[870] THE EFFECT OF EFAVIRENZ (EFV) AND NELFINAVIR (NFV) ON THE PHARMACOKINETICS (PK) OF PRAVASTATIN (P)

2nd International AIDS Society Conference on HIV Pathogenesis and Treatment

Paris, France - July 13 - 16, 2003

[TITLE:] THE EFFECT OF EFAVIRENZ (EFV) AND NELFINAVIR (NFV) ON THE PHARMACOKINETICS (PK) OF PRAVASTATIN (P)

[AUTHOR(S):] JG Gerber¹, S Rosenkranz², CJ Fichtenbaum³, B Alston⁴, SW Brobst⁵, Y Segal², J Segal² and A Aberg⁶
¹Univ of Colorado Hlth Sci Ctr, Denver, CO; ²SDAC, Harvard Sch of Publ Hlth, Boston, MA; ³Univ of Cincinnati, OH; ⁴NIAID, NIH, Bethesda, MD; ⁵Social and Sci Sys, Silver Spring, MD; and ⁶Washington Univ, St Louis, MO, USA

IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. 870
Antiviral Therapy 2003; 8(Suppl. 1):S429

[ABSTRACT:] Introduction: P is the recommended HMGCoA reductase inhibitor for the treatment of HAART-induced hypercholesterolaemia as it is least likely to have drug–drug interactions with PIs and NNRTIs. Of the pathways by which P undergoes systemic elimination, conjugation and non-CYP3A4 oxidation are the most important. ACTG 5047 demonstrated that RTV/SQV induces the metabolism of P so that overall exposure is reduced by ~50%. ACTG A5108 was designed to look at the effect of two other metabolic enzyme inducers, EFV and NFV, on the PK of P.

Methods: In this within-subject study, HIVseronegative volunteers were studied to examine this drug–drug interaction. 24-h PK of P was obtained after 3 days of therapy, and this was repeated after 12 days of NFV and 14 days of EFV. In addition the non-steady state effect of P on EFV was obtained in subjects on the EFV arm of the study. Plasma concentrations of P and EFV were measured using validated techniques, LC/MS/MS for P and HPLC-UV detection for EFV. P kinetics before and after NFV or EFV as well as the effect of P on EFV PK were compared using the Wilcoxon signed rank test.

Results: In general, all medications were well tolerated in this HIV-seronegative group. NFV administration resulted in a median 47% (range –65% to +10%, n=14) decrease in P exposure; AUC_24h mean ±SD was 89.02 ±40.75 and 50.63 ±30.93 ng*h/ml, respectively, before and after NFV (P=0.0004). EFV administration resulted in a median of 40% (range –73% to +28%, n=11) decrease in P exposure; AUC_24h mean ±SD 95.53 ±58.47 and 52.53 ±25.89 ng*h/ml, respectively, before and after EFV (P=0.0186). P had no effect on the PK of EFV, although the concomitant administration of EFV was not to steady state.

Conclusions: Although P may be safer to administer compared with other statins, the decrease in systemic exposure after administration of metabolic enzyme inducers may mandate higher doses of P than presently suggested to achieve successful serum cholesterol target.

030714
870