Human mass balance, metabolite profile and identification of metabolic enzymes of [¹⁴C]ASP015K, a novel oral janus kinase inhibitor

Abstract

1. The human mass balance of (14)C-labelled ASP015K ([(14)C]ASP015K), an orally bioavailable Janus kinase (JAK) inhibitor, was characterized in six healthy male subjects after a single oral dose of [(14)C]ASP015K (100 mg, 3.7 MBq) in solution. [(14)C]ASP015K was rapidly absorbed with tmax of 1.6 and 1.8 h for ASP015K and total radioactivity in plasma, respectively. Mean recovery in urine and feces amounted to 36.8% and 56.6% of the administered dose, respectively. The main components of radioactivity in plasma and urine were ASP015K and M2 (5'-O-sulfo ASP015K). In feces, ASP015K and M4 (7-N-methyl ASP015K) were the main components. 2. In vitro study of ASP015K metabolism showed that the major isozyme contributing to the formation of M2 was human sulfotransferase (SULT) 2A1 and of M4 was nicotinamide N-methyltransferase (NNMT). 3. The in vitro intrinsic clearance (CLint_in vitro) of M4 formation from ASP015K in human liver cytosol (HLC) was 11-fold higher than that of M2. The competitive inhibitory effect of nicotinamide on M4 formation in the human liver was considered the reason for high CLint_in vitro of M4 formation, while each metabolic pathway made a near equal contribution to the in vivo elimination of ASP015K. ASP015K was cleared by multiple mechanisms.

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects

“…The higher drug exposure in Japanese subjects is consistent with observations in a previous study, in which peficitinib C max and AUC were found to be higher in Asian subjects compared with non-Asian subjects [20]. Peficitinib is metabolized by the sulfotransferase (SULT) isoenzyme, SULT2A1, and the methyltransferase isoenzyme, nicotinamide N-methyltransferase [18]. To date no genetic polymorphisms of these isoenzymes have been reported, and the cause of higher peficitinib exposure in Asian patients remains unknown.…”

“…Plasma and urine samples were stored at − 70 °C and were sent to BML, Inc. Central Laboratory (Saitama, Japan) for analysis of peficitinib concentrations. Peficitinib concentrations in plasma and urine were measured using a validated liquid chromatography with tandem mass spectrometry method [18]. The lower limits of quantification for peficitinib in plasma and urine were 0.25 ng/mL and 2.5 ng/ mL, respectively.…”

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects with Normal and Impaired Renal Function

“…The concentrations of plasma peficitinib and H2 metabolite (sulfate metabolite, equivalent to M2 identified previously [18]) were measured using validated liquid chromatography tandem mass spectrometry (LC-MS/MS). The lower limit of quantification (LLOQ) was 0.25 ng/mL when 25 μL of plasma was used.…”

Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects

“…16 PK parameters were determined using noncompartmental analysis of plasma concentration-versus-time data using WinNonlin-Professional, version 5.3 (Pharsight Corporation, Mountain View, California). Urine samples were collected predose (ࣘ30 minutes) on day 1 and from 0 to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to 72 hours postdose.…”

“…Plasma and urine ASP015K concentrations were determined using a validated liquid chromatography-tandem mass spectrometry method. 16 PK parameters were determined using noncompartmental analysis of plasma concentration-versus-time data using WinNonlin-Professional, version 5.3 (Pharsight Corporation, Mountain View, California). All concentrations that were below the limit of quantitation were set to zero prior to computation of arithmetic means.…”