Novel Application of the Two-Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin.

Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with 14 C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa ) of ertugliflozin. Eight healthy adult men received 100-µg i.v. 14 C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100 µg 14 C-ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high-performance liquid-chromatography tandem mass spectrometry (HPLC-MS/MS). 14 C-ertugliflozin plasma concentrations were determined using HPLC-accelerator mass spectrometry (AMS) and 14 C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o. /14 C-AUCi.v. )*(14 C-Dosei.v. /Dosep.o. )) and Fa ((14 C_Total_Urinep.o. /14 C_Total_Urinei.v. )* (14 C-Dosei.v. /14 C-Dosep.o. )) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

Single- and multiple-dose pharmacokinetics of tofacitinib in healthy Chinese volunteers.

Tofacitinib is an oral Janus kinase inhibitor. The objective of this phase 1, open-label study was to characterize the single- and multiple-dose pharmacokinetics (PK) of tofacitinib in 12 healthy, adult Chinese volunteers. Eligible subjects received oral tofacitinib 10 mg once daily on days 1 and 6 and twice daily on days 2-5. Blood samples were collected on day 1 predose and over 24 hours postdose (day 2 predose), predose on days 3-6, and over 12 hours postdose on day 6. PK parameters were calculated using noncompartmental analysis. Mean concentration-time profiles for days 1 and 6 were similar, with median time to peak concentration of 0.5 hours on both days. Plasma concentrations declined rapidly following attainment of peak concentrations, with a mean terminal half-life of 3.3 hours on day 1 (single dose) and 2.5 hours on day 6 (multiple dose). No accumulation in plasma occurred with twice-daily administration: accumulation ratio of 1.04. The rapid absorption, elimination, and systemic exposures (peak and area under the concentration-time curve) observed in healthy Chinese volunteers in this study are similar to those previously reported in white subjects.

A phase I, open-label, mass balance study of [(14)C] dacomitinib (PF-00299804) in healthy male volunteers.

PURPOSE: This study aimed to characterize the primary routes of elimination of the pan-HER tyrosine kinase inhibitor, dacomitinib (PF-00299804), to evaluate the pharmacokinetics of total radioactivity and of dacomitinib and to identify the metabolites of dacomitinib in plasma, urine, and feces in the healthy volunteers. METHODS: Six male healthy volunteers (mean age 31.5 years) received a single 45-mg oral dose containing ~100 µCi [(14)C] dacomitinib. Whole blood, urine, and fecal samples were collected throughout the study and analyzed for total radioactivity by liquid scintillation counting. Safety evaluations included vital signs, 12-lead ECGs, safety laboratory tests, and monitoring of adverse events. RESULTS: 78.8 % of the radiolabeled material was excreted in feces, and 3.2 % was recovered in urine. Peak concentrations of dacomitinib in plasma occurred 12 h (median) after oral dosing. Mean terminal plasma half-life was 55 and 182 h for dacomitinib and total plasma radioactivity, respectively. Geometric mean C max was approximately 2-fold higher, and total exposure (AUCinf) was almost 6-fold higher for total radioactivity than for dacomitinib in plasma. O-desmethyl dacomitinib (PF-05199265) was the major circulating metabolite. T max of this metabolite occurred 6 h after oral dosing with dacomitinib. Plasma exposure for the metabolite was one-third that of the parent compound. There were no serious/severe adverse events or deaths during the study. Dacomitinib was well tolerated. CONCLUSIONS: In humans, [(14)C] dacomitinib underwent oxidative and conjugative metabolism. Most of the administered dose was eliminated via the fecal route, and the major circulating metabolite was PF-05199265.

Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics.

OBJECTIVE: To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment. METHODS: In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed. Changes in axitinib plasma exposures in subjects with mild or moderate hepatic impairment were predicted using computer simulations and used to guide initial dosing in the clinical study. RESULTS: Axitinib exposure was similar in subjects with normal hepatic function and those with mild hepatic impairment, but approximately twofold higher in subjects with moderate hepatic impairment. Axitinib exposure weakly correlated with measures of hepatic function but was not affected by smoking status. Axitinib protein binding was similar in the three treatment groups. No significant treatment-related adverse events were reported. CONCLUSIONS: Compared with subjects with normal hepatic function, moderate hepatic impairment increased axitinib exposure, suggesting that the oral clearance of axitinib is altered in these subjects. In addition, these data indicate a possible need for a dose reduction in subjects who develop moderate or worse hepatic impairment during axitinib treatment. A single 5-mg dose of axitinib was well tolerated in subjects with mild or moderate hepatic impairment.