Interaction of Terbinafine (Anti-fungal agent) with Perhexiline: A Case Report

Sheikh, A.; Westley, Ian S.; Sallustio, Benedetta C.; Horowitz, John D.; Beltrame, John F.

doi:10.1016/j.hlc.2013.11.012

Cited by 10 publications

(4 citation statements)

References 15 publications

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“…As a result of its toxicity (hepatotoxicity and neuropathy related to CYP2D6 polymorphism), it was removed from the market worldwide except Australia where it continues to be available for clinical use provided the patients are CYP2D6 genotyped pretreatment and a genotype-specific dose prescribed. While this strategy has worked extremely well, there are isolated cases where patients doing well later developed toxic concentrations of or toxicity to perhexiline following a co-prescription of not only strong but also moderate CYP2D6 inhibitors [96,97]. This underscores how, even when a personalized drug and its dose have been selected, careful vigilance is required for the consequences of unintentional phenoconversion.…”

Section: Routine Clinical Practicementioning

confidence: 99%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

220

217

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Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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Section: Routine Clinical Practicementioning

confidence: 99%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

220

217

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“…Indeed, one case was reported in which the plasma concentration of the anti-arrhythmic perhexiline rose remarkably during concomitant administration with TER, and at least 3 months was required for restoration to a baseline OH-perhexiline/perhexiline ratio after discontinuation of TER. 35) We believe the model developed in the present study would also be applicable to evaluation of interactions of other CYP2D6 substrate drugs with TER.…”

Section: Discussionmentioning

confidence: 90%

“…Their dispositions are characterized by very long elimination half-lives, as is the case with TER. 34) Therefore, should these metabolites possess CYP2D6-inhibitory activity, the apparent K P value might be higher than the actual level; further investigation is needed to resolve this issue.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline

Mikami

Hori

Ohtani

et al. 2017

Biological & Pharmaceutical Bulletin

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The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound K values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug-drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound K values of 13.7 and 12.4 nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

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“…1,3 In addition, rare but potentially serious adverse events (eg, hepatotoxicity, lupus) associated with terbinafine could be an unnecessary risk that a misdiagnosed patient could be exposed to, if confirmatory tests are not used. [52][53][54][55] The potential risks to the patient are just too great to ignore. With itraconazole, there is a similar risk of serious adverse events.…”

Section: Discussionmentioning

confidence: 99%