Eighth International Congress on Drug Therapy in HIV Infection Glasgow, UK - 12-16 November 2006

Int Cong Drug Therapy HIV 2006 Nov 12-16;8:Abstract No. PL5.4

A Owen, T Mahungu, C Cook, M Youle, M Johnson, D Back, S Khoo
University of Liverpool, UK; Royal Free Hospital, London, UK

PURPOSE OF THE STUDY: Variability in drug disposition is likely the cumulative result of multiple genetic and environmental effects. Standard methods for assessing multi-locus gene effects would be of clear advantage. We previously reported a cumulative scoring algorithm for nevirapine and have applied this methodology to lopinavir (LPV) pharmacogenetics.

METHODS: 87 patients receiving LPV were included. Plasma LPV C_min was sampled just before the next dose was due. Allelic discrimination was performed by real-time PCR for 9 SNPs from 6 loci (CYP2B6, CYP3A4, CYP3A5, MDR1, MRP1 and BCRP). C_min were compared between different genotypes. Criteria for inclusion of SNPs/loci as susceptibility genes were: i) P<0.05, or ii) 0.05 < P<0.10 with median [LPV] C_min outside bioequivalence range (80-125%). LPV C_mins were then compared between patients with accumulating numbers of susceptibility genes in the algorithm.

SUMMARY OF RESULTS: CYP3A5*3 (A6986G), MDR1 (C3435T), MRP1 (G-260C) and BCRP (C421A) qualified for the algorithm. We observed a stepwise increase in median [LPV] C_min with accumulating number of susceptibility genes (N=87 patients: median [LPV] C_min=4915 ng/mL): 0 (N=16; 3427 ng/mL), 1 (N=38; 4419 ng/mL), 2 (N=11; 5183 ng/mL), 3 (N=15; 5777 ng/mL), 4 (N=9; 6998 ng/mL) [z=2.5, P=0.01 by Cuzicks trend test].

CONCLUSIONS These data are preliminary but suggest that cumulative scoring algorithms can be developed to assess multi-locus genetic effects influencing LPV pharmacokinetics.

Plenary Session: Oral Papers

2006-11-12
PL5.4

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