Pharmacokinetic Enhancement of Protease Inhibitor Therapy

Abstract

Combination antiretroviral therapy with two or more protease inhibitors has become the standard of care in the treatment of HIV infection. Dual protein inhibitor (PI) regimens, such as lopinavir/ritonavir, are commonly used as initial PI therapy. As viral resistance increases and the development of mechanistically novel protease inhibitors decreases, clinicians turn to ritonavir-enhanced dual PI therapy to treat salvage patients. Potency of these combination regimens is increased while pill burden, food restrictions and often, side effects are decreased. These clinical advantages result from the enhancement of their pharmacological properties, including alterations in the absorption and metabolism process. Alterations in the absorption and metabolism of protease inhibitors when co-administered with a cytochrome P450 (CYP) enzyme inhibitor, such as low dose ritonavir, are reflected by impressive changes in pharmacokinetic parameters. For example, the addition of ritonavir 100 or 200 mg to saquinavir 1200-1800 mg has been shown to increase saquinavir area under the concentration-time curve (AUC) by approximately 300-800% compared with saquinavir alone. The ability of ritonavir to increase plasma trough concentrations (C(min)) of concomitantly administered PIs is perhaps the greatest clinical benefit of dual or ritonavir-enhanced dual PI therapy since inadequate concentrations of antiretrovirals may support long term antiretroviral resistance. For example, lopinavir 400mg alone in healthy volunteers produced plasma concentrations that briefly exceeded the concentration required to inhibit 50% of viral replication (IC(50)). Yet, when low doses of ritonavir were added, C(min) values were 50- to 100-fold greater than the concentration required to produce 50% of the maximum effect for wild-type HIV (EC(50)). The following manuscript will discuss the rationale for combining protease inhibitors and will review pertinent pharmacokinetic and clinical data on these combination regimens.

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

“…BUP is principally metabolized by CYP 3A4 (Chang et al, 2006;Iribarne et al, 1997). Since ATV (Perloff et al, 2005) and RTV (King et al, 2004) are both in vitro inhibitors of CYP 3A4, it is likely that inhibition of metabolic clearance of BUP contributes to the higher BUP concentrations observed in both studies. However, if this were the only effect, one would expect to see increased concentrations of BUP and BUP-G, but decreased concentrations of the metabolites NBUP and NBUP-G, which result from dealkylation catalyzed by CYP 3A4.…”

“…RTV is well known for its ability to greatly increase bioavailability of other protease inhibitors by inhibition of both CYP3A4 and P-glycoprotein (King et al, 2004) and ATV also exhibits both inhibitory activities (Perloff et al, 2005). In the presence of ATV and/or RTV, the gastrointestinal bioavailability of swallowed BUP may go from poor to excellent, leading to a substantial increase in overall BUP bioavailability and plasma levels, with downstream increases in metabolite concentrations as well.…”

“…ATV (Perloff et al, 2005) and RTV (King et al, 2004) may also act as inducers of CYP 3A4 and P-glycoprotein. Such induction could oppose their direct inhibitory effects.…”

Rifamycin Use in HIV-Infected Patients with Tuberculosis

“…(King et al, 2004;Burger et al, 2006b) As rifampin's inductive effects are especially strong with the PIs, only two formulations approach therapeutic concentrations when given concomitantly with rifampin: lopinavir and saquinavir, both of which must be administered with substantial doses of ritonavir. (Maartens et al, 2009) The standard dose of lopinavir-ritonavir is 400/100 mg given twice daily.…”

Approaches for the Development of Antiviral Compounds: The Case of Hepatitis C Virus

“…The HIV protease inhibitors ritonavir and atazanavir are potent inhibitors of both P-gp and CYP3A4. Therefore pharmacokinetic "boosting" has been used as a strategy in HIV therapy and may be feasible for HCV protease inhibitors for increasing peak plasma concentrations (C max ), reducing the rate of elimination (longer t 1/2 ), increasing exposure (AUC), and lowering the frequency of dosing needed to maintain sufficient drug levels (Cooper et al 2003;King et al 2004;Moyle and Back 2001). However, administration of other drugs with protease "boosting" regimens can result in complex drug interactions, which may require dose modification or drug replacement of either the protease inhibitor or the other drug.…”