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

Everolimus is widely used to prevent rejection after solid organ transplantation; however, adjustment of its dose is difficult due to its narrow therapeutic range.1 Everolimus is primarily metabolised by cytochrome P450 (CYP) 3A and is hence susceptible to drug‐drug interactions.1 Clotrimazole troche is an azole antifungal drug, which gradually dissolves in the oral cavity. It has frequently been used for the prophylaxis and treatment of oral mucosal candidiasis following solid organ transplantation2; however, no previous studies have reported an interaction between everolimus and clotrimazole troche. Here, we describe the first reported case of a drug‐drug interaction between clotrimazole troche and everolimus.

A 27‐year‐old man with dilated cardiomyopathy underwent heart transplantation. His initial oral post‐transplant immunosuppressive regimen comprised tacrolimus (twice daily at 1.4 mg and 1.2 mg), mycophenolate mofetil (twice daily at 0.5 g each), and prednisolone (twice daily at 10.0 mg and 5.0 mg). Five months after transplantation, mycophenolate mofetil was replaced with everolimus (twice daily) to prevent kidney dysfunction. The whole blood concentration of everolimus was measured using the latex‐enhanced turbidimetric immunoassay (Nanopia® TDM Everolimus; Sekisui Medical, Tokyo, Japan). The within‐assay and day‐to‐day coefficients of variation were 4.0% to 6.8% and 3.6% to 5.4%, respectively, and the limit of quantitation was 1.5 ng/mL.3 The everolimus dose was adjusted to a target trough concentration (C₀) range of 6.0 to 8.0 ng/mL. According to the protocol used at our hospital, clotrimazole troche (10.0 mg four times daily) was discontinued at 1 year after transplantation. We evaluated the change in everolimus pharmacokinetics from 50 days before to 74 days after clotrimazole discontinuation. During this period, aspartate aminotransferase and alanine aminotransferase levels were 16 to 29 (normal range, 13‐33) U/L and 8 to 16 (normal range, 8‐42) U/L (minimum‐maximum), respectively. Other medications, including dried ferrous sulphate (105.0 mg once daily), aspirin (100.0 mg once daily), spironolactone (25.0 mg once daily), losartan potassium (25.0 mg once daily), potassium gluconate (1,874.0 mg thrice daily), bifidobacterium preparation (10.0 mg thrice daily), amlodipine (2.5 mg once daily), sodium valproate (200.0 mg twice daily), lansoprazole (30.0 mg once daily), and ramelteon (8.0 mg once daily) were administered at the start of the study period. On the 41st day before clotrimazole discontinuation, alfacalcidol administration (0.5 μg once daily) was initiated. On the 10th and 43rd day after clotrimazole discontinuation, ascorbic acid/calcium pantothenate (200.0 mg/3.0 mg thrice daily) and alendronic acid (35.0 mg once weekly) administration were initiated, respectively. On the 8th and 40th day after clotrimazole discontinuation, the dose of dried ferrous sulphate was increased from 105.0 to 210.0 mg/day, and bifidobacterium preparation was discontinued, respectively. Further, on the 43rd day before clotrimazole discontinuation, the dose of prednisolone was decreased from 7.5 to 5.0 mg/day, and on the 69th day after clotrimazole discontinuation, the dose was decreased from 5.0 to 2.5 mg/day. Monitoring of the everolimus C₀ revealed a decrease in C₀ beginning 3 days after clotrimazole discontinuation (Figure 1). To maintain the target C₀, it was necessary to increase the dose of everolimus (mg/day) by approximately twofolds. Using the linear trapezoidal method, the area under the curve between 0 and 12 hours (AUC_0‐12) was calculated on the 45th day before and 52nd day after clotrimazole discontinuation. Blood concentrations before and 1, 2, 4, 6, 8, and 12 hours after everolimus administration were used to calculate the AUC_0‐12. According to the one‐compartment model, apparent oral clearance (CL/F) was calculated by dividing the after‐dinner dose by the AUC_0‐12 value. Further, on the 45th day before clotrimazole discontinuation, AUC_0‐12 and CL/F were 125.3 ng·h/mL and 6.0 L/h, respectively, whereas on the 52nd day after clotrimazole discontinuation, the values were 133.6 ng·h/mL and 11.2 L/h, respectively.

Figure 1.

Effect of clotrimazole on the everolimus dose and trough concentration. The black bars with numbers indicate the date after clotrimazole discontinuation. The date after clotrimazole discontinuation is described as a positive number, whereas that before clotrimazole discontinuation is described as a negative number. C₀, trough concentration; filled dots, everolimus dose; open dots, trough concentration

Azole antifungal drugs can significantly influence the bioavailability of everolimus via CYP3A inhibition.1 It was previously assumed that systemic absorption of clotrimazole troche is minimal and that the risk of drug interactions with CYP3A substrates is low.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.6 Although the clotrimazole bioavailability was low, clotrimazole troche may have affected everolimus bioavailability by inhibiting intestinal first‐pass metabolism. In this scenario, clotrimazole troche removal would enhance everolimus metabolism and reduce bioavailability.

In this study, clotrimazole reduced the CL/F of everolimus by 46.7%. Ketoconazole, itraconazole, and fluconazole reportedly reduced the CL/F of everolimus by approximately 95.0%, 75.0%, and 65.0%, respectively.7, 8, 9 Compared with other azole antifungal drugs, clotrimazole may have a smaller effect on the pharmacokinetics of everolimus. Although the discontinuation of clotrimazole significantly decreased the C₀ of tacrolimus, a substrate drug for CYP3A, and could cause transplant rejection in some cases,10, 11 no findings that other azoles, including ketoconazole, itraconazole, and fluconazole, increase the risk of transplant rejection have been reported.12, 13, 14 In general, the duration of drug interactions by CYP inhibitors may be influenced by the elimination half‐life of the drugs.15 The elimination half‐life of clotrimazole is shorter than those of ketoconazole, itraconazole, and fluconazole.16, 17, 18 Therefore, drug interactions between tacrolimus and clotrimazole may rapidly disappear just after clotrimazole discontinuation, thereby resulting in unexpectedly low tacrolimus concentrations and transplant rejection. It is necessary to maintain the everolimus C₀ at ≥3.0 ng/mL under tacrolimus co‐treatment to prevent transplant rejection.1 In the current case, the C₀ of everolimus decreased from 8.4 to 2.5 ng/mL after clotrimazole discontinuation. Therefore, this drastic reduction of everolimus concentration after clotrimazole discontinuation could have triggered transplant rejection. Recently, Laub et al reported that an empirical tacrolimus dose increase prevented C₀ reduction of tacrolimus after clotrimazole troche discontinuation.10 Therefore, an empirical everolimus dose increase may similarly prevent C₀ reduction of everolimus after clotrimazole troche discontinuation.

A potential limitation should be considered when interpreting the results. In our study, the CL/F of everolimus after clotrimazole discontinuation was 11.2 L/h. Meanwhile, because the CL/F of everolimus in healthy volunteers was approximately 20.0 L/h, the CL/F of everolimus in our study seems low.19 The patient was concomitantly treated with several CYP3A substrates (e.g. amlodipine, lansoprazole, and ramelteon). Further, because everolimus is primarily metabolised by CYP3A, these concomitant drugs may have affected the pharmacokinetics of everolimus.

Clotrimazole troche may inhibit everolimus metabolism, resulting in reduced everolimus bioavailability (via increased metabolism) following clotrimazole discontinuation. It is necessary to carefully adjust the everolimus dose via therapeutic drug monitoring during clotrimazole troche therapy to avoid acute rejection and other adverse effects.

CONTRIBUTORS

T.U., K.W., M.I., and M.T. were involved in research design. T.U., K.W., and M.T. conducted experiments and clinical study. T.U., K.W., and M.T. performed data analysis. All authors wrote the manuscript or contributed in the writing of the manuscript.

COMPETING INTERESTS

There are no competing interests to declare. This case study was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (reference number M27–044‐6).