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

 

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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.

• References

• 1 Birkenmeyer RD, Kagan F. Lincomycin. XI: Synthesis and structure of clindamycin, a potent antibacterial agent. J Med Chem. 1970; 13: 616-9
  CrossrefPubMedGoogle Scholar
• 2 Holly A. Stevens MD. Clindamycin. Prime Care Update Ob/Gyns. 1997; 4 (6) 251-3
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 8 Ameer BA, Sesin P, Karchmer AW. Selecting clindamycin dosing regimens. Am J Hosp Pharm. 1987; 44: 2027-8
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 12 Sun F. Disposition of clindamycin in rat and dog. Fed Proc Am Soc Exp Biol. 1970; 29: 677-82
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 14 Sun FF, Metabolismof clindamycin. II: Urinary excretion products of clindamycin in rat and dog. J Pharm Sci. 1973; 62: 1657-62
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 17 Gray JE, Weaver RN, Bollert JA, Feenstra ES. The Oral Toxicity of Clindamycin in Laboratory Animals. Toxicol Appl Pharmacol. 1972; 21: 516-31
  CrossrefPubMedGoogle Scholar
• 18 Stevens H. Prim Care Update Ob/Gyns. 1997; 4: 251-3
  CrossrefPubMed
• 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
  PubMed
• 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
  Google Scholar
• 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
  PubMed
• 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
  CrossrefPubMedGoogle Scholar
• 23 Shumaker RC. PK Cale: a basic interactive computer program for statistical and pharmacokinetic analysis of data. Drug Metab Rev. 1986; 17: 331-48
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 25 Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. New York, NY: Marcel Dekker Inc.; 1992
  Google Scholar
• 26 Swartzberg JE, Maresca RM, Remington JS. Gastrointestinal side effects associated with clindamycin. Arch Intern Med. 1976; 136: 876-9
  CrossrefPubMedGoogle Scholar
• 27 CPMP (Committee for Proprietary Medicinal Products), Note for Guidance on the Investigation of Bioavailability and Bioequivalence 2001
  PubMed