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

Miyatake, Daisuke; Shibata, Tomohisa; Toyoshima, Junko; Kaneko, Yuichiro; Oda, Kazuhiro; Nishimura, Tetsuya; Katashima, Masataka; Sakaki, Masashi; Inoue, Kazuaki; Ito, Takayoshi; Uchida, Naoki; Furihata, Kenichi; Urae, Akinori

doi:10.1002/cpdd.751

Cited by 11 publications

(16 citation statements)

References 26 publications

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“…A mass balance clinical study showed that the metabolic clearance of peficitinib occurs mainly via 2 proposed pathways catalyzed by the sulfotransferase (SULT) isoenzyme, SULT2A1, and the methyltransferase isoenzyme, nicotinamide N ‐methyltransferase (NNMT), 10 of which genetic polymorphisms have not been reported so far. The pharmacokinetics (PK) of peficitinib have been further studied in healthy subjects 11 and in Japanese subjects with impaired renal or hepatic function 12,13 . In healthy subjects, the single‐dose pharmacokinetics of peficitinib were characterized by dose proportionality for exposure (area under the plasma concentration‐time curve [AUC inf ]) and maximum observed concentration (C max ) over a 3‐ to 300‐mg dose range 11 .…”

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confidence: 99%

“…In addition, a 27% increase in exposure (AUC inf ) under fed conditions was observed 11 . The PK profile of a single oral dose of peficitinib (150 mg) was unaltered in subjects with renal or mild hepatic impairment, compared with subjects with normal renal or hepatic function 12,13 . However, exposure to peficitinib almost doubled in those with moderately impaired hepatic function 13 …”

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The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two‐Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers

Shibata

Toyoshima

Kaneko

et al. 2020

Clinical Pharm in Drug Dev

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The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open‐label, randomized, 2‐way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150‐mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150‐mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150‐mg tablet formulation of peficitinib was bioequivalent to the developmental 150‐mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation.

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The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two‐Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers

Shibata

Toyoshima

Kaneko

et al. 2020

Clinical Pharm in Drug Dev

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“…In a comparison of subjects with moderate hepatic impairment versus subjects with normal hepatic function, receiving a single dose of peficitinib 150 mg, the AUC inf GMR was 1.92 (90% CI 1.39-2.66) [62]. A reduced peficitinib dose of 50 mg once daily is therefore recommended in patients with moderate hepatic impairment [20].…”

Section: Interaction Studiesmentioning

confidence: 99%

“…A reduced peficitinib dose of 50 mg once daily is therefore recommended in patients with moderate hepatic impairment [20]. However, the AUC inf was not markedly different between subjects with mild hepatic impairment and those with normal hepatic function (GMR: 1.19 [90% CI 0.86-1.64]) [62]. Mean terminal elimination half-life (t ½ ) (10.-43-11.16) was comparable between subjects with normal hepatic function and those with mild or moderate hepatic impairment [62].…”

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confidence: 99%

Peficitinib for the treatment of rheumatoid arthritis: an overview from clinical trials

Tanaka

Izutsu

2020

Expert Opinion on Pharmacotherapy

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Introduction: The treatment of rheumatoid arthritis (RA), a chronic, systemic, autoimmune disease, has been greatly advanced by the introduction of biologic disease-modifying antirheumatic drugs (DMARDs); however, many patients still fail to achieve disease remission. Peficitinib, an orally bioavailable inhibitor of the Janus kinase (JAK) receptor family, was approved in Japan in 2019 and Korea in 2020 for the treatment of RA. Areas covered: This review provides an overview of JAK inhibitors currently marketed or in development; the pharmacodynamics and pharmacokinetics of peficitinib; and the efficacy and safety data for peficitinib from Phase 2b and 3 trials. Expert opinion: Peficitinib has proven clinical efficacy in Asian patients (Japan, Korea, and Taiwan) with RA who have an inadequate response to conventional DMARDs. In Phase 3 trials, clinical improvements and prevention of joint destruction were demonstrated for both 100 mg and 150 mg once-daily peficitinib versus placebo, and treatment for up to 52 weeks was well tolerated. Safety signals, in particular the increased incidence of herpes zoster-related disease, appeared in line with other JAK inhibitors. Post-launch monitoring will establish the long-term safety and effectiveness of this drug, and further studies are necessary to determine its potential use in non-Asian populations.

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“…In this study, a population PK model was constructed to analyse the pooled PK data for peficitinib and to identify significant covariates, with the aim of optimizing the dosing regimen for RA patients based on the magnitude of exposure change under any condition. Table 1 summarizes the designs, including blood sampling times for measurement of plasma peficitinib concentration, of the 5 clinical pharmacology studies 13,[16][17][18] (PK10, PK11, PK12, PK20 and PK27) used for constructing the prior population PK model of peficitinib in healthy volunteers (prior healthy volunteer model) and the 1 phase 2 study 7 (RAJ1) and 2 phase 3 studies 10,11 (RAJ3 and RAJ4) used for constructing the population PK model of peficitinib for RA patients (RA patient model). All clinical studies were conducted in accordance with ethical principles of the Declaration of Helsinki, Good Clinical Practice, and the International Conference on Harmonization guidelines, and were approved by the relevant institutional review boards.…”

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confidence: 99%

Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis

Toyoshima

Shibata

Kaibara

et al. 2020

Brit J Clinical Pharma

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To analyse the population pharmacokinetics (PK) of peficitinib in patients with rheumatoid arthritis (RA) and assess the potential PK covariates to identify the requirement for dose adjustment in RA patients. Methods: The analysis incorporated 2464 observations from 98 healthy volunteers and 4919 observations from 989 RA patients. A population PK model for peficitinib in RA patients was constructed by a nonlinear mixed effect model using NONMEM with prior information from a healthy volunteer model. Results: A 2-compartment model with sequential zero-and first-order absorption and lag time was constructed for RA patients. Covariate exploration in the RA patient model revealed that estimated glomerular filtration rate (eGFR) and lymphocyte count had a significant effect on apparent total systemic clearance (CL), which was 91.7 L/h (2.3% relative standard error). Compared with the mean population CL, the model predicted mean changes in CL of 12.3 and −10.7% in patients with observed minimum and maximum lymphocyte count of 500 and 4600 10 6 /L, respectively, and mean changes in CL of −17.8 and 16.7% in patients with minimum and maximum eGFR of 36.4 and 188 mL/min/1.73m 2 , respectively. The simulated population mean area under plasma concentration-time curve for 24 hours after dosing showed a 1.35-fold increase in patients with severe renal impairment (eGFR 22.5 mL/min/1.73m 2) compared with patients with reference eGFR (91.5 mL/min/1.73m 2). Conclusion: The population PK model identified eGFR and lymphocyte count as covariates for CL. The magnitude of changes was not considered clinically relevant, indicating no requirement for dose adjustment. K E Y W O R D S population analysis, pharmacokinetics, rheumatoid arthritis * Affiliation at the time of analysis. This manuscript was a nonclinical modelling study, and there was no associated clinical responsibility for patients. As such, there is no Principal Investigator on this publication.

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

Cited by 11 publications

References 26 publications

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two‐Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two‐Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers

Peficitinib for the treatment of rheumatoid arthritis: an overview from clinical trials

Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis

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