Clinical Pharmacokinetics of Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue inhibitors of reverse transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.

Role of Clinical Pharmacist to Reduce Risk in Patients Involving Antiretroviral Drugs at Abidjan Cohort

“…Our estimate of risk (27.57%) is similar to G. Kigen results (27.00%) [20] and our observation was same to the previous surveys from the Netherlands, the United States, and Kenya where potential CSDIs were reported in 14-41% patients [2][3][4][5]. We observed that, risk for CSDIs have affected about 30% of patients.…”

“…The interactions mechanism is either inducers or inhibitors of CYP enzymes. Further, PIs are substrates and/or inhibitors of drug transporters such as P-glycoprotein which may result in pharmacokinetic drug interactions [2][3][4]. Indeed, managing drug-drug interactions is one of the major challenges in the optimization of HIV therapy [5,6].…”

Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers

“…In the latter study ritonavir was dosed at 500 mg b.i.d., which, on a daily basis, is five times the dose used in the current study. Efavirenz is reported to have both inhibitory and inducing effects on CYP3A4 [25], and ritonavir depends mainly on CYP3A4 for its metabolism [9]. These data suggest that efavirenz coadministration may accelerate the metabolism of ritonavir administered at a low dose, which has also been reported previously [18].…”

Drug Interactions Between Antiretroviral Drugs and Comedicated Agents

“…In contrast to the NRTIs, the NNRTIs are not incorporated in the proviral DNA, but bind directly to the viral reverse transcriptase to block polymerase activity by causing a disruption of the enzyme catalytic site. [6] The NNRTIs are extensively metabolised by the liver via the CYP enzyme system. Besides substrates, NVP and EFV are both inducers of CYP3A4, whereas DLV acts as a potent inhibitor of CYP3A4.…”

“…antidepressives or antibacterials) is used in addition to the antiretroviral regimen. Since both non-nucleoside reverse transcriptase inhibitors (NNRTIs) and PIs are extensively metabolised by the cytochrome P450 (CYP) system, [6,7] there is a considerable potential for pharmacokinetic interactions when these drugs are administered concomitantly with drugs metabolised via the same pathway. Awareness, recognition and management of drug interactions are important in the optimisation of pharmaceutical care to HIVinfected patients, helping to prevent adverse events and/or loss in efficacy of the drugs administered.…”