• To compare the steady state Cmax, Cmin, AUC0-12h, and the t1/2 of RTV and IDV in HIV-infected patients treated with IDV/RTV 800/100 mg, in the presence and absence of added fos-APV 700 mg twice a day (bid)
  

• To evaluate the Cmax, Cmin, AUC0-12h, and the t1/2 APV in a double boosted PI regimen of IDV/fos-APV/RTV 800/700/100 mg bid as compared to historical results of APV pharmacokinetics in a regimen of APV/RTV 700/100 mg bid
  

BACKGROUND: Because of their potent antiviral effects, protease inhibitor (PI)-containing antiretroviral regimens (ARV) have become one of the cornerstones of HIV treatment. Success with their use has however been dampened by increasing emergence of resistant viral gene mutation with consequent treatment failure. Since the availability of newer antiviral agents with activity against resistant viral strains are limited, clinicians are increasingly resorting to ritonavir (RTV) enhanced dual PI therapy to treat salvage patients.

In the presence of RTV, the metabolism of concomitantly administered PIs by the cytochrome P450 3A4 (CYP3A4) isoenzyme is inhibited; higher plasma and tissue drug levels are maintained with less variability. The enhanced pharmacokinetics result in prolonged suppression of viral replication including strains with moderate phenotypic resistance leading to improved therapeutic outcomes. RTV enhanced dual PI therapy offers additional advantages as combinations of PIs with different and non-overlapping mutation patterns would be expected to delay emergence of viral resistance, coupled with the notion that the selection of resistance to two or more agents may require a greater number of mutations than that required to overcome a single PI. Furthermore, these combination regimens often result in reduction in pill burden, food restrictions, and may be associated with more tolerable side effect profiles.

For these reasons, RTV enhanced indinavir (IDV) and fos-amprenavir (fos-APV) combinations appear promising for salvage therapy as these two agents are pharmacokinetically enhanced by RTV, and have unique resistant mutation profiles when compared with other PIs. Additionally, since clinically limiting interaction is known to occur between fos-APV and lopinavir/ritonavir (LPV/r), the interactions between IDV, fos-APV, and RTV may be different in a manner that could be clinically beneficial in salvage therapy. Importantly, we will evaluate IDV/fos-APV/RTV at a dose of 800/700/100 mg bid as we anticipate that fos-APV may lower IDV concentrations similarly to lopinavir (LPV), although likely to a lesser extent; such that a dual benefit of enhanced efficacy and improved tolerability could be achieved. The pharmacokinetic profile of this combination regimen therefore merits evaluation to allay concerns of clinically important drug-drug interactions before introduction into clinical practice.

AIMS: The aim of this pilot study therefore is to evaluate the impact of the addition of fos-APV on the pharmacokinetic parameters (plasma trough concentrations (Cmin), the peak concentrations (Cmax), the elimination half-life (t1/2β), and the area under the concentration-time curve (AUC12)) of IDV and RTV at steady state in HIV infected patients.

METHODS: Fifteen HIV-infected subjects already being treated with IDV/RTV containing ARV therapy (800/100 mg bid) will be recruited from the Grady Infectious Disease Clinic (IDP). Initially, blood samples will be collected at time 0, 1, 2, 3, 4, 6, 8, 10, and 12 hours for a baseline 12-hour pharmacokinetics study of RTV and IDV. Fos-APV 700 mg bid will be added to this regimen for 5 days. At the end of which blood samples will be collected at time 0, 1, 2, 3, 4, 6, 8, 10, and 12 hours for IDV, RTV and APV pharmacokinetic parameters.

Pharmacokinetic Analysis: Plasma concentrations of IDV, APV, and RTV will be determined with sensitive and validated reverse-phase high-performance liquid chromatography (HPLC). The Cmax, Cmin, t1/2β, and AUC12 of these PIs will be determined using non-compartmental pharmacokinetic methods.

Statistical Analysis: IDV and RTV pharmacokinetic indices before and after the addition of fos-APV will be compared using a non-parametric two-sided paired t-test.