More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to the ongoing limitations of drug resistance and adverse effects, new treatment options are still required. A number of promising new agents in existing or new drug classes are in development or have recently been approved by the US FDA. Since these agents will be used in combination with other new and existing antiretrovirals, understanding the potential for drug interactions between these compounds is critical to their appropriate use. This article summarizes the drug interaction potential of new and investigational protease inhibitors (darunavir), non-nucleoside reverse transcriptase inhibitors (etravirine and rilpivirine), chemokine receptor antagonists (maraviroc, vicriviroc and INCB 9471), integrase inhibitors (raltegravir and elvitegravir) and maturation inhibitors (bevirimat).Advances in the treatment of human immunodeficiency virus (HIV) infection include the discovery of new antiretroviral agents and an improved understanding of the optimal combination of these agents for therapeutic benefit. Currently, the most potent antiretroviral regimens are those that include a combination of medications targeting different stages of the HIV life cycle. In 2007, two new classes of antiretrovirals were approved by the US FDA, and a number of other novel antiretrovirals in new classes and existing classes are being developed. All of these drugs are promising options for treatment-experienced patients. However, each class has a unique drug-interaction profile, making the optimal combination of these drugs challenging. Encouragingly, some of these new agents are not substrates of either cytochrome P450 (CYP) enzymes or drug transport proteins. This increases their potential to be used in combination with currently available antiretroviral agents without concern for subtherapeutic or supratherapeutic exposures. This article reviews the drug-drug interaction data, as well as drug-drug interaction potential, for antiretrovirals that have recently become available or are currently undergoing later phase clinical study. New protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are featured, as are new agents in the chemokine receptor antagonist class, the integrase inhibitor class, and the maturation inhibitor class. A summary of interactions between antiretrovirals can be found in tables I-III, and a summary of interactions between these new antiretrovirals and concomitant medications is presented in table IV. DarunavirDarunavir is a new protease inhibitor recently approved for the treatment of HIV-1-infected patients. In the US, the approved dose of darunavir is 600 mg, administered in conjunction with 100 mg of ritonavir, every 12 hours with food. Darunavir is recommended for use in treatment-experienced (multiple protease inhibitor-resistant) adult patients (figure 1a).1.1.1 Pharmacology-The molecular weight of darun...
ASPIRE I and II were prospective, 3-way sequential crossover studies in healthy volunteers to compare the safety and pharmacokinetics of saquinavir/ritonavir (SQV/RTV) with saquinavir/atazanavir (SQV/ATV) administered either once daily (QD, ASPIRE I) or twice daily (BID, ASPIRE II). Treatments were separated by 10 days, and pharmacokinetic analyses were performed on days 11, 32, and 53. SQV pharmacokinetics were significantly higher when dosed with RTV compared to ATV (P < .05 for all comparisons). ATV pharmacokinetics were similar within treatment arms. ATV Cmin increased approximately 60%, and Cmax decreased approximately 35% with BID dosing compared with QD dosing. Women had higher exposure for all 3 protease inhibitors (PIs) compared with men after adjusting for weight. Adverse effects were primarily gastrointestinal-related with SQV/RTV and hyperbilirubinemia with SQV/ATV. Although SQV plasma concentrations were higher when coadministered with RTV, a combination of SQV/ATV administered BID may be a viable alternative in HIV-infected, PI-naive subjects intolerant to RTV.
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