Pharmacokinetic Enhancers in HIV Therapeutics

Abstract

Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.

Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook

“…Permeation enhancers can be used to improve absorption across cell membranes [4]. Pharmacokinetic boosting, where a drug is taken concomitantly with a cytochrome P450 inhibitor, can be used to reduce first-pass metabolism and has been useful in the context of HIV therapy with lopinavir/ritonavir combination [13]. These methods have been successful in addressing barriers that prevent APIs from accessing the systemic circulation.…”

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

“…PIs largely undergo phase I metabolism by cytochrome P450 3A4 (CYP3A4) and are also substrates of P-glycoprotein (P-GP; ABCB1) (6). Consequently, PIs are commonly administered in combination with pharmacokinetic (PK) boosters, such as ritonavir (RTV) or cobicistat (COBI), which act by inhibiting CYP3A4-mediated PI metabolism and P-GP-mediated PI efflux, thereby improving the PK profile of PIs by prolonging PI half-life and increasing PI bioavailability (7)(8)(9).…”

Voriconazole and cobicistat-boosted antiretroviral salvage regimen co-administration to treat invasive aspergillosis in an HIV-infected patient

“…Cobicistat shows a theoretically better drug-drug interaction profile, due to the more selective 3A4 isoenzyme inhibition, but clinical experience with drugs other than ARVs is lacking. 3,8 A middle-aged male patient with HIV since 1987, treated since the early 1990s with several ARV regimens and experienced multiple virological failures causing an MDR strain (62V/65R/ 101E/181C/184I mutations, conferring resistance to lamivudine/ emtricitabine/didanosine/abacavir/nevirapine/efavirenz/rilpivirine/ etravirine and partial resistance to tenofovir). In 2014 he had an undetectable viral load and CD4 lymphocyte count .1000 cells/mm 3 , and was on 800/100 mg of darunavir/ritonavir once daily and 400 mg of raltegravir twice daily.…”

“…Nevertheless, cobicistat could be an alternative in those cases, due to its higher specificity for 3A4 inhibition. 8,10 However, clinical experience is extremely limited beyond cobicistat co-administration with elvitegravir and some PIs. Despite that the combination of elvitegravir/cobicistat and darunavir is not recommended for the potential reduction of darunavir plasma levels (as seen in our case), this reduction of darunavir AUC has, probably, no clinical relevance for simplification of patients virologically suppressed for long periods.…”

“…6 Of the current generation of PI/r options, atazanavir/ritonavir does not appear to increase the risk of myocardial infarction or stroke 7 and causes less carotid intimal thickening than either darunavir/ritonavir or raltegravir. 8 Few clinical data are available to judge the contribution of darunavir/ritonavir to major cardiovascular events. However, darunavir/ritonavir has superior intentionto-treat efficacy compared with atazanavir/ritonavir 9 and is the only PI/r recommended for initial combination ART (cART) in resource-rich settings by all major international consensus antiretroviral guidelines.…”