Relative fasting bioavailability of two formulations of nateglinide 60 mg in healthy male Chinese volunteers: an open-label, randomized-sequence, single-dose, two-way crossover study

Abstract

Background: Nateglinide, N-(trans-4-isopropylcyclohexyl-carbonyl)-d-phenylalanine, is a potent insulin secretagogue designed to restore early-phase insulin secretion. It increases pancreatic insulin secretion by competitively binding to sulfonylurea receptors inhibiting adenosine triphosphate-sensitive potassium channels and thus reducing blood glucose levels. The drug has a rapid onset (causing immediate insulin release) and a short duration (allowing insulin to return to baseline levels between meals) of insulinotropic action.

Objective: To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic parameters and relative fasting bioavailability of new generic (test) formulation of nateglinide with the reference formulation of nateglinide in healthy Chinese male volunteers.

Methods: This open-label, single-dose, randomized-sequence, 2-way crossover study was performed at Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned in a 1:1 ratio to receive a single 60-mg (0.88 mg/kg) dose of the 2 formulations, followed by a 1-week washout period and then administration of the alternate formulation. Study drugs were administered after a 10-hour overnight fast. Concentrations of nateglinide were determined by using a validated LC-MS method. For analysis of pharmacokinetic properties, including C(max), AUC(0-10), and AUC(0-∞), blood samples were obtained at intervals over the 10-hour period after study drug administration. As established by the State Food and Drug Administration, the formulations were assumed bioequivalent if 90% CIs for the test/reference ratios of ln-transformed values of C(max) and AUC (obtained by using ANOVA) were within the predetermined equivalence range (80%-125%). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and by questioning subjects about adverse events.

Results: The 90% CIs for nateglinide were as follows: C(max), 98.4% to 118.6%; AUC(0-10), 99.5% to 110.3%. Both C(max) and AUC(0-10) met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation was estimated to be 102.1% (13.5%). One volunteer (5%) experienced a headache after administration of the test formulation. This resolved spontaneously within 1 hour and was considered by the investigators to be mild. No serious adverse events were reported. No period or sequence effects were observed.

Conclusions: In this study of healthy Chinese male volunteers, a single 60-mg dose of nateglinide (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-11001754.