Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals

Abstract

Background: Nevirapine is metabolized by CYP2B6 and polymorphisms within the CYP2B6 gene partly explain inter-patient variability in pharmacokinetics. The aim of this study was to model the complex relationship between nevirapine exposure, weight and genetics (based on combined analysis of CYP2B6 516G > T and 983T > C single nucleotide polymorphisms).

Methods: Non-linear mixed-effects modelling was used to estimate pharmacokinetic parameters from 275 patients. Simulations of the nevirapine concentration profile were performed with dosing regimens of 200 mg twice daily and 400 mg once daily for individuals with body weights of 50, 70 and 90 kg in combination with CYP2B6 genetic variation.

Results: A one-compartment model with first-order absorption best described the data. Population clearance was 3.5 L/h with inter-patient variability of 24.6%. 516T homozygosity and 983C heterozygosity were associated with 37% and 40% lower clearance, respectively. Body weight was the only significant demographic factor influencing clearance, which increased by 5% for every 10 kg increase. For individuals with higher body weight, once-daily nevirapine was associated with a greater risk of sub-therapeutic drug exposure than a twice-daily regimen. This risk was offset in individuals who were 516T homozygous or 983C heterozygous in which drug exposure was optimal for > 95% of patients with body weight of ≤ 70 kg.

Conclusions: The data suggest that a 400 mg once-daily dose could be implemented in accordance with CYP2B6 polymorphism and body weight. However, the use of nevirapine once daily (immediate release; off-label) in the absence of therapeutic drug monitoring is not recommended due to the risk of inadequate exposure to nevirapine in a high proportion of patients. There are different considerations for the extended-release formulation (nevirapine XR) that demonstrate minimal peak-to-trough fluctuations in plasma nevirapine levels.

Figure 1.

Goodness of fit plots for the final pharmacokinetic model illustrating (a) population predictions of nevirapine versus observed concentrations, (b) individual predictions of nevirapine versus observed concentrations (where the continuous lines show the lines of unity and the broken lines show the lines of regression) and (c) weighted residuals versus time post-dose (where the continuous line shows the line at an ordinate value of zero).

Figure 2.

Ninety percent PIs determined from simulated data of nevirapine (a) 200 mg twice daily and (b) 400 mg once daily. The mean population prediction is shown as a continuous line and the 90% PI is shown as a broken line. NVP, nevirapine.

Figure 3.

Steady-state 90% PI (P5–P95) determined from simulated data of nevirapine (NVP) administered at different doses. The mean population prediction (continuous thick line) and the 90% PI (grey area) are represented for each category. The broken horizontal line is at an ordinate value of 3 mg/L (proposed MEC). (a) Steady-state NVP concentrations predicted at a 200 mg twice-daily dose. Proportion below the MEC: 516GG, 50 kg 12%, 70 kg 19% and 90 kg 28%; 516TT, 50 kg 0.3%, 70 kg 1% and 90 kg 3%; and 983TC, 50 kg 0.2%, 70 kg 1% and 90 kg 2%. (b) Steady-state NVP concentrations predicted at a 400 mg once-daily dose. Proportion below the MEC: 516GG, 50 kg 20%, 70 kg 31% and 90 kg 43%; 516TT, 50 kg 1%, 70 kg 3% and 90 kg 7%; and 983TC, 50 kg 0.6%, 70 kg 2% and 90 kg 6%.