Phase 1, Randomized, Double‐Blind, Placebo‐Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers

Fukumura, Kazuya; Yokota, Takaaki; Baba, Yoshitaka; Ferreira, Juan Camilo Arjona

doi:10.1002/cpdd.387

Cited by 18 publications

(48 citation statements)

References 21 publications

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“…10 No major safety or tolerability issues were observed in either study. 10,11 Another phase 1 study, in which healthy subjects were administered 2 mg of [oxadiazole-14 C]-or [carbonyl-14 C]-naldemedine, showed that nor-naldemedine was the primary metabolite observed in the plasma and accounted for 9% to 13% of the systemic exposure of unchanged naldemedine. 10,11 Another phase 1 study, in which healthy subjects were administered 2 mg of [oxadiazole-14 C]-or [carbonyl-14 C]-naldemedine, showed that nor-naldemedine was the primary metabolite observed in the plasma and accounted for 9% to 13% of the systemic exposure of unchanged naldemedine.…”

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confidence: 88%

“…10,11,22 Therefore, prior and concomitant medications were recorded, and P-gp receptor and CYP3A enzyme inhibitors were prohibited from 2 weeks before admission to the clinical research units until study completion. 10,11,22 Therefore, prior and concomitant medications were recorded, and P-gp receptor and CYP3A enzyme inhibitors were prohibited from 2 weeks before admission to the clinical research units until study completion.…”

Section: Study Populationmentioning

confidence: 99%

“…8 Naldemedine minimally crosses the blood-brain barrier and, therefore, effectively treats opioid-induced constipation without negating the analgesic effects of opioid therapy. 10 Moreover, systemic exposure to naldemedine was nearly dose proportional for single ascending doses, and only slight increases in peak plasma concentration (C max ) and area under the concentrationtime curve (AUC 0-t ) (1-to 1.3-fold) were observed following multiple daily doses of naldemedine. 10 Moreover, systemic exposure to naldemedine was nearly dose proportional for single ascending doses, and only slight increases in peak plasma concentration (C max ) and area under the concentrationtime curve (AUC 0-t ) (1-to 1.3-fold) were observed following multiple daily doses of naldemedine.…”

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confidence: 99%

“…10 Moreover, systemic exposure to naldemedine was nearly dose proportional for single ascending doses, and only slight increases in peak plasma concentration (C max ) and area under the concentrationtime curve (AUC 0-t ) (1-to 1.3-fold) were observed following multiple daily doses of naldemedine. 10 Naldemedine is primarily metabolized via cytochrome P450 (CYP)3A4 to nor-naldemedine. 10 Naldemedine is primarily metabolized via cytochrome P450 (CYP)3A4 to nor-naldemedine.…”

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confidence: 99%

“…11 Following administration of [oxadiazole-14 C]-naldemedine, 57% of the total radioactivity was recovered in the urine, and 35% was recovered in the feces. 11 Although it has been demonstrated that naldemedine is metabolized and excreted by the kidney and the liver, 10,11 the pharmacokinetics and safety of naldemedine in subjects with renal or hepatic impairment have yet to be determined. 11 Although it has been demonstrated that naldemedine is metabolized and excreted by the kidney and the liver, 10,11 the pharmacokinetics and safety of naldemedine in subjects with renal or hepatic impairment have yet to be determined.…”

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confidence: 99%

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The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

Fukumura

Yamada

Yokota

et al. 2019

Clinical Pharm in Drug Dev

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Naldemedine is a peripherally acting μ-opioid-receptor antagonist for the treatment of opioid-induced constipation. Two phase 1 single-dose studies investigated the pharmacokinetics and safety of a 0.2-mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end-stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Pharmacokinetic assessments indicate that dose adjustments for naldemedine are not necessary for subjects with any degree of renal impairment or for subjects with mild or moderate hepatic impairment. In subjects with renal impairment compared with healthy subjects with normal renal function, the geometric mean ratios of naldemedine area under the concentration-time curve (AUC 0-inf ) ranged from 82.8% (90%CI 69.5% to 98.6%) to 137.8% (90%CI 114.0% to 166.5%). Renal clearance decreased with reduced renal function (normal function 1.3 L/h; mild impairment 1.1 L/h; moderate impairment 1.0 L/h; severe impairment 0.5 L/h), and only 2.7% of naldemedine was removed by hemodialysis. In subjects with hepatic impairment compared with healthy subjects with normal hepatic function, the geometric mean ratio of AUC 0-inf ranged from 82.8% (90%CI 65.7% to 104.5%) to 105.2% (90%CI 83.4% to 132.6%). Naldemedine was well tolerated in both healthy subjects and subjects with renal or hepatic impairment, and reported adverse events were generally consistent with the known safety profile.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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confidence: 88%

Section: Study Populationmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

Fukumura

Yamada

Yokota

et al. 2019

Clinical Pharm in Drug Dev

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Population Pharmacokinetics and Exposure-Response Relationships of Naldemedine

2018

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PurposeTo characterize population pharmacokinetic (PK) of naldemedine, to identify factors which influence naldemedine PK, and to evaluate their clinical relevancy based on exposure-response relationships.MethodsA population PK model was developed with pooled naldemedine concentrations from healthy subjects, patients with chronic non-cancer pain and opioid-induced constipation (OIC), and cancer patients with OIC. Exposure-response analyses were performed with efficacy (responder or non-responder) and safety (occurrence of gastrointestinal disorders or not) data in phase 2b and phase 3 studies.ResultsNaldemedine plasma concentrations were adequately described by a 2-compartment model with first-order absorption and absorption lag time. The final model included the effects of age, creatinine clearance, race, and gender on apparent total clearance; the effects of body weight, health status, and food condition on apparent volume of central compartment; and the effect of age on first-order rate of absorption. When subjects took 0.2 mg of naldemedine once daily, the probability of spontaneous bowel movement (SBM) responders was predicted to be approximately 50%, while that of severe gastrointestinal disorders was predicted to be less than 3%. The influence of the covariates on PK was not considered clinically significant because similar efficacy and safety were expected based on the exposure-response analysis.ConclusionsThe covariates are identified in the population PK analysis; however, no dose-adjustment is required for them based on the exposure-response analysis.Electronic supplementary materialThe online version of this article (10.1007/s11095-018-2501-7) contains supplementary material, which is available to authorized users.

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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

et al. 2020

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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.

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Phase 1, Randomized, Double‐Blind, Placebo‐Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers

Cited by 18 publications

References 21 publications

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

Population Pharmacokinetics and Exposure-Response Relationships of Naldemedine

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

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