Comparative pharmacokinetics study of two different clindamycin capsule formulations: a randomized, two-period, two-sequence, two-way crossover clinical trial in healthy volunteers

Utpal Kumar Sanki; Badal Kumar Mandal; Venkatesh Chandrakala

doi:10.1055/s-0031-1296241

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2011; 61(9): 538-543
DOI: 10.1055/s-0031-1296241

Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics

Editio Cantor Verlag Aulendorf (Germany)

Comparative pharmacokinetics study of two different clindamycin capsule formulations: a randomized, two-period, two-sequence, two-way crossover clinical trial in healthy volunteers

Authors

Utpal Kumar Sanki

¹School of Advanced Sciences, Vellore Institute of Technology (VIT) University, Vellore, Tamilnadu, India
Badal Kumar Mandal

¹School of Advanced Sciences, Vellore Institute of Technology (VIT) University, Vellore, Tamilnadu, India
Venkatesh Chandrakala

¹School of Advanced Sciences, Vellore Institute of Technology (VIT) University, Vellore, Tamilnadu, India

Abstract

The comparative pharmacokinetic (PK) study of two brands of clindamycin hydrochloride (CAS 21462-39-5) was carried out on 32 healthy Indian subjects in an open label randomized, two way crossover, two period, two sequence, two treatment trial with a minimum washout period of 7 days. Plasma samples were collected at 10 min interval for the 1^st hour, at 1 h interval for the next 6 h, at 2 h interval for next 12 h and finally at the 24^th hour (pre-dose as baseline value) after drug administration. The concentrations of clindamycin in plasma were determined using high performance liquid chromatography (HPLC) technique with UV detector [lower limit of quantitation (LLOQ) 0.05 μg · mL⁻¹). All PK parameters were calculated from data on clindamycin content in plasma using a non-compartmental model. Primary PK parameters were maximum plasma concentration (C_max), area under the curve from zero to t^th hour (AUCT) and area under the curve from zero to infinite (AUCI), whereas secondary PK parameters were elimination half-life (t_halt), elimination rate constant (K_el) and time to reach maximum plasma concentration (T_max). All primary PK parameters (log transformed) were subjected to ANOVA analysis and two one-sided Student’s t-test (TOST) to construct the 90% confidence intervals. The result of ANOVA showed that all primary PK parameters at 90% confident intervals were within the limit of 80–125%. All the values such as 95.7–109.00% for C_max( 99.5–117% for AUCT and 99.1% to 114% for AUCI showed pharmacokinetic equivalence and indicated that this comparative pharmacokinetic study was well designed to conclude that the test formulation and reference formulation were pharmaco-kinetically equivalent and hence bioequi-valent with respect to rate and extent of absorption.

Key words

Bioequivalence - Clindamycin - Macrolide antibiotic - Pharmacokinetics

Full Text

References

References
1 Birkenmeyer RD, Kagan F. Lincomycin. XI: Synthesis and structure of clindamycin, a potent antibacterial agent. J Med Chem. 1970; 13: 616-9
2 Holly A. Stevens MD. Clindamycin. Prime Care Update Ob/Gyns. 1997; 4 (6) 251-3
3 Klepser ME, Nicolau DP, Quintiliani R, Nightingale CH. Bactericidal activity of low-dose clindamycin administered at 8- and 12-hour intervals against Staphylococcus aureus, Streptococcus pneumoniae, and Bacteroides fragilis. Anti-microb Agents Chemother. 1997; 41: 630-5
4 Lewis RE, Klepser ME, Ernst EJ, Lund BC, Biedenbach DJ, Jones RN. Evaluation of low-dose, extended-interval clindamycin regimens against Staphylococcus aureus and Streptococcus pneumoniae using a dynamic in vitro model of infection. Antimicrob Agents Chemother. 1999; 43: 2005-9
5 Xue IB, Davey PG, Phillips G. Variation in postantibiotic effect of clindamycin against clinical isolates of Staphylococcus aureus and implications for dosing of patients with osteomyelitis. Antimicrob Agents Chemother. 1996; 40: 1403-7
6 Athamna A, Athamna M, Medlej B, Bast DJ, Rubinstein E. In vitro post-antibiotic effect of fluoroquinolones, macro-lides, blactams, tetracyclines, vancomycin, clindamycin, linezolid, chloramphenicol, quinupristin/dalfopristin and rifampicin on Bacillus anthracis. J Antimicrob Chemother. 2004; 53: 609-15
7 Xue. Davey IBPG, Phillips G. Variation in the postantibiotic effect of clindamycin against clinical isolates of Staphylococcus aureus and implications for dosing of patients with osteomyelitis. Antimicrob Agents Chemother. 1996; 40: 1403-7
8 Ameer BA, Sesin P, Karchmer AW. Selecting clindamycin dosing regimens. Am J Hosp Pharm. 1987; 44: 2027-8
9 Gatti G, Flaherty J, Bubp J, White J, Borin M, Gambertoglio J. Comparative study of bioavailabilities and pharmacokinetics of clindamycin in healthy volunteers and patients with AIDS. Antimicrob Agents Chemother. 1993; 37: 1137-43
10 De Haan RM, Metzler CM, Schellenberg D, Van den Bosch WD, Masson EL. Pharmacokinetic studies of clindamycin hydrochloride in humans. Int J Clin Pharmacol. 1972; 6: 105-19
11 Levinson RS, Mitan SJ, Steinmetz JI, Gattermeir DJ, Schumacher RJ, Joffrion JL. An open-label, two-period, crossover study of the systemic bioavailability in healthy women of clindamycin phosphate from two vaginal cream formulations. Clin Ther. 2005; 12: 1894-900
12 Sun F. Disposition of clindamycin in rat and dog. Fed Proc Am Soc Exp Biol. 1970; 29: 677-82
13 Wynalda MA, Hutzler JM, Koets MD, Podoll T, Wienkers LC. In vitro metabolism of clindamycin in human liver and intestinal microsomes. Drug Metab. Dispos. 2003; 31: 878-87
14 Sun FF, Metabolismof clindamycin. II: Urinary excretion products of clindamycin in rat and dog. J Pharm Sci. 1973; 62: 1657-62
15 Gatti G, Malena M, Casazza R, Borin M, Bassetti M, Crucia-ni M. Penetration of clindamycin and its metabolite N-de-methylclindamycin into cerebrospinal fluid following intravenous infusion of clindamycin phosphatein patients with AIDS. Antimicrob Agents Chemother. 1998; 42: 3014-17
16 Klepser ME, Banevicius MA, Quintiliani R, Nightingale CH. Characterization of bactericidal activity of clindamycin against Bacteroides fragilis via kill curve methods. Antimicrob Agents Chemother. 1996; 40: 1941-4
17 Gray JE, Weaver RN, Bollert JA, Feenstra ES. The Oral Toxicity of Clindamycin in Laboratory Animals. Toxicol Appl Pharmacol. 1972; 21: 516-31
18 Stevens H. Prim Care Update Ob/Gyns. 1997; 4: 251-3
19 The European Agency for the Evaluation of Medicinal Products, Human Medicines Evaluation Unit, International Conference on Harmonisation. Guideline for Good Clinical Practice [EMEA web site, accessed March 26, 2007.]. http://www.emea.eu.int
20 FDA Guidance for Industry: Bioavailability and Bioequiva-lence Studies for Orally Administered Drug Products. Rock-ville, MD: Office of Generic Drugs, Division of Bioequiva-lence, US Food and Drug Administration; 2003
21 Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations [US Food and Drug Administration (FDA) web site, accessed March 18, 2007] http://www.fda.gov/cder/guidancelS356fnl.pdf
22 Fieger-Buschges H, Schubler G, Larsimont V, Blume H. Determination of clindamycin in human plasma by high-performance liquid chromatography using coupled columns. J Chromatog. 1999; 724: 281-6
23 Shumaker RC. PK Cale: a basic interactive computer program for statistical and pharmacokinetic analysis of data. Drug Metab Rev. 1986; 17: 331-48
24 Chiou WL. Critical evaluation of potential error in pharmacokinetic studies using the linear trapezoidal rule method for the calculation of the area under the plasma level–time curve. J Pharmacokinet Biopharm. 1987; 6: 539-6
25 Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. New York, NY: Marcel Dekker Inc.; 1992
26 Swartzberg JE, Maresca RM, Remington JS. Gastrointestinal side effects associated with clindamycin. Arch Intern Med. 1976; 136: 876-9
27 CPMP (Committee for Proprietary Medicinal Products), Note for Guidance on the Investigation of Bioavailability and Bioequivalence 2001