Nevirapine exposure was not associated with hypersensitivity in patients from Malawi

Although there is a risk of hypersensitivity, nevirapine (NVP) is used widely in first line regimens in resource- limited settings.

The relationship between drug exposure and hypersensitivity with NVP is unknown. It is possible that it is influenced by the effect of polymorphisms in CYP2B6 and CYP3A5 on drug metabolism.

Laura Dickenson and colleagues from Malawi and Liverpool showed findings from a study designed to develop a population pharmacokinetic (PK) model for NVP serum concentrations, and, in turn, to determine the impact of patient demographics, hypersensitivity and genetics on the PK of the drug.

The population PK model included 180 drug-naive HIV-positive patients (of which 101 were women), starting NVP-based treatment at Queen Elizabeth Central Hospital, Malawi between March 2007 and September 2008. At the time of PK sampling, they were a median age of 34 years old, with a median CD4 cell count of 156 cells/mm3 (range 1-812). The median duration of treatment was 6 weeks (1-26). Twenty-five patients were hypersensitive and 23 coinfected with hepatitis B or C.

The investigators performed rich and sparse sampling in 40 and 140 patients respectively. PK data were available for single nucleoside polymorphisms (SNPs): CYP3A5*6, CYP3A5*3, CYP2B6 983T>C, CYP2B6 516G>T and CYP2B6 785A>G in 89/180 patients. Genotyping was performed using Sequenom iPLEX.

The investigators used non-linear mixed effects modelling (NON-MEM, VI 2.0) to investigate the effects of patient demographics, hypersensitivity, hepatitis and CYP3A5 and CYP2B6 on NVP apparent oral clearance (CL/F).

They found a one-compartment model with first order absorption best described the data. For the final model (n=89) NVP CL/F (relative standard error RSE%) was 2.67 (5%) with interindividual, interoccasion variability of 30% (29%) and 32% (26%) respectively.

The apparent volume of distribution and absorption rate constant were 141L (22%) and 0.77h-1 (31%) respectively.

They reported that none of the available patient demographics were associated with NVP CL/F. Nor did they find an association between NVP CL/F and hypersensitivity or hepatitis.

Only CYP2B6 983T>C and CYP3A5*3 had an impact on NVP CL/F; reducing it by 25% in 983C heterozygotes (allelic frequency 18%) and 40% in CYP3A5*3 homozygotes (allelic frequency 5%).

They concluded that NVP exposure was not associated with the development of hypersensitivity, which is more likely to be an immunological phenomenon. They added that further studies are warranted to determine the mechanism of NVP hypersensitivity.

Dickenson L et al. Population pharmacokinetic and pharmacogenetic analysis of nevirapine in hypertensive and tolerant HIV-infected patients from Malawi. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Poster abstract P181. Published in Journal of the International AIDS Society 2010 13(Suppl 4):P181. http://www.jiasociety.org/content/13/S4/P181