Pharmacokinetic properties and bioequivalence of two compound formulations of 1500 mg ampicillin (1167 mg)/probenecid (333 mg): a randomized-sequence, single-dose, open-label, two-period crossover study in healthy Chinese male volunteers

Abstract

Background: Ampicillin/probenecid is an antimicrobial formulation indicated for the treatment of respiratory, urinary tract, and gastrointestinal infections. Ampicillin sodium is the active antimicrobial ingredient that can act on the phase of bacterial breeding and inhibit the biosynthesis of bacterial mucopeptide in the cell wall. Probenecid acts synergistically by competitively inhibiting an organic anion transporter in renal tubules, increasing the plasma concentrations, and thus extending the plasma elimination t(1/2).

Objective: The aim of this study was to assess and compare the pharmacokinetic (PK) properties, bioavailability, and bioequivalence of a newly developed dispersible tablet formulation (test) of ampicillin/ probenecid with those of an established branded capsule formulation (reference) in healthy Chinese male volunteers.

Methods: A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 6 dispersible tablets (test) or branded capsules (reference) (1500 mg total; 250 mg each containing ampicillin 194.5 mg and probenecid 55.5 mg), followed by a 7-day washout period and administration of the alternate formulation. Plasma samples were collected over a 24-hour period following administration and analyzed for ampicillin and probenecid content by HPLC. PK parameters such as C(max), AUC(0-t), and AUC(0-infinity) were also determined. The formulations were considered bioequivalent if the geometric mean ratios of the log-transformed C(max) and AUC values were within the equivalence range (80%-125%) predetermined by the State Food and Drug Administration (SFDA) of the People's Republic of China. Tolerability was based on the observation of adverse events (AEs), monitoring of vital signs (blood pressure, heart rate, temperature, electrocardiography) and laboratory tests (hematology, blood biochemistry, hepatic function, urinalysis), and subject's interview on AEs.

Results: The study was performed in 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.2] years; weight, 64.1 [5.5] kg; height, 173.7 [5.3] cm; and body mass index, 21.2 [1.6] kg/m(2)). The mean (SD) C(max), T(max), AUC(0-24), and AUC(0-infinity) after administration of the test and reference formulations, respectively, were as follows: ampicillin, C(max), 13.45 (3.43) versus 15.04 (5.68) microg/mL, T(max), 1.58 (0.49) versus 1.78 (0.55) hours, AUC(0-24), 50.78 (13.39) versus 57.44 (17.27) micro/mL/h, and AUC(0-infinity), 51.95 (13.45) versus 58.74 (17.19) microg/mL/h; probenecid, C(max), 15.56 (2.94) versus 16.01 (2.88) microg/mL, T(max), 2.85 (0.78) versus 3.30 (1.51) hours, AUC(0-24), 129.23 (27.59) versus 127.29 (26.89) microg/mL/h, and AUC(0-infinity) 133.85 (28.80) versus 131.21 (28.25) microg/mL/h. On ANOVA, neither period nor sequence effects were observed for any of the PK properties. The 90% CIs of ampicillin for the log-transformed ratios of C(max), AUC(0-24), and AUC(0-infinity)) were 86.5% to 108.0%, 96.7% to 107.8%, and 83.3% to 100.7%, respectively, and the corresponding values for probenecid were 90.2% to 108.3%, 96.8% to 107.8%, and 97.2% to 108.5%. No AEs were observed or reported up to 1 week after study end.

Conclusions: In this small study in healthy Chinese male volunteers, a single 1500-mg dose of the dispersible tablet formulation (test) of ampicillin/probenecid met the SFDA's regulatory criteria for bioequivalence to the reference capsule formulation based on the rate and extent of absorption. Both formulations were well tolerated.