Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects

Abstract

Background Naldemedine is a peripherally acting μ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. Objectives To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. Methods Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (C max) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. Results A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC 0-inf 1.78-fold and C max 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC 0-inf 2.91-fold and 1.90-fold, and C max 1.12fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC 0-inf by 83% and C max by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. Conclusions Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Analysis of Predictive Factors for Diarrhea after the Administration of Naldemedine

“…In a phase I study, there were no NAL-related adverse events. 23) The healthy individuals were not administered opioid analgesics in the present study, so we believe that they don't have developed withdrawal symptoms. NAL is also a substrate for P-glycoprotein.…”

“…The combination of cyclosporine, a P-glycoprotein inhibitor, increased the AUC of NAL by 1.78-fold. 23) However, the combination of Pglycoprotein did not correlate with NAL-induced diarrhea for the results of the multivariate analysis. In the present study, only 7 patients received the combination of P-glycoprotein (2.9%), and, thus, the detection power has been insufficient.…”

“…the curve (AUC) by 2.91-and 1.90-fold, respectively. 23) We hypothesized that the combination of CYP3A4 inhibitors contributed to increase in the incidence of diarrhea by elevating the exposure level of NAL. In a phase I study, there were no NAL-related adverse events.…”

“…The concomitant use of CYP3A4 inhibitor and NAL increase blood concentration of NAL. 23) In addition, the incidence of NAL-induced diarrhea was higher in patients receiving 0.4 mg/d than in those receiving the approved dose of 0.2 mg/d, in phase II trial. 24,25) Therefore, CYP3A4 inhibitors may affect the incidence of NAL-induced diarrhea as a result of increasing blood levels of NAL.…”

Predictors for Effectiveness of Naldemedine in Patients with Cancer Pain: A Retrospective, Single-Institution Analysis

“…OIC control may thus be di cult. On the other hand, naldemedine is primarily metabolized by cytochrome P450 3A4 (CYP3A4) to form nor-naldemedine [17]. In this study, some patients were receiving chemotherapy with taxanes at the time of evaluation of naldemedine effectiveness.…”