Case-control exploration of relationships between early rash or liver toxicity and plasma concentrations of nevirapine and primary metabolites.

OBJECTIVE: This investigation measured trough nevirapine and five oxidative metabolite concentrations in plasma specimens collected from patients who exhibited a rash or liver function abnormality during the first 6 weeks of treatment.
METHOD: Patient selection came from three clinical trials, totaling 1,357 patients, from which frozen specimens had been stored and were available for assay. The control patients were matched according to trial, steroid use, CD4 cell count, gender, race, and hepatitis B/C status. Observed plasma metabolite concentrations were compared using signed rank tests.
RESULTS: A total of 49 case-control pairs were studied. Women had significantly greater exposure than men to nevirapine and four of the five metabolites at week 2, but the plasma concentrations were comparable by week 4. Steroid (prednisone) co-medication produced significantly different plasma nevirapine and metabolite concentrations for the majority of case-control comparisons at week 3, a week after cessation of steroid treatment, but only occasionally produced a measurable difference at other weeks.
CONCLUSION: During the first 6 weeks of nevirapine therapy, the rashes and liver enzyme elevations that occurred appear to be idiosyncratic. There were no strong relationships observed between the plasma concentrations of nevirapine or any of its five metabolites to a casedefining event. The systemic exposure of the metabolite 12-hydroxynevirapine and its successor 4-carboxynevirapine, hypothesized in the skin rash female Brown Norway rat model as reactive intermediates for idiosyncratic immune-mediated adverse reactions, were comparable between case and control samples and were comparable in proportion to the precursor nevirapine exposure.