Angela D.M. Kashuba, BScPhm, PharmD, DABCP; Amanda H. Corbett, PharmD


October 07, 2002


What is the current dose(s) suggested for combining lopinavir/ritonavir with saquinavir?

Response from Angela D.M. Kashuba, BScPhm, PharmD, DABCP and Amanda H. Corbett, PharmD

Several triple protease inhibitor (PI) regimens are currently being investigated, especially for treating PI-experienced HIV-infected patients. Because PIs are metabolized by, and can affect, P450 enzyme activity, doses must be carefully chosen to prevent concentrations that are either suboptimal or potentially toxic. The combination of saquinavir and lopinavir/ritonavir has been evaluated by a number of investigators.[1,2,3,4,5,6]

The lopinavir/ritonavir package insert states that a single 800-mg dose of saquinavir in healthy volunteers receiving lopinavir/ritonavir for 10 days resulted in a similar saquinavir AUC and higher Cmin compared with those observed in HIV-infected subjects receiving the standard dose of saquinavir (1200 mg 3 times daily) as the sole PI in an antiretroviral regimen.[1]

Further to these data, investigators at Abbott Laboratories evaluated saquinavir exposure in healthy volunteers given a regimen of saquinavir plus lopinavir/ritonavir dosed to steady state.[2] Subjects were given saquinavir (1200 mg 3 times daily) on days 1-5. On day 6, lopinavir/ritonavir (400 mg/100 mg twice daily) and saquinavir (800 mg or 1200 mg twice daily) were administered and continued for an additional 10-15 days. Pharmacokinetic (PK) evaluations were conducted on days 5, 15, and 20. Saquinavir exposure was substantially higher when coadministered with lopinavir/ritonavir. When the regimen of saquinavir (800 mg twice daily) in combination with lopinavir/ritonavir was compared with saquinavir (1200 mg 3 times daily) alone, the ratio of central values (RCV) for saquinavir Cmax was 6.3, for AUC24 was 9.6, and for Cmin was 16.7. No significant difference in saquinavir exposure was seen between the 800-mg and 1200-mg twice-daily saquinavir doses (RCV for Cmax was 1.00 [90% confidence interval, 0.82, 1.23], for AUC24 was 1.00 [90% CI, 0.82, 1.23], and for Cmin was 1.04 [90% CI, 0.82, 1.32]). Lopinavir concentrations did not differ from those observed in historical controls.

Hellinger and colleagues[3] studied 28 HIV-infected, PI-experienced, lopinavir-naive patients. All of these patients were given saquinavir (1000 mg twice daily) along with lopinavir/ritonavir (400/100 mg twice daily). The median troughs for saquinavir and lopinavir were 1.1 mcg/mL and 7.1 mcg/mL at week 4 and 0.82 mcg/mL and 6.9 mcg/mL at week 12. This saquinavir exposure is greater than the trough concentrations observed when given as saquinavir 1200 mg 3 times daily[7] or as saquinavir (1000 mg twice daily) plus ritonavir (100 mg twice daily).[8,9] CD4+ cell counts increased by a mean of 94 cells/mm3 and 65% of patients achieved HIV-1 RNA levels < 50 copies/mL (by intention-to-treat analysis) after 12 weeks of therapy.

Finally, a group of antiretroviral-experienced patients from the Frankfurt HIV Cohort was evaluated.[4] These 27 patients had either extensive resistance and/or toxicity to nucleoside reverse transcriptase inhibitors and thus were not treated with these agents. They received saquinavir (1000 mg twice daily) plus lopinavir/ritonavir (400 mg/100 mg twice daily) for 17 weeks. A 24-hour PK analysis was performed after 14 days of therapy. The median saquinavir trough concentration was 1250 ng/mL, which is approximately 6-fold higher than that seen in historical controls given saquinavir (1000 mg twice daily) plus ritonavir (100 mg twice daily). The lopinavir concentrations were not affected by the administration of saquinavir. At a median follow-up of 17 weeks (range, 5-62 weeks), the median CD4+ cell count increased by 73 cells/mm3 and median viral load decreased by 2.7 log10 copies/mL.

Response from Angela D.M. Kashuba, BScPhm, PharmD, DABCP and Amanda H. Corbett, PharmD

Based on the above data, using 1000 mg of saquinavir twice daily with the standard dose of lopinavir/ritonavir (400 mg/100 mg twice daily) can be recommended. With this dose, saquinavir exposure is similar to or greater than that achieved with standard saquinavir dosing (saquinavir 1000 mg plus ritonavir 100 mg twice daily),[8,9] and HIV-1 RNA and CD4+ cell counts respond appropriately. Although 800-mg twice-daily or 1200-mg twice-daily saquinavir regimens used in combination with lopinavir/ritonavir may also be effective, no clinical data on responses to therapy with these doses have been published.


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