Masaya Tachibana

Clinical Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Factor Xa Inhibitor Edoxaban in Healthy Volunteers

This is a clinical safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) study of a single ascending dose (SAD) and a multiple ascending dose (MAD) of the oral direct factor Xa inhibitor edoxaban in healthy males. The placebo‐controlled, single‐blind, randomized, 2‐part study consists of a SAD arm with 85 subjects (10, 30, 60, 90, 120, 150 mg) and a MAD arm with 36 subjects (90 mg daily, 60 mg twice daily, 120 mg daily). Effects of food and formulation (tablet vs solution) are assessed in a crossover substudy. In the SAD, doses are well tolerated up to 150 mg. Exposure is proportional to dose. PK profiles are consistent across dose with rapid absorption, biphasic elimination, and terminal elimination half‐life of 5.8 to 10.7 hours. In the MAD, mean accumulation after daily dosing is 1.10 to 1.13 and consistent with elimination half‐life of 8.75 to 10.4 hours. Intrasubject variability ranges from 12% to 17% for area under the curve. In general, plasma edoxaban concentrations are linearly correlated with coagulation parameters. Edoxaban is safe and well tolerated with no dose‐dependent increases in adverse events. It is concluded that single and multiple doses of edoxaban are safe and well tolerated up to 150 mg with predictable PK and PD profiles.

Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers.

The primary objective of this study was to assess the effect of a standard high‐fat meal on the single‐dose (60 mg) pharmacokinetics (PK) of edoxaban in healthy Japanese and Caucasian male volunteers matched by body mass index. This was an open‐label, randomized, 2‐period crossover study. All 32 enrolled volunteers completed the study per protocol. Both serial blood and urine samples were collected, and edoxaban concentrations were analyzed by a validated liquid chromatography/tandem mass spectrometry method. Activated partial thromboplastin and prothrombin times were obtained as measures of pharmacodynamic effect. The point estimates of the geometric mean ratios (fed/fasted) for AUC0‐t, AUC0‐∞, and Cmax demonstrated modest increases ranging from 6% to 22% across PK parameters for both race cohorts. The disposition was similar in both Japanese and Caucasian matched volunteers with slightly higher AUC values (ranging from 7%‐9%) in Caucasians. There were no serious adverse events during the study. All drug‐related adverse events were mild and self‐limited, and none were bleeding related. Both Japanese and Caucasian volunteers demonstrated a modest but clinically insignificant food effect. It was concluded that edoxaban can be administered without regard to food.

Population Pharmacokinetics of Edoxaban in Japanese Atrial Fibrillation Patients With Severe Renal Impairment

This is a population pharmacokinetic (PopPK) analysis to predict PK of edoxaban, a direct‐acting oral anticoagulant, in nonvalvular atrial fibrillation (NVAF) patients with severe renal impairment (SRI; creatinine clearance [CLcr] <30 mL/min). Data from a phase 3 study recently conducted in Japanese NVAF patients (n = 90), including patients with SRI, were used to update the ENGAGE PopPK model that had been developed based on pooled data from the phase 3 ENGAGE AF‐TIMI 48 study and 13 phase 1 PK studies, which included few patients with SRI. The final model indicated that the ENGAGE PopPK model was applicable to Japanese patients in that the model‐simulated and study‐observed concentration‐time profiles were in agreement. Estimated model parameters after the addition of Japanese SRI data were consistent with those derived from the original ENGAGE PopPK data set. The model‐predicted exposure in NVAF patients with SRI who received edoxaban at a 15‐mg, once‐daily dose was similar to that in patients with normal renal function or with mild renal impairment receiving a 30‐mg dose. This suggests that efficacy and safety data from the ENGAGE AF study can be used to support dose setting for NVAF patients with SRI.

Coadministration of probenecid and cimetidine with mirogabalin in healthy subjects: A phase 1, randomized, open‐label, drug–drug interaction study

The primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure.

Abstract CT024: First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors

Background: DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for the ROS1 and NTRK receptors. Non-clinical pharmacology studies demonstrated activity of DS-6051b against tumors harboring ROS1 or NTRK fusion genes in cell culture and xenograft models. The objectives of this first in human (FIH) study are to assess safety and tolerability of DS-6051b in cancer subjects and identify the maximum tolerated dose (MTD) and the tentative RP2D. Pharmacokinetics (PK), QT prolongation, and tumor responses are also assessed in this study (Clinical Trial Information: NCT02279433). Methods: Dose escalation initially followed an accelerated titration design enrolling a single subject at each dose level, and then adopted the modified continuous reassessment method using a Bayesian logistic regression model and escalation with overdose control. Adult subjects with advanced solid tumors harboring ROS1 or NTRK1-3 fusion genes; or with neuroendocrine carcinoma; or with advanced solid tumors with tumor-induced pain are eligible for the study. DS-6051b is orally administered once-daily in 21-day cycles. Tumor assessments are performed every 3 cycles using RECIST 1.1 criteria. Plasma PK samples and time-matched ECG data are collected at multiple time points. Results: A total of 22 subjects have been enrolled at 50, 100, 200, 400, 800, and 1200 mg once daily (QD) dose levels. Enrolled population included 11 subjects with neuroendocrine carcinomas, 9 subjects with advanced solid tumors with tumor-induced pain, 1 subject with ROS1 fusion-positive NSCLC liver metastases, and 1 subject with leiomyosarcoma with a ROS1 point mutation. Two dose-limiting toxicities occurred in subjects who received 1200 mg QD, consisting of grade 3 transaminase elevations. The MTD is 800 mg QD. The most frequent (?20%) TEAEs were diarrhea, nausea, vomiting, dehydration, dizziness, dysgeusia, and fatigue, which were predominantly grade ?2. Cmax and AUC increased with the dose. Plasma terminal half-life was 11-24 hours. Steady state AUC was approximately 3 to 4-fold higher than that of Cycle 1 Day 1. Two subjects showed partial response: One with neuroendocrine carcinoma, who received 800 mg QD (33% decrease in tumor size), and one with ROS1 fusion-positive NSCLC liver metastases, who received 1200 mg QD (44% decrease in tumor size). Notably, the latter subject had progressed on crizotinib (best objective response stable disease) and ceritinib (progressive disease). Conclusions: DS-6051b has been well tolerated up to 800 mg QD in subjects with advanced solid tumors. The observed efficacy signals in two subjects with partial response warrant further evaluation. This trial is now selectively accruing subjects with ROS1 fusion-positive tumors. Citation Format: Kyriakos P. Papadopoulos, Erkut Borazanci, Daniel Von Hoff, Leena Gandhi, Amita Patnaik, Masaya Tachibana, Hamim Zahir, Roohi Gajee, Terri Goldberg, Giorgio Senaldi, Sai-Hong Ou. First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT024.

Abstract C85: Drug interaction study of tivantinib in cancer subjects using a cocktail approach.

Background: Tivantinib (ARQ197) is an orally administered cMET inhibitor currently under development as a cancer therapy. Nonclinical studies have indicated that tivantinib and its major metabolites have the potential to inhibit cytochrome P450 (CYP) 3A4, 2C19, 2C9, and 1A, and the P-glycoprotein (P-gp) at the clinical concentrations being studied in phase 3 studies. The objective of this drug interaction study was to assess the effect of tivantinib at steady state levels on the pharmacokinetics of CYP- and P-gp-specific probe drugs (modified Cooperstown 5 + 1 Cocktail) after multiple BID doses of tivantinib. Methods: This was a phase 1, open-label, single-sequence, crossover study ([NCT01517399][1]) in subjects with advanced solid tumors. Each subject was administered five probe drugs in the absence or presence of tivantinib (360 mg BID): midazolam (CYP3A4), omeprazole (CYP2C19), S-warfarin (CYP2C9), caffeine (CYP1A), and digoxin (P-gp). Serial blood samples were collected to determine the pharmacokinetics of the probe drugs. Pharmacokinetic parameters were computed using a non-compartmental approach. Log-transformed pharmacokinetic parameters were analyzed using a linear mixed-effects model with treatment as fixed effects and subject as a random effect, and the ratio of geometric least-square (LS) means and the 90% CI for test treatment (Probe drug administered with tivantinib) to reference treatment (probe drug administered alone) were calculated. No drug interaction was concluded if the 90% CI of the LS mean ratios are within the range of 0.8-1.25. Results: Twenty eight cancer subjects were enrolled. The ratios of geometric LS mean (90% CI) for total exposure parameter (AUClast) were as follows: midazolam, 0.83 (0.67, 1.02); omeprazole, 0.89 (0.60, 1.31); S[[Unable to Display Character: ‑]]warfarin, 0.88 (0.76, 1.02); caffeine, 0.97 (0.89, 1.05); and digoxin, 0.69 (0.51, 0.94). Small changes in exposure were observed for midazolam, omeprazole, and warfarin with AUClast decreased ∼17%. Consistent with decrease in omeprazole AUClast (∼11.1%), the mean omeprazole/5-hydroxyomeprazole AUC ratio decreased by 12.8%. For digoxin, mean AUClast decreased by 30.9%. No interaction was determined on the caffeine pharmacokinetics. The effect on peak exposures (Cmax) was similar to the effect on AUClast. Treatment with tivantinib in combination with probe drugs omeprazole/warfarin/caffeine/midazolam or digoxin was generally well tolerated. Conclusion: These results suggested that coadministration of tivantinib 360 mg BID has a small or no effect on the pharmacokinetics of probe drugs used in this study. It is likely that the observed effect of tivantinib on CYP1A2, CYP2C9, CYP2C19, CYP3A4 and P-gp is of minimal clinical significance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C85. Citation Format: Masaya Tachibana, Kyriakos P. Papadopoulos, John Strickler, Igor Puzanov, Roohi Gajee, Yibin Wang, Hamim Zahir. Drug interaction study of tivantinib in cancer subjects using a cocktail approach. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C85. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01517399&atom=%2Fmolcanther%2F12%2F11_Supplement%2FC85.atom