A Case of a Potential Drug Interaction between Clobazam and Etravirine-Based Antiretroviral Therapy

Naccarato, Mark; Yoong, Deborah; Kovacs, Colin; Gough, Kevin

doi:10.3851/imp1953

Cited by 25 publications

(13 citation statements)

References 17 publications

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“…CBD inhibits CYP 2C19 and CYP 3A4, which catalyze the metabolism of nCLB . This inhibition likely leads to an accumulation of nCLB, which studies have shown to be about 20–100% as potent as CLB .…”

Section: Discussionmentioning

confidence: 99%

“…CBD inhibits CYP 2C19 and CYP 3A4, which catalyze the metabolism of nCLB. [14][15][16][17] This inhibition likely leads to an accumulation of nCLB, which studies have shown to be about 20-100% as potent as CLB. 12 In addition, genetic polymorphism exists for CYP 2C19 expression, resulting in rare poor CYP 2C19 metabolizers, 24 in which plasma levels of N-desmethylclobazam are fivefold higher in plasma than in CYP 2C19 extensive metabolizers.…”

Section: Discussionmentioning

confidence: 99%

“…14,15 CLB metabolism similarly involves CYP 3A4, the primary enzyme in its metabolic pathway, and, to a lesser extent, CYP 2C19. Both of these enzymes catalyze the metabolism of N-desmethylclobazam (norclobazam; nCLB), the active metabolite of CLB, 12,16,17 which in animal and in vitro studies have shown to be about 20-100% as potent as CLB. 12 The elimination half-lives of CLB and nCLB are 36-42 and 71-82 h, respectively.…”

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confidence: 99%

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Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy

et al. 2015

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SUMMARYObjective: Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. Methods: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. Results: We report elevated CLB and nCLB levels in these subjects. The mean (AE standard deviation [SD]) increase in CLB levels was 60 AE 80% (95% confidence interval (CI) [À2-91%] at 4 weeks); the mean increase in nCLB levels was 500 AE 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. Significance: Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy

et al. 2015

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“…Clobazam is similarly hepatically metabolized and there is a case report of neurotoxicity from increased concentrations of clobazam when co-administered with the NNRTI etravirine. [53] Felbamate and vigabatrin are normally reserved for refractory epilepsy cases and the associated adverse side effects of aplastic anemia and liver failure (felbamate) and vision loss (vigabatrin) could be particularly devastating in the HIV population. Zonisamide is an attractive candidate because its once daily dosing is favorable for compliance, particularly in patients with neurocognitive impairment.…”

Section: Treatmentmentioning

confidence: 99%

Safe Treatment of Seizures in the Setting of HIV/AIDS

Siddiqi

Birbeck

2013

Curr Treat Options Neurol

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OPINION STATEMENT HIV+ patients are at increased risk for developing seizures due to the vulnerability of the central nervous system to HIV-associated diseases, immune dysfunction and metabolic disturbances. In patients with acute seizures, standard protocols still apply with urgent seizure cessation being the priority. Management of the person with established epilepsy who contracts HIV is challenging, but the decision to initiate chronic antiepileptic drug (AED) therapy in an HIV+ patient is also difficult. Chronic treatment guidelines emphasize the interactions between AEDs and antiretroviral (ARV) medications, but provide no explicit advice regarding when to initiate an AED, what medication to select, and/or the duration of treatment. Epidemiologic data regarding seizure recurrence risk in HIV+ individuals is not available. The risk of further seizures likely depends upon the underlying etiology for the seizure(s) and patients’ immune status and may be increased by the use of efavirenz (an ARV). The issues for consideration include AED-ARV interactions, organ dysfunction, seizure type, and drug side effects which may worsen or be confused with symptoms of HIV and/or epilepsy. Co-administration of enzyme inducing (EI)-AEDs and ARVs can result in virological failure, breakthrough seizure activity, AED toxicity and/or ARV toxicity. Where available, the AED of choice in HIV+ patients is levetiracetam due to its broad spectrum activity, ease of use, minimal drug interactions, and favorable side effect profile. Lacosamide, gabapentin, and pregabalin are also favored choices in patients with partial onset seizures and/or those failing levetiracetam. Where newer AEDs are not available, valproic acid may be the treatment of choice in terms of an AED which will not cause enzyme induction-associated ARV failure, but its side effect profile causes other obvious problems. In resource-limited settings (RLS) where only EI-AEDs are available, there are no good treatment options and further pressure needs to be placed upon policymakers to address this care gap and public health threat.

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“…Four of these cases 41,42,84,85 had N-desmethylclobazam concentrations >3000 ng/mL; 3 cases 41,42,85 had concentrations > 4 times 3000 ng/mL, including 1 case 85 >10 times 3000 ng/mL. N-desmethylclobazam concentrations were not measured in 2 cases, 83,86 but their clobazam concentrations were >3000 ng/mL or 10 times higher than the upper recommended limit of 300 ng/mL.…”

Section: Literature Reviewmentioning

confidence: 87%

Clobazam Therapeutic Drug Monitoring

Leon

Spina

Díaz

2013

Therapeutic Drug Monitoring

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Background Clobazam was recently approved for Lennox-Gastaut syndrome in the US. There is no published review article focused on clobazam therapeutic drug monitoring (TDM) in English. Methods More than two hundred clobazam articles identified by a PubMed search were carefully reviewed for information on clobazam pharmacokinetics. Clobazam is mainly metabolized by a cytochrome P450 (CYP) isoenzyme, CYP3A4, to its active metabolite, N-desmethylclobazam. Then, N-desmethylclobazam is mainly metabolized by CYP2C19 unless the individual has no CYP2C19 activity (poor metabolizer, PM). Results Using a mechanistic approach to reinterpret the published findings of steady-state TDM and single-dosing pharmacokinetic studies, four different serum clobazam concentration ratios were studied. The available limited steady-state TDM data suggest that the serum N-desmethylclobazam/clobazam ratio can be useful for clinicians, including identifying CYP2C19 PMs (ratio >25 in the absence of inhibitors). There are three possible concentration/dose (C/D) ratios. The clobazam C/D ratio has the potential to measure the contribution of CYP3A4 activity to the clearance of clobazam from the body. The N-desmethylclobazam C/D ratio does not appear to be a good measure of clobazam clearance and should be substituted with the total (clobazam+N-desmethylclobazam) C/D ratio. Conclusions Future clobazam TDM studies need to use trough concentrations after steady-state has been reached (>3 weeks in normal individuals and several months in CYP2C19 PMs). These future studies need to explore the potential of clobazam and total C/D ratios. Better studies on the relative potency of N-desmethylclobazam compared to the parent compound are needed to provide weighted total serum concentrations that correct for the possible lower N-desmethylclobazam pharmacodynamic activity. Standardization and more studies of C/D ratios from clobazam and other drugs can be helpful to move TDM forward.

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A Case of a Potential Drug Interaction between Clobazam and Etravirine-Based Antiretroviral Therapy

Cited by 25 publications

References 17 publications

Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy

Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy

Safe Treatment of Seizures in the Setting of HIV/AIDS

Clobazam Therapeutic Drug Monitoring

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