Pitavastatin Concentrations Are Not Increased by CYP3A4 Inhibitor Itraconazole in Healthy Subjects

Abstract

Itraconazole is a synthetic triazole antifungal agent which is known to be a potent inhibitor of cytochrome P450 (CYP) 3A4, and may cause drug-drug interactions with the many drugs metabolized by this route, including some statins. In this study, the influence of concomitant administration of a single oral dose of pitavastatin with itraconazole at steady state was investigated to determine the potential for pharmacokinetic interaction and any effects on safety. Eighteen subjects were enrolled into the study. The AUC and Cmax of pitavastatin alone were 138 ng h/mL and 63.8 ng/mL, and pitavastatin with itraconazole were 106 ng h/mL and 49.5 ng/mL, respectively. Comparison of the 90% confidence interval of the geometric mean ratio of AUC0-t and Cmax against a standard reference of 0.80-1.25 demonstrated that the lower limit was breached for both pitavastatin and its lactone metabolite (0.71-0.84 and 0.69-0.88 for AUC0-t and Cmax , respectively, for pitavastatin, 0.86-0.97 and 0.76-0.86 for AUC0-t and Cmax , respectively, for pitavastatin lactone). The safety and tolerability of pitavastatin was not affected by co-administration with itraconazole. This study suggests that pitavastatin is not a CYP3A4 substrate in humans.

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A

“…However, the other potent CYP3A inhibitor clarithromycin slightly increased the AUC and C max values of pitavastatin (GMR ∼1.2) and decreased exposure of pitavastatin lactone (GMR ∼0.8–0.9), resulting in a ∼30% decreased pitavastatin lactone/pitavastatin AUC ratio ( Table ). These results agree with data previously reported with conventional doses of pitavastatin coadministered with rifampin, itraconazole, or clarithromycin …”

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

“…Diltiazem has been determined to be a weak in vitro inhibitor of OATP1B1 and OATP1B3 (260 and 170 µM, respectively) (Nakakariya et al, 2016). Coadministration of pravastatin with diltiazem (120 mg twice a day) did not affect the oral AUC and Cmax of pravastatin, indicating no clinical OATP1B inhibition potential (Azie et al, 1998 The mechanistic static model approach would predict no pharmacokinetic interaction at the liver inlet and plasma concentrations attained because the overall estimated R-value is low (< 1.17) ( shown to have no influence on AUC of pitavastatin (Nakagawa et al, 2013, Prueksaritanont et al, 2017. Pitavastatin is a more sensitive and selective OATP1B clinical probe than rosuvastatin due to lack of complications from drug metabolizing enzymes and gut efflux transporters (Prueksaritanont et al, 2014).…”

Pitavastatin: focus on safety and drug interactions

“…В исследовании на группе здоровых добровольцев не отмечено существенного нарастания уровня питавастатина в плазме крови при совместном использовании с ингибитором цитохрома CYP3А4 интраконазолом [20].…”