Authors: ES Furfine, MM Berry, O Naderer, M Tisdale, D Stein, B Sadler, and MD Rogers; Glaxo Wellcome

Researchers from Glaxo wellcome reported on a novel combination of three protease inhibitors for people who have resistance to protease inhibitors. The utility of this proposed regimen is preliminary because the the 3-way PK interaction has not been studied to date, and the magnitude of the interaction of ritonavir on both drugs will need to be confirmed in a formal PK study. The proposed dose of APV 600mg+ SQV800mg+ RTV 100mg is postulated by Glaxo to optimize the pharmacokinetics of both APV and SQV. Glaxo is conducting a clinical study exploring APV/RTV dosing in both twice and once daily dosing regimens, but clinical data isn't available yet. 600/100 APV/RTV bid and 1200/200 APV/RTV are being investigated in those clinical studies in HIV+ individuals for safety and antiviral efficacy. It's premature to experiment with this regimen until these studies provide adequate data on safety of interactions and proper dosing. In addition, the new amprenavir prodrug is under development in clinical studies. Dosing of amprenavir with the prodrug will be with less pills. The possibility of an improved side effect profile and equivalence of antiviral activity with current form of amprenavir is being explored in human studies. PK data on various RTV/APV dosing regimens was presented at the 7^th Retrovirus Conference and is referred to in this article. To view the NATAP report of the data presented, click here.

In Vitro data Suggests that Saquinavir May Re-sensitize APV-resistant Virus to APV. HIV with APV-specific I50V mutation exhibits hypersensitivity to SQV; prototypical SQV resistant virus (48V/90M) remains fully susceptible to APV. When triple mutated HIV (46I/47V/50V) was passaged in SQV, the 84L addition appeared, increasing resistance to SQV, but increasing sensitivity to APV. Passage with other protease inhibitors resulted in dual-PI resistance. Cross-sectional studies of isolates from PI experienced patients have shown retained phenotypic sensitivity (<4-fold resistance) to APV in 55%-92% of subjects (depending on the PI-resistance profile of the person) , and susceptibility to SQV in 28-80%. This data and other data suggest that the cross-resistance profile of APV may lend itself to being a productive component in a salvage regimen. Individuals with resistance to other protease inhibitors may have some sensitivity to APV. The amount of sensitivity often may depend on the amount of PI-resistance a person may have. The person may not have full sensitivity to APV but possibly enough sensitivity to provide some antiviral activity as part of a multi-drug combination. Increasing APV blood levels (AUC & Cmin) of APV by boosting levels with RTV theoretically ought to improve the antiviral activity of APV.

Berrey reported that GW PRO10017/10022 utilized APV 450mg/RTV 300 or 100 mg, demonstrating in seronegatives that the Cmin of APV was about 10-14 fold above that seen with APV 450 mg alone, approximately 4-fold above the Cmin for APV 1200mg. Modelled data estimate the Cmin for APV 600mg/RTV 100mg was about 6 fold above that of APV 1200 mg, or 13-fold above wild-type IC50. This data is available in the NATAP article linked to above. The combination of SQV 1600 mg (Fortovase) with RTV 100 mg once daily has shown Cmin at 24 hours (0.5 mg/mL) about 5-fold greater than SQV 1200 mg 3 times daily (@ 8 hours: 0.09mg/mL). This data was presented by Mike Saag at the Sept. '99 ICAAC meeting. It can be viewed in detailed table format in the NATAP report of ICAAC Summaries by clicking here.

Berrey and others from Glaxo are proposing that APV 600mg+ SQV 800 mg+ RTV 100mg twice daily would provide enhanced concentrations of both APV and SQV based on the Cmin at 12 hours. Berrey reported that in PRO2001, APV and SQV were co-administered with no impact on the Cmin of APV (see AUC data below), and with increased diarrhea as the predominant adverse event. Abstract 727 at the 7^th Retrovirus Conference reported: PK data revealed that Cmin of SQV and IDV were reduced when coadministered with APV. The addition of RTV 100mg would be expected to increase the Cmin of SQV in the proposed combination. But as stated above, the three-way PK interaction of APV/SQV/RTV has NOT been studied yet, and as Glaxo also stated the magnitude of the interaction of RTV on APV/SQV will need to be confirmed in a formal PK study. At the World AIDS Conference in Geneva '98, poster number 12389 reported amprenavir increased SQV Cmax by 21%, AUC by 18%,but Cmin data was not available yet. The poster also reported amprenavir Cmin was unchanged by SQV, but APV AUC was decreased by 36%, and APV Cmax decreased 40%. Again, the addition of RTV may increase APV AUC.