The Triple Protease Inhibitor Regimen Amprenavir + Saquinavir + Ritonavir May Be a Viable Salvage Regimen in Heavily PI-experienced Individuals

Potent, durable antiretroviral salvage regimens for HIV-infected patients are needed. Generally, patients in whom prior protease inhibitor (PI)-containing regimens have failed (and who have developed genotypic resistance) have great difficulty in achieving optimal viral suppression and immunologic recovery with successive therapies.

Recently, triple-PI regimens, which include two active PIs along with ritonavir/ RTV (Norvir) as a pharmacokinetic-enhancing agent, have been examined for salvage therapy. These have included the combination of Kaletra (lopinavir [LPV]/RTV; Abbott Laboratories) with either amprenavir/ APV (Agenerase), saquinavir/ SQV (Invirase), indinavir/ IDV (Crixivan), or nelfinavir/ NFV (Viracept).

Pharmacokinetic studies with these triple-PI regimens have reported variable interactions. Additionally, in subjects treated for 6-96 weeks, these triple-PI salvage regimens have shown mean or median 1.13-5.5 log decreases in HIV RNA and 88-248 cell/mm³ increases in CD4⁺ T cells/mm³.

Recently, Furfine et al proposed a combination of APV, SQV, and RTV for use in PI-experienced subjects. This regimen has the theoretical advantages of non-overlapping APV and SQV resistance profiles and in vitro synergy.

Although this regimen may be used in clinical practice, no formal investigation of the pharmacokinetics of this regimen has been published to date.

The primary aim of this study was to quantify the change in SQV and APV exposure when combined and used with low-dose ritonavir/ RTV (Norvir) and to evaluate 24-week safety and immunologic and virologic response. It was a randomized, non-blinded, prospective study and the first study to evaluate the pharmacokinetics, safety, and short-term efficacy of this triple-PI regimen.

There were 11 HIV-1-infected, antiretroviral-experienced, male and female subjects > =18 years old, median HIV-1 RNA and CD4+ T-cell count of 4.86 log copies/mL and 106 cells/mm3, respectively.

Subjects were randomly assigned to receive saquinavir 1000 mg/ritonavir 100 mg every 12 hours or amprenavir 600 mg/ritonavir 100 mg every 12 hours for 7 days.

After 12-hour pharmacokinetic sampling, the third protease inhibitor (PI) was added, and pharmacokinetics sampling was repeated 14 days later. Subsequent PI dosage adjustments were based on real-time pharmacokinetic assessment.

Saquinavir did not affect amprenavir or ritonavir pharmacokinetics. Amprenavir decreased area under the concentration-time curve (AUC0-12h) and C12h for saquinavir 82 and 61%, and 74 and 75% for ritonavir.

An adjusted PI regimen of amprenavir 600 mg/saquinavir 1400 mg/ritonavir 200 mg every 12 hours returned saquinavir exposure to baseline.

At 24 weeks, HIV RNA declined a median of 1.55 log copies/mL and CD4+ T-cell counts increased a median of 52 cells/mm3.

Gastrointestinal events predominated and were mild to moderate.

These data suggest that amprenavir/saquinavir/ritonavir may be a viable salvage regimen in heavily PI-experienced individuals. New formulations of amprenavir and saquinavir may simplify this regimen.

Discussion

Using a combination of 3 PIs is one approach to treating highly antiretroviral-experienced patients. Triple-PI investigations using combinations of LPV/RTV and either APV, SQV, or IDV have reported variable drug exposures and variable virologic and immunologic responses.

The combination of APV, SQV, and RTV may have advantages over these combinations. HIV-1 isolates with resistance to APV have demonstrated hypersusceptibility to SQV. Additionally, APV and SQV are synergistic when combined in vitro.

Increasing SQV to 1400 mg and RTV to 200 mg every 12 hours resulted in an increase in SQV AUC of 195% and an increase in RTV AUC of 221%. Because these AUCs were only 26% (SQV) and 17% (RTV) lower than SQV/RTV administered alone, we believe this dosing strategy could be a reasonable approach when APV, SQV, and RTV are used together. However, a larger patient population is required to confirm these results.

Nine of the 11 subjects were concomitantly taking tenofovir. Previous reports have demonstrated tenofovir interactions with NRTIs and PIs. In our subjects, it did not appear that tenofovir affected the pharmacokinetics of our PI regimen, although our numbers were too small for formal comparisons.

However, preliminary data from a recently completed study evaluating the interaction between tenofovir and SQV has demonstrated no appreciable effects on SQV pharmacokinetics (personal communication, Andrew Hill, 2003).

New formulations of APV and SQV are either available or being developed that might decrease the pill burden of this regimen. Fosamprenavir (Lexiva, GlaxoSmithKline) is an APV prodrug that was approved by the Food and Drug Administration in October of 2003.

This drug may be given in one 700-mg capsule with 100 mg of RTV twice daily and achieve similar or higher exposures to the original formulation given 600 mg every 12 hours with RTV 100 mg every 12 hours.

Additionally, a 500-mg tablet of SQV is currently being developed by Roche Pharmaceuticals that may provide even further decrease in pill burden.

Preliminary data from a pharmacokinetic investigation suggest that a regimen of SQV 1000 mg twice daily may be combined favorably with fosamprenavir 700 mg twice daily and RTV 200 mg twice daily. However, no clinical data are yet available.

In conclusion, write the investigators, this is the first study to investigate the pharmacokinetics and preliminary virologic response to HIV-infected patients treated with the PI combination of APV/SQV/RTV.

“Due to the effects of APV on drug-metabolizing enzymes, SQV and RTV doses must be increased to achieve SQV exposure similar to that of the commonly used SQV 1000 mg/ RTV 100 mg every-12-hour regimen.”

“Based on these data in a small number of individuals, the combination of APV 600 mg/SQV 1400 mg/RTV 200 mg every 12 hours may be a viable regimen in a highly antiretroviral-experienced patient population, with limited adverse effects.”

“A larger investigation of this promising combination using the new formulations of APV and SQV is warranted.”

07/02/04

Reference

A H Corbett and others. The Pharmacokinetics, Safety, and Initial Virologic Response of a Triple-Protease Inhibitor Salvage Regimen Containing Amprenavir, Saquinavir, and Ritonavir. Journal of Acquired Immune Deficiency Syndromes 36(4): 921-928. August 1, 2004.

E S Furfine and others. Virologic and pharmacokinetic rationale for a new salvage regimen: APV/SQV/RTV bid. Abstract 16 (poster).  3^rd International Workshop on Salvage Therapy for HIV Infection; April 12-14, 2000; Chicago, IL.