Male or female volunteers 18–80 years of age who were considered by the investigator to be healthy except for controlled hypertension or diabetes and problems associated with the primary diagnosis of renal impairment, with a body weight of ≥50 kg and a body mass index between 19.0 and 36.0 kg/m2 were eligible to enroll. Additional inclusion criteria included a creatinine clearance (CLCR) ≥90 mL/min for subjects with normal renal function, ≥60 to <90 mL/min for subjects with mild renal impairment, ≥30 to <60 mL/min for subjects with moderate renal impairment, and <30 mL/min for subjects with severe renal impairment . Subjects with end-stage renal disease (ESRD) were on intermittent hemodialysis.
Exclusion criteria included, but were not limited to, a predisposition to easy bruising or bleeding disorders; a medical history of gastric or duodenal ulceration; any trauma within 1 week of screening; extensive ecchymosis; hemoptysis; gingival bleeding; hematemesis; repeated or significant nose bleeds; peri-orbital hematoma; retinal detachment; menorrhagia; hematuria; melanoma; an acute clinically significant illness within 30 days prior to day −1; a history of abdominal, thoracic, or nonperipheral vascular surgery within 6 months prior to day −1; a history of cancer other than basal cell or stage 1 squamous cell carcinoma of the skin that had not been in remission for ≥5 years prior to day −1; any protocol-specified prohibited medications or supplements; a serum creatinine kinase level >3 times the upper limit of normal; sustained systolic blood pressure ≥155 mmHg or ≤90 mmHg or a diastolic blood pressure ≥95 mmHg or ≤50 mmHg; resting pulse rate of <51 or >100 beats per minute; abnormal electrocardiogram (ECG) at screening or check-in day; alanine aminotransferase or aspartate aminotransferase level >1.5 times the upper limit of normal; active liver or gall bladder disease; or a history of drug/alcohol abuse.
The study was conducted in compliance with the institutional review board regulations, Good Clinical Practice regulations and guidelines, and all applicable local regulations. This was a phase I, open-label, parallel-group study. The use of a single dose of fasiglifam in this study was chosen because the multiple-dose PK parameters of fasiglifam and M-1 are linear and time independent  and, therefore, can be extrapolated from single-dose PK studies. All subjects received a single oral dose of fasiglifam 50 mg (Takeda Pharmaceutical Co. Ltd, Osaka, Japan) in the morning after an overnight fast of ≥10 h; subjects with ESRD requiring dialysis fasted for ≥2 h. Subjects were admitted to the clinic on day −1 and were confined to the clinic until the collection of the 168-h postdose PK samples on day 8 and the completion of all scheduled procedures. Standardized meals containing 30 % fat were provided to all subjects during the confinement period.
Up to 64 subjects were planned for enrollment in the study: up to 32 subjects with normal renal function and eight within each category of renal impairment. Subjects with normal renal function were matched by sex, weight, age, and smoking status. Subjects with normal renal function could be matched to more than one subject with renal impairment, but to no more than one subject within each impairment group.
For the determination of plasma concentrations of fasiglifam and its metabolite M-1, blood samples (4 mL) were collected from all subjects at 15 min predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 h postdose. For subjects with ESRD, additional 4-mL arterial samples were collected at 1, 2, 3, and 4 h postdose (if subjects were still on dialysis). Three (10 mL) blood samples were collected 15 min predose from all subjects for protein-binding assessments. All voided urine was collected from subjects with normal renal function, and mild, moderate, and severe renal impairment at −12 to 0 h predose, and then at 24-h intervals up to 7 days postdose.
Plasma Protein Binding
The in vitro protein binding of fasiglifam was determined ex vivo using ultracentrifugation of predose plasma samples from the study subjects spiked with [14C] fasiglifam at a nominal concentration of 1 µg/mL.
Plasma and urine concentrations of fasiglifam and fasiglifam M-1 were measured using validated liquid chromatography with tandem mass spectrometry with a range of 5.00–10,000 ng/mL.
The PK parameters of fasiglifam and fasiglifam M-1 were derived using non-compartmental analysis methods with Phoenix WinNonlin Version 6.3 (Pharsight Corp, Cary, NC, USA). Measurements below the limit of quantification of 5.00 ng/mL were treated as 0 when deriving PK parameters. The PK parameters assessed for fasiglifam and fasiglifam M-1 (unless otherwise specified) included maximum observed plasma concentration (C
max); time to C
max); area under the plasma concentration-time curve (AUC) from time 0 to the time of last quantifiable concentration (t), calculated using the linear trapezoidal rule (AUC
); area under the plasma concentration-time curve from 0 to infinity calculated from AUC
+ lqc/λz, where lqc is the last quantifiable concentration and λz is the terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase (AUC∞); t
1/2 calculated as ln (2)/λz; apparent clearance after extravascular administration, calculated as dose/AUC∞ after a single dose (CL/F; calculated for fasiglifam only); apparent volume of distribution during the terminal phase after extravascular administration, calculated as (CL/F)/λz (Vz/F; for fasiglifam only); area under the unbound plasma concentration-time curve from time 0 to infinity, calculated as AUC∞ percent unbound (AUC∞,u
; calculated for fasiglifam only); maximum observed unbound plasma concentration (C
; calculated for fasiglifam only); oral clearance of unbound fasiglifam, calculated as CL/F percent unbound (CL
/F; calculated for fasiglifam only).
The urinary parameters included total amount of drug excreted in urine from time 0 to time t (Ae
); fraction of drug excreted in urine, calculated as (Ae
/dose) × 100 (f
; calculated for fasiglifam only); and CL
calculated as Ae
Physical examinations and 12-lead ECGs were performed on day −1, predose, and at study exit or early termination (ET). Vital signs were examined on day −1, predose on day 1, and 1, 2, 4, 8, 12, 24, and 48 h postdose, and at study exit or ET. Clinical laboratory evaluations comprising routine hematology, serum chemistry, and urinalysis were included in the safety assessments. Participants were also monitored for adverse events (AEs) and the incidence of hypoglycemia. Blood glucose was measured by fingerstick prior to breakfast (predose on day 1); at lunch and dinner during confinement, which lasted from day −1 to study exit on day 8; or if signs or symptoms of hypoglycemia occurred.
The safety analysis set, which included all subjects who were enrolled in the study and received the study drug, was used for demographics and safety summaries. The PK set included all subjects with one or more measurable concentration(s) of fasiglifam. Descriptive statistics [N, mean, standard deviation (SD), percent coefficient of variation (%CV), median, minimum, and maximum] were used to summarize plasma concentrations of fasiglifam and fasiglifam M-1 by renal function group and collection time point. Similar descriptive statistics were used to summarize the plasma and urine PK parameters of fasiglifam and fasiglifam M-1, and the percent of unbound fasiglifam in plasma by renal function group. In addition, geometric means were calculated for C
max and AUC. The relationship between renal function and fasiglifam T
, λz, and CL
/F were evaluated with regression analyses. CLCR was a continuous variable in the regression model. Based on the results from the regression models for each PK parameter, individual parameter predictions and the 95 % prediction intervals were calculated for a hypothetical subject with CLCR at about the midpoint of each renal function category. Subjects with ESRD were not included in the regression analyses because CLCR was not determined in these subjects. Instead, an analysis of covariance with renal function as the factor and baseline weight as the covariate was used to compare the PK of ESRD subjects with that of normal subjects.