Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Clotrimazole troches are commonly used as prophylaxis for thrush that may develop in immunocompromised patients.• Conflicting data suggest that clotrimazole may induce or inhibit cytochrome P450 (CYP) 3A4. WHAT THIS STUDY ADDS?• We have demonstrated that clotrimazole increased the area under the concentration-time curve and decreased the apparent oral clearance of midazolam following oral administration without affecting the pharmacokinetic properties of midazolam after intravenous administration. • These data permit the suggestion that clotrimazole may cause clinically relevant changes in the pharmacokinetics or pharmacodynamics of concurrently administered oral CYP3A substrates that undergo significant first-pass metabolism in this patient population. AIMSThe aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma. METHODSWe conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg -1 with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters. RESULTSTen healthy volunteers aged 21-26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 Ϯ 13 l h -1 [95% confidence interval 48, 66] to 36 Ϯ 9.8 l h -1 (95% confidence interval 29, 43) (P = 0.003). These changes were accompanied by a decrease in the area under the concentration-time curve (mean difference 22 mg h -1 l -1 , P = 0.001) and bioavailability (mean difference 0.21, P = NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches. CONCLUSIONSOral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.

Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

“…In total, 38 and 44 publications that included reported CL values were identified for gentamicin and midazolam, respectively. These papers reported a total of 66 and 57 CL values for gentamicin and midazolam, respectively.…”

Associations of ABCB1 3435C>T and IL-10-1082G>A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients

“…Among all significant covariates, BMI correlated positively with SRL log (C/D), similar to a previous finding showing higher initial tacrolimus blood levels in overweight renal transplant recipients (22). Additionally, SRL concentration/dose ratios were increased during clotrimazole or statins co-administration and were decreased during tacrolimus or prednisone co-administration, suggesting CYP3A enzyme competition between substrates (statins and tacrolimus) as well as CYP3A induction and inhibition by corticosteroids (23,24) and clotrimazole, respectively (25,26). The effect of steroids may influence the observation that prednisone sparing sirolimus protocols have high rates of SRL related adverse effects such as mouth ulcers (27,28).…”

Clotrimazole troches can alter everolimus pharmacokinetics in post‐transplant patients: A case report

“…4 However, the drug interaction has gained attention since Shord et al recently reported that clotrimazole troche inhibited the intestinal metabolism of midazolam, a substrate drug for CYP3A, without affecting the systemic metabolism. 5 In the current case, the CL/F of everolimus increased by 1.9-fold after clotrimazole discontinuation. Everolimus is metabolised by CYP3A in the liver and intestines.…”

“…It was previously assumed that systemic absorption of clotrimazole troche is minimal and that the risk of drug interactions with CYP3A substrates is low . However, the drug interaction has gained attention since Shord et al recently reported that clotrimazole troche inhibited the intestinal metabolism of midazolam, a substrate drug for CYP3A, without affecting the systemic metabolism . In the current case, the CL/F of everolimus increased by 1.9‐fold after clotrimazole discontinuation.…”