Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity

Baranyai, Dorothea; Muro, Eva; Gödtel-Armbrust, Ute; Schirmer, Markus; Kisanga, Elton R.; Diczfalusy, Ulf; Fillekes, Quirine; Schuurman, Rob; Burger, David M.; Wojnowski, Leszek

doi:10.1093/jac/dku086

Cited by 2 publications

(2 citation statements)

References 18 publications

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“…In addition, carbamazepine, as a CYP3A4 inducer, has been associated with hastened clearance of nevirapine, 164,165 a CYP3A4 substrate, 166 which may also increase the risk of nevirapine resistance. [167][168][169][170] Divalproex/valproic acid Valproic acid displayed clinically significant DDIs when co-administered with zidovudine.…”

Section: Carbamazepinementioning

confidence: 99%

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Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

2018

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Psychotropic medications are frequently co-prescribed with antiretroviral therapy (ART), owing to a high prevalence of psychiatric illness within the population living with HIV, as well as a 7-fold increased risk of HIV infection among patients with psychiatric illness. While ART has been notoriously associated with a multitude of pharmacokinetic drug interactions involving the cytochrome P450 enzyme system, the magnitude and clinical impact of these interactions with psychotropics may range from negligible effects on plasma concentrations to life-threatening torsades de pointes or respiratory depression. This comprehensive review summarizes the currently available information regarding drug–drug interactions between antiretrovirals and pharmacologic agents utilized in the treatment of psychiatric disorders—antidepressants, stimulants, antipsychotics, anxiolytics, mood stabilizers, and treatments for opioid use disorder and alcohol use disorder—and provides recommendations for their management. Additionally, overlapping toxicities between antiretrovirals and the psychotropic classes are highlighted. Knowledge of the interaction and adverse effect potential of specific antiretrovirals and psychotropics will allow clinicians to make informed prescribing decisions to better promote the health and wellness of this high-risk population.

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Section: Carbamazepinementioning

confidence: 99%

Section: Mood Stabilizersmentioning

confidence: 99%

Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

2018

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Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug-resistant tuberculosis

Brill

Svensson

Pandie

et al. 2017

International Journal of Antimicrobial Agents

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Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67-99%) and M2 clearance to 119% (92-156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17-35%) and M2 clearance to 59% (44-69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.

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Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity

Abstract: The induction of nevirapine elimination reduces HIV-1 resistance mutations, but this effect is modulated by individual CYP3A activity. The study suggests that CYP3A4 activity could be monitored using an endogenous marker and, if needed, boosted to improve clinical endpoints.

Cited by 2 publications

References 18 publications

Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug-resistant tuberculosis

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