the nonlinear-mixed-effect modelling approach implemented in NONMEMTM (ADVAN6, TOL5; FOCE INTERACTION estimation method). The PK models were used for simulating entire concentration-time profiles (NONMEMTM) for different percentiles (P0.05-0.95) of the individual PK parameter distributions.
Results: An integrated 2 compartment PK model was developed for the combined mother plasma and breast milk data. Due to sparse data, absorption rate constant K12 was fixed to 1.66 h-1 [1]. V/F was estimated to be 104.3 L and CL/F to be 1.45 L/h resulting in a long half-life of 50.3 h. Inter-compartmental clearance was high, being 122 L/h. Inter-individual variability (IIV) was implemented in CL (29% CV).
A PK model for newborns was developed with K12 set to 1.66 h-1 [1]. Different input routes from mothers to newborns were combined with an estimated ‘bioavailability’ (F’) of 14% and a plasma/placenta-plasma/breast milk transfer rate constant of 4.5 h-1. V2/F and CL/F were estimated to be 22.7 L and 265 mL/h, respectively, and resulted in a half-life of 59.4 h. IIV was implemented for F’ (20% CV), V2/F (46% CV) and CL/F (42% CV). Simulated concentration-time profiles revealed a long-term exposure for mothers and newborns with NVP above IC90 (= 16 ng/mL) for 10-24 d and 10-27 d (P0.05-P0.95), respectively.
Conclusion: A population PK model for mother plasma/breast milk was successfully developed and a first model proposed for child plasma data: To comprehensively describe the different input routes further investigations are ongoing. Based on the final PK models further simulations will be performed to assess dosing regimens for newborns.
References:
[1] 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).
