Antiretroviral concentrations in the presence and absence of valproic acid

Abstract Objectives An unexpected drug–drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential underlying mechanisms, plasma protein displacement has been suggested. The aim of this study was to assess plasma concentrations of several antiretrovirals when administered with or without valproic acid. Methods We performed a therapeutic drug monitoring registry analysis and identified patients concomitantly taking antiretrovirals and valproic acid and without clinical affecting conditions or interacting drugs. Results One hundred and thirty-four patients were identified. Median (IQR) age and BMI were 49.7 years (45–56) and 23.4 kg/m2 (20.8–26.3) and 78 were male (58.2%). Despite small groups, we observed no major effect on antiretroviral exposure, even when considering highly protein-bound compounds (such as etravirine), with the exception of dolutegravir trough concentrations [median (IQR) = 132 ng/mL (62–227) in individuals on valproic acid versus 760 ng/mL (333–1407) in those not receiving valproic acid]. Conclusions Valproic acid does not have a major effect on antiretrovirals other than dolutegravir. The mechanism of this unexpected drug–drug interaction may be the combination of protein displacement, reduced absorption and CYP3A4 induction.

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Faculty of 1000 evaluation for Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.717958759.793470403 ◽

2013 ◽

Author(s):

Glenn Tillotson

Keyword(s):

Drug Interaction ◽

Protease Inhibitor ◽

Healthy Volunteers ◽

Integrase Inhibitor ◽

Hiv Integrase ◽

Hcv Protease ◽

Drug Drug Interaction ◽

Clinically Significant

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Lack of a Clinically Significant Drug–Drug Interaction in Healthy Volunteers Between the Hepatitis C Virus Protease Inhibitor Boceprevir and the HIV Integrase Inhibitor Raltegravir

Clinical Infectious Diseases ◽

10.1093/cid/cis824 ◽

2012 ◽

Vol 56 (2) ◽

pp. 300-306 ◽

Cited By ~ 22

Author(s):

Clara T. M. M. de Kanter ◽

Maren I. Blonk ◽

Angela P. H. Colbers ◽

Bas J. J. W. Schouwenberg ◽

David M. Burger

Keyword(s):

Drug Interaction ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Protease Inhibitor ◽

Healthy Volunteers ◽

Integrase Inhibitor ◽

Hiv Integrase ◽

Drug Drug Interaction ◽

Clinically Significant

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The dolutegravir/valproic acid drug–drug interaction is primarily based on protein displacement

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab021 ◽

2021 ◽

Author(s):

P D J Bollen ◽

H A B Prins ◽

A Colbers ◽

K Velthoven-Graafland ◽

B J A Rijnders ◽

...

Keyword(s):

Valproic Acid ◽

Drug Interaction ◽

Controlled Trial ◽

Underlying Mechanism ◽

Hiv Rna ◽

Parallel Increase ◽

Drug Drug Interaction ◽

To Receive ◽

Protein Displacement

Abstract Objectives The dolutegravir/valproic acid drug–drug interaction (DDI) is suggested to be caused by protein displacement. Here, we assess the underlying mechanism. Methods Participants in a randomized controlled trial investigating valproic acid as an HIV latency reversing agent were recruited in a predefined pharmacokinetic substudy if they were on once-daily 50 mg dolutegravir-containing combination ART (cART) for >12 months with a plasma HIV-RNA <50 copies/mL (trial registration: ClinicalTrials.gov NCT03525730). Participants were randomized to receive 30 mg/kg/day valproic acid orally (divided into two equal doses) for 14 days or not. Total and unbound dolutegravir concentrations were measured on day 0 (before intake of valproic acid and 6 h after intake of valproic acid) and on days 1, 7, 14 and 42. Intra- and inter-subject dolutegravir concentrations and geometric means (GMs) were evaluated. Results Six of 10 participants on dolutegravir were randomized to receive valproic acid. During 14 days of valproic acid treatment, the GM total dolutegravir concentration decreased sharply from 1.36 mg/L on day 0 to 0.85, 0.31 and 0.20 mg/L on days 0, 1, 7 and 14, respectively, while total dolutegravir concentrations in the controls remained comparable during the same period: 1.27–1.49 mg/L. We observed a parallel increase in unbound dolutegravir fractions ranging from 0.39% to 0.58% during valproic acid administration, compared with 0.25% to 0.28% without valproic acid. Unbound dolutegravir concentrations were above the established in vitro EC90 value for unbound dolutegravir in 85% of the tested samples. Conclusions This study confirms protein displacement as the main mechanism for this DDI, although additional mechanisms might be involved too. If dolutegravir is taken with food, this DDI is probably not clinically relevant.

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Amiodarone Rifampicin Drug–Drug Interaction Management With Therapeutic Drug Monitoring

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000487 ◽

2018 ◽

Vol 40 (2) ◽

pp. 159-161 ◽

Cited By ~ 3

Author(s):

Thijs H. Oude Munnink ◽

Anna Demmer ◽

Roel H. J. Slenter ◽

Kris L. L. Movig

Keyword(s):

Drug Interaction ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Therapeutic Drug ◽

Drug Drug Interaction ◽

Interaction Management

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Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz504 ◽

2019 ◽

Vol 75 (3) ◽

pp. 648-655 ◽

Cited By ~ 3

Author(s):

Scott L Letendre ◽

Anthony Mills ◽

Debbie Hagins ◽

Susan Swindells ◽

Franco Felizarta ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Steady State ◽

Antiviral Activity ◽

Plasma Concentrations ◽

Integrase Inhibitor ◽

Virological Suppression ◽

Hiv Integrase ◽

Long Acting ◽

Hiv 1

Abstract Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF. Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

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Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

Scientific Reports ◽

10.1038/srep04362 ◽

2014 ◽

Vol 4 (1) ◽

Cited By ~ 10

Author(s):

Anu Marahatta ◽

Bidur Bhandary ◽

Seul-Ki Jeong ◽

Hyung-Ryong Kim ◽

Han-Jung Chae

Keyword(s):

Valproic Acid ◽

Drug Interaction ◽

Plasma Concentrations ◽

Interaction Study ◽

Drug Interaction Study

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Advantages of everolimus therapeutic drug monitoring in oncology when drug–drug interaction is suspected: A case report

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220904761 ◽

2020 ◽

Vol 26 (7) ◽

pp. 1743-1749 ◽

Cited By ~ 1

Author(s):

Geoffrey Strobbe ◽

Diane Pannier ◽

Ilyes Sakji ◽

Alexandre Villain ◽

Frédéric Feutry ◽

...

Keyword(s):

Drug Interaction ◽

Case Report ◽

Therapeutic Drug Monitoring ◽

Drug Interactions ◽

Drug Monitoring ◽

Plasma Concentrations ◽

Response To Treatment ◽

Therapeutic Drug ◽

High Doses

Introduction Drug interactions involving everolimus are fairly well known because of its common use, primarily as an immunosuppressant. Several recommendations regarding therapeutic drug monitoring are also available for the use of everolimus-based immunosuppression regimens. However, everolimus use in oncology differs substantially, particularly because of the high doses involved. Therapeutic drug monitoring, although sometimes necessary, is not recommended as a routine in oncology. Thus, it was deemed inapplicable due to the lack of clear recommendations. Case report Here, we present a case where a patient was prescribed everolimus for renal cell carcinoma. The patient benefitted from a pharmaceutical consultation prior to treatment initiation, and a drug interaction with verapamil was suspected. Management and outcome: Therapeutic drug monitoring of everolimus was proposed. Based on the everolimus values reported in the literature, trough plasma concentration in the patient was greatly increased. The patient was then diagnosed with grade 4 oral mucositis, thereby requiring temporary suspension of everolimus treatment. Management of adverse effects was performed through multiple medicated mouthwashes. Discussion Therapeutic drug monitoring for everolimus is important for potential drug interactions or the occurrence of severe adverse events. In such cases, dose adjustments should be managed according to everolimus plasma concentrations. Clear oncological recommendations regarding plasma everolimus thresholds are required for a successful follow-up of the patient’s condition and to ensure adequate response to treatment.

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Abstract PS5-16: Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring

10.1158/1538-7445.sabcs20-ps5-16 ◽

2021 ◽

Author(s):

Fanny Leenhardt ◽

Matthieu Gracia ◽

Catherine Perrin ◽

Claudia Muracciole-Bich ◽

Bénédicte Marion ◽

...

Keyword(s):

Drug Interaction ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Serum Levels ◽

Therapeutic Drug ◽

Drug Drug Interaction

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Isoniazid Mediates theCYP2B6*6Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02532-14 ◽

2014 ◽

Vol 58 (7) ◽

pp. 4145-4152 ◽

Cited By ~ 13

Author(s):

Michael H. Court ◽

Fawziah E. Almutairi ◽

David J. Greenblatt ◽

Suwagmani Hazarika ◽

Hongyan Sheng ◽

...

Keyword(s):

Drug Interaction ◽

Plasma Concentrations ◽

Liver Microsomes ◽

Selective Inhibition ◽

Recombinant Enzymes ◽

Antituberculosis Drugs ◽

Antituberculosis Therapy ◽

Dependent Inhibition ◽

Drug Drug Interaction

ABSTRACTEfavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with theCYP2B6*6/*6genotype (but not theCYP2B6*1/*1genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction.In vitrostudies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [Ki] = 368 μM) and pyrazinamide (Ki= 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [KI] = 30 μM; maximal rate constant of inactivation [kinact] = 0.023 min−1) and recombinant CYP2A6 (KI= 15 μM;kinact= 0.024 min−1) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes orCYP2B6*6genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.

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