Third International Congress Drug Therapy in HIV Infection 3-7 November 1996 Glasgow, UK

SAQUINAVIR PHARMACOKINETICS ALONE AND IN COMBINATION WITH RITONAVIR IN PATIENTS WITH HIV DISEASE

C. Merry^1,2, M. Barry¹, F. Mulcahy², J. Heavey², J. Tjia¹, S. Gibbons¹, and D. Back^1
1Department of Pharmacology & Therapeutics, University of Liverpool, P.O. Box 147, Liverpool, L69 3BX; ²Department of Genitourinary Medicine, St. Jame's Hospital, Dublin

Int Cong Drug Therapy HIV 1996 Nov 3-7;3:Abstract No. OP6.1
AIDS 1996, Vol. 10 (Suppl. 2);S13

The introduction of protease inhibitor drugs e.g. saquinavir (SQV) and ritonavir (RIT) represents a significant advance in HIV therapy. As with nucleoside analogues, viral resistance may develop to SQV and RIT therefore combination therapy may be more effective than monotherapy. The most influential isozyme involved in the metabolism of the protease inhibitors is cytochrome P450 3A (CYP3A). RIT is a potent inhibitor of CYP3A and inhibits SQV metabolism in healthy volunteers. We investigated the kinetics of SQV when administered alone and in combination with RIT in 6 HIV+ male patients (aged 28-45 years) with advanced HIV disease (CDC stage IV, mean CD4 count 25 × 10⁶L^-1) who were considered for combination therapy with SQV plus RIT. Steady state SQV profiles were obtained on two occasions following treatment with SQV 600 mg t.d.s. and SQV 600 mg t.d.s. + RIT 300 mg b.d. Blood samples were obtained at times 0, 1, 2, 3, 4, 6, & 8 hours post dosing. SQV concentration in the plasma was determined by HPLC.

For patients on SQV alone there was a twelve fold variability in SQV AUC_0-8h (293-3446 ng.h.ml^-1). In combination with RIT there was a 16 fold increase in maximum concentration (C_max 369 ± 122 vs 5980 ± 2059 ng.ml^-1; mean ± s.e.m.)(See figure) and a 21 fold increase in the AUC_0-8h (1771 ± 606 vs 39,696 ± 14,676 ng.h.ml^-1; mean ± s.e.m.).

For some patients SQV 600 mg t.d.s. results in very low plasma SQV levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy is considered then the dose of SQV should be greatly reduced.

Presenting author: C. Merry

1996-11-03
0P6.1

Originally published in AIDS Volume 10, Supplement 2 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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