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

Abstract

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.

Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis

“…As absorption phase data was limited for patients with RA, we used prior information from the prior healthy volunteer model to construct the RA patient model. Although food intake has previously been shown to increase AUC inf by 27% and 36%, 12,13 food intake (fasted, high‐fat fed, or normal fed) in the phase 1 studies was not included in the models because apparent differences among food conditions were relatively smaller than IIV. In phase 2 and 3 studies, all patients with RA took the study drug in the morning in a fed condition.…”

“…The pharmacokinetic (PK) characteristics of peficitinib in healthy volunteers were investigated in previous clinical pharmacology studies. These studies showed that peficitinib was absorbed rapidly, as demonstrated by time to maximum observed concentration (T max ) of 1.0–1.8 hours, and that food intake increased the area under the plasma concentration–time curve (AUC inf ) by 27–36% 12,13 . The mean terminal half‐life (t 1/2 ) of peficitinib ranged from 2.8 to 12.9 hours, 12 and dose‐proportional exposure was demonstrated within the dose ranges studied across single doses (3–300 mg) 12,14 .…”

“…These studies showed that peficitinib was absorbed rapidly, as demonstrated by time to maximum observed concentration (T max ) of 1.0-1.8 hours, and that food intake increased the area under the plasma concentration-time curve (AUC inf ) by 27-36%. 12,13 The mean terminal half-life (t 1/2 ) of peficitinib ranged from 2.8 to 12.9 hours, 12 and dose-proportional exposure was demonstrated within the dose ranges studied across single doses (3-300 mg). 12,14 In addition, urinary excretion of peficitinib accounted for 9-15% of the oral dose, and 3 conjugated metabolites were found in plasma and urine (H2: sulfated; H4: methylated; H1: sulfated and methylated).…”

“…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.…”

“…Inter-individual variability (%) was calculated as follows: √(exp(ω 2 )-1) × 100 b 1000 successful runs for 1000 bootstrap datasets c Variability described as percentage of the estimates multiplied by 100. ALAG, absorption lag time; CL, apparent total systemic clearance; D, duration; eGFR, estimated glomerular filtration rate; IIV, interindividual variability; Ka, first-order absorption rate constant; LYM, lymphocyte count; Q, apparent intercompartmental clearance; RA, rheumatoid arthritis; RSE; relative standard error, Vc, apparent distribution volume of the central compartment; Vp, apparent distribution volume of the peripheral compartment 36%,12,13 food intake (fasted, high-fat fed, or normal fed) in the phase 1 studies was not included in the models because apparent differences among food conditions were relatively smaller than IIV. In phase2 and 3 studies, all patients with RA took the study drug in the morning in a fed condition.…”