Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV treatment

ABSTRACT

Introduction: Drugs used in HIV treatment; all protease inhibitors, some non-nucleoside reverse transcriptase inhibitors, and pharmacoenhancers ritonavir and cobicistat can inhibit cytochrome P450 (CYP) enzymes. CYP inhibition can cause clinically significant drug–drug interactions (DDI), leading to increased drug exposure and potential toxicity.

Areas covered: A complete understanding of pharmacodynamics and CYP-mediated DDI is crucial to prevent adverse side effects and to achieve optimal efficacy. We summarized the pharmacodynamics of all the CYP inhibitors used for HIV treatment, followed by a discussion of drug interactions between these CYP inhibitors and other drugs, and a discussion on the effect of CYP polymorphisms. We also discussed the potential advancements in improving the pharmacodynamics of these CYP inhibitors by using nanotechnology strategy.

Expert opinion: The drug-interactions in HIV patients receiving ARV drugs are complicated, especially when patients are on CYP inhibitors-based ART regimens. Therefore, evaluation of CYP-mediated drug interactions is necessary prior to prescribing ARV drugs to HIV subjects. To improve the treatment efficacy and minimize DDI, novel approaches such as nanotechnology may be the potential alternative approach. However, further studies with large cohort need to be conducted to provide strong evidence for the use of nano-formulated ARVs to effectively treat HIV patients.

Trial registration: ClinicalTrials.gov identifier: NCT00002162.

KEYWORDS:

• Antiretroviral therapy
• CYP inhibitors
• drug–drug interactions
• HIV
• nanoparticles
• pharmacodynamics

Article highlights

• Most of the drugs used in HIV such as protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), and pharmacokinetics enhancers (PK enhancers) are metabolized by cytochrome P450 (CYP) pathway.

• PK enhancers, all PIs, and some NNRTIs are also CYP inhibitors, which are expected to have a higher chance of interfering with drug metabolism causing unexpected pharmacodynamic changes and drug–drug interactions. Among all the CYP inhibitors used for HIV treatment, RTV and COBI are the most potent CYP inhibitors of both CYP3A4 and CYP2D6.

• The drug groups most implicated in CYP-mediated interactions with CYP inhibitors-based antiretroviral therapy (ART) include statins, anti-TB drugs, antifungals, and anticonvulsants.

• Acquisition of the knowledge of CYP-mediated drug–drug interactions will help clinicians to manage patients on ART regimens more efficiently.

To improve the treatment efficacy and minimize the drug–drug interactions, novel approaches which can bypass CYP metabolism may be the potential alternative future direction.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institutes of Health (grant nos. AA022063 and DA047178) and National Institute on Alcohol Abuse and Alcoholism.