Dose In Japanese Patients Research Articles

MO25-2 Phase 1 study of tusamitamab ravtansine every 2 weeks with loading dose in Japanese patients with advanced solid tumors

MO25-2 Phase 1 study of tusamitamab ravtansine every 2 weeks with loading dose in Japanese patients with advanced solid tumors

PD-1 inhibition with retifanlimab and/or arginase inhibition with INCB001158 in Japanese patients with solid tumors: A phase I study.

Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors. Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients. Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy. Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients.

Integrated safety analysis of filgotinib treatment for rheumatoid arthritis in patients from Japan over a median of 1.5 years.

Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA). Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest. Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE). Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA.

Apixaban in Japanese patients with cancer-associated venous thromboembolism: a multi-center phase II trial

Recent pivotal phase III trials involving direct oral anticoagulant (DOAC) versus low molecular weight heparin have demonstrated the utility of DOACs in Western patients with cancer-associated venous thromboembolism (VTE). However, these trials did not include Japanese patients. This phase II trial evaluated the safety and efficacy of apixaban in Japanese patients with cancer-associated VTE (UMIN000028447). Apixaban was initiated at 10mg twice daily for 7days, followed by 5mg twice daily for 23weeks. The primary endpoint was the incidence of major or clinically relevant non-major (CRNM) bleeding events during the treatment period. The study was terminated due to safety concerns after enrolling 27 patients. Median age was 71years; median body weight was 51.3kg; and major primary tumor sites were the gastrointestinal tract (26%) and lung (19%). During the median follow-up period of 5.4months, major or CRNM bleeding occurred in in 26% of patients (major, n = 5; CRNM, n = 2; 95% confidence interval, 11-46%). No recurrent VTE or VTE-related death occurred. Estimated overall survival at 6months was 68%. This study demonstrated the excessive bleeding risk of apixaban at the standard dose in Japanese patients with cancer-associated VTE.

A Phase 1 Study of KHK4083: A Single‐Blind, Randomized, Placebo‐Controlled Single‐Ascending‐Dose Study in Healthy Adults and an Open‐Label Multiple‐Dose Study in Patients With Ulcerative Colitis

OX40 plays an essential role in maintaining late T‐cell proliferation and survival by suppressing apoptosis and by inducing T‐cell memory formation. Here, we report the results of the phase 1 study of KHK4083, a fully human antimonoclonal antibody specific for OX40. In this study, we aimed to assess the safety and tolerability of a single intravenous or subcutaneous administration of KHK4083 compared with placebo in healthy Japanese and Caucasian subjects and determined the pharmacokinetics (PK) and immunogenicity. Also, we assessed the preliminary efficacy and pharmacodynamics of multiple intravenous doses in Japanese patients with moderate to severe ulcerative colitis (UC). Drug‐related treatment emergent adverse events occurred in 21 healthy subjects (58.3%) and 5 patients with UC (62.5%) after administration of KHK4083. There were no serious adverse events. The PK profile of a single intravenous dose of 10 mg/kg KHK4083 was similar in healthy Japanese and Caucasian subjects. Of 8 UC patients, a clinical response was observed in 3 patients (37.5%) and clinical remission in 2 patients (25.0%) in week 6. Our study demonstrated the safety and tolerability of single and multiple administrations of KHK4083 in healthy Japanese and Caucasian subjects and Japanese patients with moderate to severe UC. It also indicated favorable pharmacological properties of the drug.

A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

SummaryBackground This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW.Trial registration: NCT02836600 (ClinicalTrials.gov) registered on July 19, 2016.

Approach to Evaluating QT Prolongation of Quetiapine Fumarate in Late Stage of Clinical Development Using Concentration-QTc Modeling and Simulation in Japanese Patients With Bipolar Disorder

PurposeQuetiapine has been reported to prolong the QT interval, and has been used as a positive control in thorough QT studies. The objective of the present study was to evaluate, in the late stages of clinical development, the QT-prolongation effects of the extended-release (XR) formulation of quetiapine at the approved dose in Japanese patients with bipolar disorder, using concentration–QT modeling and simulation. MethodsPlasma concentrations of quetiapine and 4 of its metabolites (M1, M2, M4, and M5), and the QT interval corrected using the Fridericia formula (QTcF), were used for the concentration–QT analysis. Data from intensive electrocardiogram monitoring at predose and at 4, 6, 10, and 24 h after the administration of the last dose were pooled from a Phase I trial (6949-CL-0006) and from sparse sampling in late-stage clinical trials (6949-CL-0005, -0021, −0022, and −0023) in Japanese patients (N = 505). The upper limit of 1-sided 95% confidence interval (CI) of the changes from baseline in QTcF (ΔQTcF) at the geometric mean Cmax of a therapeutic dose of 300 mg once daily was predicted using a linear mixed-effects model, with the intercept as a random effect specifying a subject effect. FindingsFor quetiapine and M2, but not M1, M4, or M5, positive slopes were observed between ΔQTcF and concentration. The predicted upper limits of the 1-sided 95% CIs did not exceed the regulatory threshold of 10 msec. Therefore, QTc prolongation is unlikely to be clinically relevant at the approved dose of quetiapine XR. ImplicationsIn this pooled data analysis of the QT-prolongation effects of the quetiapine XR, positive relationships between ΔQTcF and quetiapine and M2 concentrations were observed. However, the predicted upper limits of the 1-sided 95% CIs did not exceed 10 msec. Therefore, QTc prolongation is unlikely to be clinically relevant at the approved dose. ClinicalTrials.gov identifiers: NCT01725282, NCT01919008, NCT01725308, NCT01737268, and NCT02362412.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652, a Reversible Fatty Acid Amide Hydrolase Inhibitor, in Healthy, Nonelderly, Japanese Men and Elderly, Japanese Men and Women: A Randomized, Double-blind, Placebo-controlled, Single and Multiple Oral Dose, Phase I Study

PurposeThis study aimed to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of ASP3652, a peripherally acting inhibitor of peripheral fatty acid amide hydrolase (FAAH) after 30-, 100-, 300-, 600-, and 900-mg single and 100- and 300-mg BID multiple oral dose in Japanese patients. MethodsThis was a randomized, double-blind, placebo-controlled, single and multiple oral dose Phase I study in healthy, nonelderly men and elderly men and women. The study consisted of 2 parts: in the single oral dose part, 40 healthy, nonelderly men were randomized to receive placebo or ASP3652; in the multiple oral dose part, 48 enrolled nonelderly men and elderly men and women were randomized to receive placebo or ASP3652. In both parts, the investigator judged whether the individuals were healthy based on the results of physical examinations and screening. The safety profile was assessed by examining adverse events, defined as any untoward medical occurrence in an individual administered the study drug and that did not necessarily have a causal relationship with the study treatment; clinical laboratory evaluations; vital signs; the Profile of Mood States scale; and standard 12-lead ECGs and 12-lead ECGs for QT assessment. Pharmacokinetic parameters were estimated using unchanged ASP3652 concentrations in plasma and urine. Pharmacodynamic parameters were estimated using FAAH activity and plasma anandamide, oleoylethanolamide, and palmitoylethanolamide concentrations. Safety and tolerability profiles were compared with the placebo group. FindingsASP3652 was rapidly absorbed to reach Cmax in a single dose and near steady-state at approximately 3 days after the start of multiple dosing. The Cmax and AUC of ASP3652 were slightly higher than dose proportional after a single dose of ASP3652 at 30–900 mg. There was no apparent accumulation based on Cmax and AUC0–12 after multiple doses. Although no differences were found in Cmax or AUC0–12 by age in men, Cmax and AUC0–12 were slightly higher in elderly women than elderly men. FAAH activity was inhibited in a dose-dependent manner, and plasma levels of anandamide, oleoylethanolamide, and palmitoylethanolamide increased in all dose groups after single and multiple doses of ASP3652. The incidence of adverse events after multiple doses, which ranged from 44.4% to 66.7%, was similar across all treatment groups, including the placebo group. ImplicationsSingle and multiple doses of ASP3652 were well tolerated and increased endogenous cannabinoids.

1024-P: Effect of Tirzepatide, a Dual GIP and GLP-1 Receptor Agonist, on Glycemic Control and Body Weight in Japanese Patients with T2DM

Tirzepatide (TZP), a novel dual GIP and GLP-1 receptor agonist (RA), has shown superior glycemic control and weight loss compared to a selective GLP-1 RA. A Phase 1, double-blind, placebo-controlled, randomized, parallel-dose group, 8-week multiple ascending dose study investigated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of TZP administered QW in 48 Japanese patients with T2DM. This study consisted of 1 fixed dose (5 mg) and 2 dose titration (2.5-2.5-5-5-10-10-10-10 mg and 5 5 10 10 10 10 15 15 mg) cohorts of TZP. With TZP, there were marked reductions from baseline to Week 8 in fasting serum glucose, HbA1c, and body weight. The half-life of plasma TZP concentration was approximately 5 days and supports QW dosing regimen. All doses of TZP were well tolerated. The most frequently reported treatment-emergent adverse events (AEs) were decreased appetite and gastrointestinal AEs (constipation, diarrhea, abdominal discomfort, abdominal distension, vomiting, and nausea). These AEs were generally dose dependent and mild in severity. The safety, tolerability, PK, and PD profiles of TZP in this study appeared comparable to other Phase 1 and 2 studies in non-Japanese patients with T2DM. The data support Phase 3 development of TZP for QW dosing in Japanese patients with T2DM. Disclosure K. Ohwaki: Employee; Self; Eli Lilly and Company. K. Furihata: None. H. Mimura: Employee; Self; Eli Lilly and Company. T. Oura: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T. Imaoka: Employee; Self; Eli Lilly and Company.

The efficacy and toxicity of cabazitaxel for treatment of docetaxel-resistant prostate cancer correlating with the initial doses in Japanese patients

BackgroundWe analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC).MethodsWe retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22.5 mg/m2, n = 36) and low (≤20 mg/m2, n = 80) CBZ doses. Factors associated with survival and grade 4 neutropenia were evaluated.ResultsPSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group than in the low-dose group (29 and 14%, P = 0.073). The median PFS time for the all-patient, high- and low-dose groups was 2.8 months (95% confidence interval [CI] 1.9–4.4), 2.1 months (1.2–5.5), and 3.0 months (2.0–4.4), respectively (P = 0.904). The median OS times were 16.3 months (95% CI 9.7–30.9), 30.9 months (11.8–47.4), and 10.2 months (8.6–20), respectively (P = 0.020). In multivariate analyses, PFS was significantly associated with existing bone metastasis at diagnosis (P = 0.005) and OS with PSA > 100 ng/ml (P = 0.007), hemoglobin < 12 g/dl (P = 0.030), and low initial CBZ dose (P = 0.030). Grade 4 neutropenia occurred in 53 patients (45%) and was associated with a low CBZ dose (hazard ratio 0.21, 95% CI 0.08–0.59, P = 0.002).ConclusionsCBZ at a higher initial dose may have similar response rate and response duration, but longer survival duration after treatment with higher toxicity than a lower initial dose for docetaxel-resistant CRPC in Japanese patients.

Effectiveness and safety of initiating adalimumab plus ≥12 mg/week methotrexate with adjustable dosing in biologic-naïve patients with early rheumatoid arthritis: HAWK study postmarketing surveillance in Japan

Objectives: This real-world study assessed the effectiveness and safety outcomes of initiating adalimumab and methotrexate (≥12 mg/week) with adjustable dosing in Japanese patients with early rheumatoid arthritis (RA).Methods: This single-arm, prospective postmarketing observational study (conducted from September 2012 to March 2017 at 119 sites) enrolled biologic-naïve patients with early RA (≤2 years duration) and a Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) >3.2 who were treated with methotrexate for ≥3 months and had initiated treatment with adalimumab and methotrexate (≥12 mg/week). This report presents 52-week data. The primary outcome was the proportion of patients who achieved DAS28-CRP scores <2.6 at week 52.Results: Overall, 293 of 346 enrolled patients were included in the effectiveness population: women, 73%; mean (standard deviation) age, 54.3 (13.9) years; DAS28-CRP score, 4.51 (0.90); and modified total Sharp score (mTSS), 7.69 (9.98). At week 52, 77% of patients achieved clinical remission (DAS28-CRP <2.6), 92.3% achieved low disease activity (DAS28-CRP ≤3.2), and 86% of evaluable patients experienced structural remission (ΔmTSS ≤0.5).Conclusion: Adalimumab plus methotrexate (≥12 mg/week) with adjustable dosing was well tolerated, and could be a beneficial treatment option for Japanese patients with early RA.

An open-label feasibility study of nintedanib combined with docetaxel in Japanese patients with locally advanced or metastatic lung adenocarcinoma after failure of first-line chemotherapy

PurposeThis open-label feasibility study assessed the tolerability of nintedanib 200 mg in combination with docetaxel 75 mg/m2 as a starting dose in Japanese patients with a body surface area (BSA) < 1.5 m2 and locally advanced or metastatic lung adenocarcinoma.MethodsEligible patients received docetaxel 75 mg/m2 every 21 days and nintedanib administered at 200 mg twice daily (bid), starting on day 2 of each cycle. Treatment was continued until disease progression or undue toxicity. The primary endpoint was the number of patients experiencing dose-limiting toxicities (DLTs) in cycle 1 (days 1–21).ResultsOf 10 treated patients, 2 patients (20%) experienced DLTs during cycle 1. These DLTs were grade 3 liver enzyme elevations [alanine aminotransferase (2 patients) and aspartate aminotransferase (2 patients)], and grade 2 hyperbilirubinemia (1 patient). Nine patients met the predefined criteria for nintedanib 200 mg bid plus docetaxel 75 mg/m2 to be considered a tolerable starting dose. All patients experienced ≥ 1 adverse event (AE) during the treatment period (all drug-related), but no patients experienced AEs that led to discontinuation of nintedanib. Of the five serious AEs reported during treatment, none were drug-related. There was no apparent effect of nintedanib on the pharmacokinetics of docetaxel. The objective response and disease control rates were 40 and 70%, respectively.ConclusionNintedanib 200 mg bid plus docetaxel 75 mg/m2 is a tolerable starting dose in Japanese patients with a BSA < 1.5 m2 with locally advanced or metastatic lung adenocarcinoma.ClinicalTrials.gov numberNCT02300298.

Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T)

Objective: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy.Methods: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed.Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs.Conclusion: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer.

This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). In this open-label, nonrandomized, two-cohort, dose-escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (≈1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day −5 (fasting state) and day −2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide. Of 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced ≥1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug-related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade ≥4 DR-TEAEs or new safety signals were observed. C max and AUC (0–t last) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean C max increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0–t last) increased 2.5-fold after both doses under fed conditions. Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients.

Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer

PurposeThis trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC).MethodsIn this open-label, nonrandomized, two-cohort, dose-escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (≈1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day −5 (fasting state) and day −2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide.ResultsOf 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced ≥1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug-related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade ≥4 DR-TEAEs or new safety signals were observed. Cmax and AUC (0–tlast) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean Cmax increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0–tlast) increased 2.5-fold after both doses under fed conditions.ConclusionsDarolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients.

Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non–small-cell Lung Cancer

IntroductionIn this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non–small-cell lung cancer. MethodsRetrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. ResultsThe total area under the observed plasma concentration-time curve (AUC0-24) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC0-24 of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC0-24 between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC0-24 of gefitinib with H2RA tended to be lower than that without H2RA. ConclusionIf the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully.

A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors

PurposeTo evaluate the safety, tolerability, pharmacokinetics, and efficacy of the intravenously administered pan-PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors.MethodsA Phase I open-label study in Japanese patients with advanced or refractory solid tumors was carried out. Patients received a single intravenous dose of either copanlisib 0.4 mg/kg or copanlisib 0.8 mg/kg, dosed intermittently on days 1, 8, and 15 of a 28-day cycle. Safety was monitored throughout the study. Plasma copanlisib levels were measured for pharmacokinetic analysis.ResultsTen patients were enrolled and treated; three received copanlisib 0.4 mg/kg and seven received copanlisib 0.8 mg/kg. Overall, median duration of treatment was 6.2 weeks. No patients treated at 0.4 mg/kg experienced a dose-limiting toxicity, and the maximum tolerated dose in Japanese patients was determined to be 0.8 mg/kg. Adverse events were recorded in all ten patients; the most common were hyperglycemia, hypertension, and constipation. Copanlisib pharmacokinetic exposures displayed near dose-proportionality, with no accumulation. No patients achieved a complete or partial response, and disease control rate was 40.0%.ConclusionsCopanlisib was well tolerated in Japanese patients with advanced or refractory solid tumors, and the maximum tolerated dose was determined to be 0.8 mg/kg. Copanlisib demonstrated near dose-proportional pharmacokinetics and preliminary disease control, warranting further investigation.Clinical trial registration numberNCT01404390.

Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors.

In clinical studies in Western countries, the recommended doseof combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m2 ombrabulin with 75 mg/m2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors. This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3+3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m2 combined with cisplatin 75 mg/m2. The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities. Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients. Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients.

Single and multiple dose pharmacokinetics and pharmacodynamics of omarigliptin, a novel, once-weekly dipeptidyl peptidase-4 inhibitor, in healthy Japanese men.

Aims/IntroductionOmarigliptin is a novel, potent, long‐acting oral dipeptidyl peptidase‐4 inhibitor being developed as a once‐weekly (q.w.) treatment for type 2 diabetes mellitus patients, with 25 mg and 12.5 mg tablets recently being approved as market formulations in Japan.Materials and MethodsThis was a two‐part, double‐blind, randomized, placebo‐controlled study in healthy Japanese men to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of omarigliptin after single dose (5–100 mg) and multiple dose (1–50 mg q.w. for 3 weeks) administration.ResultsOmarigliptin was rapidly absorbed with a time to maximum concentration of 0.5–4 h. The pharmacokinetic profile was biphasic with a long terminal half‐life >100 h. The area under the concentration–time curve from 0 to 168 h, maximum concentration and the concentration at 168 h post‐dose increased dose‐dependently after 3 weeks of once‐weekly dosing for doses ranging 1–50 mg, with accumulation ratios ranging 1.03–1.35 and 0.87–1.36 for the area under the concentration–time curve from 0 to 168 h and maximum concentration, respectively. Plasma dipeptidyl peptidase‐4 inhibition levels 1 week post‐dose increased with dose, ranging 79.2–94.0% after 5–100 mg single dose administration and 51.3–90.2% after 1–50 mg multiple once‐weekly dose administration. Administration with food did not meaningfully alter the pharmacokinetics of omarigliptin. Omarigliptin was generally well tolerated, with no hypoglycemia being reported.ConclusionThe results of the present study in healthy Japanese men showed that omarigliptin was well tolerated and had a pharmacokinetic and dipeptidyl peptidase‐4 inhibition profile that supports once‐weekly dosing in Japanese patients with type 2 diabetes mellitus.

Influence of Genetic Polymorphisms and Concomitant Anxiolytic Doses on Antidepressant Maintenance Doses in Japanese Patients with Depression.

To prevent recurrent depression, patients should ideally continue treatment for >6 months with the antidepressant dose that effectively suppressed acute depressive symptoms. However, there are inter-individual differences in the antidepressant doses required to achieve response and maintenance. Therefore, this study was conducted to examine the role of clinical features, including genetic polymorphisms, on the antidepressant dose required for maintenance therapy in 82 Japanese patients with depression. We calculated the antidepressant dose using the imipramine equivalent scale and the dose of concomitant anxiolytics and hypnotics using the diazepam equivalent scale. The 82 participants were classified into two groups based on the median imipramine equivalent dose, and we examined the influence of patient characteristics and the presence of genetic polymorphisms of brain-derived neurotropic factor (BDNF; rs6265) and cyclic adenosine monophosphate responsive element-binding protein 1 (CREB1; rs2253306, rs4675690, rs769963) on the antidepressant maintenance dose. Using a multivariate logistic regression analysis, we found that the concomitant diazepam equivalent dose and presence of the CREB1 rs4675690 polymorphism were significantly associated with the antidepressant maintenance dose. We concluded that these factors influenced the antidepressant dose in maintenance therapy among Japanese patients with depression. However, further research is required in large cohorts.