Prolonged‐Release Tacrolimus Is Less Susceptible to Interaction With the Strong CYP3A Inhibitor Voriconazole in Healthy Volunteers

Abstract

The nature and extent of drug-drug interactions between oral drugs is affected by numerous modulators. The effect of the formulation (prolonged release (PR) vs. immediate release (IR)) of a victim drug during treatment with a CYP3A (cytochrome P450 enzyme 3A4) inhibitor is unknown but expected to be smaller with PR. We studied PR and IR tacrolimus during treatment with the strong CYP3A inhibitor voriconazole in 18 healthy volunteers in a pharmacokinetic, four-phase, crossover trial. The exposure increase was significantly smaller after PR tacrolimus than after IR tacrolimus (AUC (area under the curve) 2.62-fold vs. 6.02-fold, P < 0.001; C max (maximum concentration) 2.02-fold vs. 2.7-fold, P = 0.026) and less variable (AUC increase 1.6 to 4.8-fold vs. 1.8 to 19-fold). CYP3A5 genotype, voriconazole exposure, and CYP3A4 phenotype (determined with a midazolam microdose) were not related to the relative change in tacrolimus exposure. Thus, when considering drug-drug interactions with CYP3A inhibitors, the formulation of orally administered victim drugs should also be considered.

Differential Effect of a Continental Breakfast on Tacrolimus Formulations With Different Release Characteristics

“…Inclusion and exclusion criteria were very similar to those used in our previous trial. 7 In the present trial, female volunteers could be included if they were using highly effective contraceptive measures. Female-specific exclusion criteria were pregnancy, lactation, and Fridericia's corrected QT interval >460 milliseconds.…”

Investigation of the Impact of CYP3A5 and CYP2C19 Polymorphisms on Drug-Drug Interactions between Tacrolimus and Voriconazole Based on Physiologically-Based Pharmacokinetic Modeling

“…Second, we did not take into account the dosage form of oral tacrolimus during the treatment with voriconazole. Andrew et al has found out that pro-longed tacrolimus is less susceptible to interaction with voriconazole in healthy volunteers [14] . Third, our prediction results require further validation from more real-world data to implement the findings.…”

“…After the rat-based PBPK model was built up successfully, it was scaled to whole-body PBPK model of human. And the datasets from three clinical trails [14,30] were used to evaluate the performance of human PBPK model. The model performance was evaluated using two methods.…”

“…Moreover, based on the observational clinical data in solid organ recipients, CYP3A5 expressers were associated with lower changes in concentration-to-dose ratio of tacrolimus after coadministration with voriconazole. And, comparing with CYP3A5 nonexpressers, DDIs between tacrolimus and voriconazole were expected to be smaller in expressers [13] , However, a study demonstrated that the extent of the interaction was not different between CYP3A5 expressers and nonexpressers [14] . All of these indicates that the effect of CYP3A5 and CYP2C19 genotypes on DDIs between tacrolimus and voriconazole is worth considering.…”

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply

“…9,10 Differences in the extent of metabolism by CYP3A enzymes also make LCPT less susceptible to certain drug interactions. 11 Additionally, a lower Cmax achieved by LCPT decreases peak-related side effects, such as neurotoxicities. 12 Both the regulated absorption and reduction in peaks have led to speculation that use may reduce opportunistic infections, such as BK polyomavirus, but this theory requires further investigation.…”