Antiretroviral boosting by cobicistat, a structural analog of ritonavir

When approaching pharmacokinetic drug–drug interactions (DDIs) involving inhibition of Cytochrome-P450 (CYP)-mediated drug clearance, we usually assume that such DDIs are unwanted and potentially hazardous. Impairment of the victim drug's clearance by an inhibitory perpetrator elevates plasma concentrations of the victim, and we are warned of possible toxicity, or even lethal consequences. But inhibitory DDIs may also be deliberately produced, for favorable therapeutic purposes. The pharmacokinetic mechanism and outcome are the same, but our terminology shifts from ominous to optimistic—we call it boosting, dose-sparing, augmentation, or enhancement.1, 2 An early example is the augmentation or dose-sparing of cyclosporine by ketoconazole. Organ transplant recipients face lifelong anti-rejection treatment with cyclosporine, an expensive medication that stresses the financial means of patients and the budgets of insurance systems. Coadministration of ketoconazole impairs CYP3A-mediated clearance of cyclosporine. Dosage requirements for cyclosporine are substantially reduced, anti-rejection efficacy is maintained at a lower daily dosage, and the cost of treatment is reduced.3-6 Pharmacokinetic boosting now is commonplace in contemporary antiretroviral therapy.7-9 Oral administration of the viral protease inhibitor lopinavir, when unboosted, yields only low systemic exposure, due to extensive CYP3A-mediated presystemic extraction, and possibly enteric efflux transport by P-glycoprotein. Coadministration of lopinavir with low doses of ritonavir—the most potent of available CYP3A inhibitors—increases systemic exposure to lopinavir by about 75-fold, thereby augmenting lopinavir's antiretroviral activity.10 The fixed-dose combination of lopinavir and ritonavir (Kaletra®) contains enough ritonavir per dose unit (33.3 mg) to produce extensive CYP3A inhibition, but not enough to contribute to net antiretroviral activity. Though clinicians often co-administer ritonavir to boost antiretroviral drugs other than lopinavir, the medications must be given separately. Aside from Kaletra, no other fixed-dose combinations containing ritonavir are clinically available, probably because of patent protection issues as well as the regulatory burden of establishing safety and efficacy of fixed-dose drug combinations. Cobicistat (formerly GS-9350) has been developed by Gilead Sciences, Inc. (Foster City, CA) as an agent specifically intended for pharmacokinetic augmentation in antiretroviral treatment.11-14 Though a new molecule by regulatory criteria, cobicistat is closely similar to ritonavir in structure (Figure 1). Like ritonavir,15, 16 cobicistat is a potent CYP3A inhibitor, with a probable time-dependent (mechanism-based) component of inhibition.17-19 In clinical pharmacokinetic studies, CYP3A inhibition and antiretroviral augmentation by cobicistat and ritonavir were similar.20, 21 Cobicistat is approved for clinical use in the United States as part of a fixed-dose combination (Stribild®) also containing elvitegravir, emtricitabine, and tenofovir. In clinical trials, antiretroviral regimens augmented by cobicistat or ritonavir were similar in terms of efficacy, safety, and tolerability.22-24 Whether cobicistat is meaningfully different from ritonavir as a pharmacokinetic enhancer remains to be established. In any case, a drawback of cobicistat is that it is only available in North America as embedded in a fixed drug combination. The sole agent has been approved (Tybost®) by the European Medicines Agency, but is not available as such in the United States. Without the sole agent, American clinicians have no flexibility to select and titrate cobicistat dosage, along with choices and doses of antiretroviral drugs, to match the needs of individual patients. Likewise, the embedded cobicistat provides no additional options for drug development scientists facing the aftermath of the FDA's restriction of ketoconazole.25 Ritonavir is the only inhibitor providing maximal CYP3A inhibition comparable to ketoconazole for use in DDI studies involving candidate drugs metabolized by CYP3A. Cobicastat, if available as a sole agent, could provide another option. We urge the sponsor and the FDA to move forward to make cobicistat available in the United States as a sole agent for clinical and research purposes. —David J.