Pharmacokinetics and Bioequivalence Study of Clindamycin Hydrochloride Formulations after Single-dose Administration in Healthy Chinese Male Volunteers

Abstract

The aim of the present study was to compare the bioavailability of clindamycin (CAS 18323-44-9) from three clindamycin hydrochloride (CAS 21 462-39-5) capsules (clindamycin 75 mg capsule as test 1 preparation, 150 mg capsule as test 2 preparation and a commercially available original 150 mg capsule of the drug as reference preparation) in 24 Chinese healthy male volunteers, aged between 22 and 28. The study was conducted according to a randomized, double-blind, 3-period, 3-treatment, 3-sequence, single-dose, crossover design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 14 h post-dose, and clindamycin plasma concentrations were determined with a validated liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Maximum plasma concentrations (C_max) of 3.06 ± 1.10 µg/mL (test 1), 3.10 ± 1.59 µg/mL (test 2) and 3.06 ± 1.15 µg/mL (reference) were achieved. Areas under the plasma concentration-time curve (AUC_0–∞) of 10.73 ± 4.29 µg · h/mL (test 1), 10.54 ± 4.10 µg · h/mL (test 2) and 11.29 ± 4.98 µg · h/mL (reference), AUC_0–t of 10.32 ± 4.09 µg · h/mL, 10.26 ± 3.96 µg · h/mL, 10.94 ±

4.86 µg · h/mL were calculated. The median T_max was 0.80 ± 0.52 h, 0.77 ± 0.37 h, 1.01 ± 0.6 h for test 1, test 2 and reference formulation, respectively. Plasma elimination half-lives (t_1/2) of 2.72 ± 0.58 h (test 1), 2.39 ± 0.37 h (test 2) and 2.63 ± 0.66 h (reference) were determined. Both primary target parameters, AUC_0–∞ and AUC_0–t were tested parametrically by analysis of variance (ANOVA) and relative bioavailabilities were 98.0 ± 16.2% (test 1) and 97.2 ± 20.3% (test 2) for AUC_0–∞, 97.5 ± 16.3% (test 1) and 97.8 ± 20.2% (test 2) for AUC_0–∞. Bioequivalence between test and reference preparation was demonstrated for both parameters, AUC_0–∞ and AUC_0–t. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%–l25%. That means that the two test formulations are bioequivalent to the reference formulation for clindamycin.

Key words

Antibiotics - CAS 18323-44-9 - CAS 21462-39-5 - Clindamycin - Clindamycin hydrochloride, bioequivalence, pharmacokinetics

• References

• 1 La Follette G, Gambertoglio J, White JA, Knuth DW, Lin ET. Determination of clindamycin in plasma or serum by high-performance liquid chromatography with ultraviolet detection. J Chromatogr. 1988; 431: 379-388
• 2 Yu LL, Chao CK, Liao WJ, Twu TY, Liu CM, Yang TH et al. Determination of clindamycin in human plasma by liquid chromatography-electrospray tandem mass spectrometry: application to the bioequivalence study of clindamycin. J Chromatogr B Biomed Sci Appl. 1999; 724: 284-294
• 3 Batzias GC, Delis GA, Koutsoviti-Papadopoulou M. A new HPLC/UV method for the determination of clindamycin in dog blood serum. J Pharm Biomed Anal. 2004; 35: 545-554
• 4 Phillips I. Clinical used and control of rifampicin and clindamycin. J Clin Pathol. 1971; 24: 410-418
• 5 DeHaan RM, Metzler CM, Schellenberg D, VandenBosch WD, Masson EL. Pharmacokinetic studies of clindamycin hydrochloride in humans. Int J Clin Pharmacol. 1972; 6: 105-119
• 6 Gatti G, Malena M, Casazza R, Borin M, Bassetti M, Cruciani M. Penetration of clindamycin and its metabolite Ndemethylclindamycin into cerebrospinal fluid following intravenous infusion of clindamycin phosphate in patients with AIDS. Antimicrob Agents Chemother. 1998; 42: 3014-3017
• 7 Si H Yang, Myung G Lee. Dose-independent pharmacokinetics of clindamycin after intravenous and oral administration to rats: Contribution of gastric first-pass effect to low bioavailability. Int J Pharm. 2007; 332: 17-23
• 8 Gatti G, Flaherty J, Bubp J, White J, Borin M, Gambertoglio J. Comparativestudy of bioavailabilities and pharmacokinetics of clindamycin in healthy volunteersand patients with AIDS. Antimicrob Agents Chemother. 1993; 37: 1137-1143
• 9 Mazur D, Schug BS, Evers G et al. Bioavailability and selected pharmacokineticparameters of clindamycin hydrochloride after administration of a new 600 mg tablet formulation. Int J Clin Pharmacol Ther. 1999; 37 (8) 386-392
• 10 Schulz HU, Steinijans VW. Striving for standards in bioequivalence assessment:a review. Int J Clin Pharmacol Ther Toxicol. 1991; 29: 293-298
• 11 Gardner S. Bioavailability and bioequivalence requirements. Procedures for establishing a bioequivalence requirement. Fed Reg. 1977; 42: 1624-1653
• 12 Note for Guidance on the Investigation of Bioavailability and Bioequivalence Committee for Proprietary Medicinal Products. CPMP/EWP/QWP/1401/ 98. London; 26 July 2001.