Efavirenz and nevirapine are the most widely used agents for treatment of HIV in children. Sources of variability in their pharmacokinetics and its association with virological outcome and adverse events in African children are poorly characterised, thereby limiting treatment optimisation. To fill this gap we studied population pharmacokinetics (PK) of efavirenz and nevirapine in 478 children from CHAPAS-3 (aged 0.3-1.5 years) using non-linear mixed effects modelling and identified predictors of treatment outcome and PK thresholds most predictive of increased risk of nonsuppression using Cox proportional hazards regression models and likelihood profiling. Efavirenz PK was described by 2-compartment disposition model with 1st-order elimination and transit-compartment absorption and nevirapine by 1-compartment model with elimination through a well-stirred liver model and transit-compartment absorption. Combined effect of SNPs 516GT and 983TC was the strongest predictor of between-subject variability in clearance (89% and 68% decrease between fastest/slowest CYP2B6 metabolic subgroups for efavirenz and nevirapine, respectively). PK was affected by weight, described with allometric scaling. Nevirapine intrinsic clearance displayed diurnal variations (oscillations of amplitude 29%, maximum at 12 noon), while age affected pre-hepatic bioavailability (31.7% lower at birth and increasing exponentially). In antiretroviral treatment (ART)-naïve children (n=325) increased exposures were associated with decreased risk of non-suppression for both drugs. In efavirenz, risk further increased for children>8 years and for younger boys; in nevirapine for high pre-ART VL, low pre-ART CD4% and low adherence. Thresholds most predictive of non-suppression in efavirenz were: Cmid-dose=1.12 mg/L, Cmin=0.65 mg/L and AUC0-24=28 mg∙h/L, while nevirapine had no clear threshold. Adverse events were infrequent in efavirenz, whereas in nevirapine transient transaminase elevations >grade 1 were associated with Cmin>12.4 mg/L. Non-nucleoside reverse transcriptase inhibitors dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C, in particular for efavirenz where we observe 10-fold differences in exposures between metabolic subgroups. Moreover the target Cmin and AUC0-24 could be lowered in children for efavirenz. Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/25063 |
| Date | January 2017 |
| Creators | Bienczak, Andrzej Marek |
| Contributors | Denti, Paolo, McIlleron, Helen |
| Publisher | University of Cape Town, Faculty of Health Sciences, Division of Clinical Pharmacology |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, Doctoral, PhD |
| Format | application/pdf |
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