Effect of diurnal variation,CYP2B6genotype and age on the pharmacokinetics of nevirapine in African children

Abstract

ObjectivesTo characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children.MethodsNon-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration–time data from 414 children aged 0.3–15 years.ResultsNevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterized using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metabolizer status [extensive metabolizer (EM) 516GG|983TT, reference; intermediate metabolizer (IM) 516GT|983TT or 516GG|983TC, 17% lower; slow metabolizer (SM) 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow metabolizer (USM) 516GG|983CC, 68% lower]. Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening Cmin values in the different metabolizer groups were 5.01 (3.01–7.47), 6.55 (3.65–13.32), 11.59 (5.44–22.71) and 12.32 (12.32–27.25) mg/L, respectively. Evening Cmin values were <3 mg/L in 43% of EM weighing <6 kg and 26% of IM weighing <6 kg, while 73% of SM and 88% of USM in all weight-bands had evening Cmin values >8 mg/L. Cmin was not markedly affected by administration time, but was altered by unequal splitting of the daily dose.ConclusionsDiurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children weighing <6 kg with EM or IM metabolizer status should receive the same dose as children weighing 6–10 kg.

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

“…19 Children on nevirapine were switched to efavirenz-based ART if aged >3 years and diagnosed with tuberculosis or experienced nevirapine-related AEs, or to boosted protease inhibitor-based (PI) ART if <3 years with these events or for clinical or immunological failure (or if efavirenz-intolerant). Samples for PK analysis (described previously) 5 were taken at week 6, 36, and every 24 weeks thereafter. VL was assayed retrospectively on stored plasma taken at enrolment and weeks 48, 96 and 132 or 144.…”

“…A previously developed model describing the steady-state population-PK of nevirapine 5 was used to derive empirical Bayesian estimates for each child at each PK visit for: CL (clearance), C min (evening trough concentration), C max (maximum concentration), and AUC 0–24 (area under the curve). Due to diurnal variability in clearance 5 , this analysis included measurements relating to daytime exposures only.…”

“…Due to diurnal variability in clearance 5 , this analysis included measurements relating to daytime exposures only.…”

“…26 The best-fitting dichotomous threshold for nevirapine C min in the Cox model was identified by profile likelihood as described previously for efavirenz. 27 Following the same method, we conducted simulations introducing unexplained residual variability on predicted concentrations from the population-PK model (additive error 0.32 mg/L, proportional error 5.26%) 5 to derive 95% confidence intervals (CI) for this threshold (2.5 th and 97.5 th percentile of most predictive cut-offs from 500 simulations). The sensitivity, specificity, accuracy, and positive and negative predictive values of the identified threshold for VL suppression were compared to those of the 10 th , 25 th , and 50 th percentiles of estimated nevirapine C min in this study, and cut-offs proposed in the literature.…”

“…3–5 In adults, low nevirapine concentrations have been associated with increased risk of virological failure 6–8 and high exposures with increased risk of skin rashes 9–11 and hepatotoxicity. 7,12 Based on the concentration-response relationship, a therapeutic range of 3–8 mg/L has been suggested for nevirapine therapeutic drug monitoring (TDM).…”