Pharmacokinetic and Safety Evaluations of Ketoprofen Gels in Subjects with Adult Periodontitis

Abstract

This clinical trial used a randomized, partially double-blind, controlled parallel design to evaluate the pharmacokinetics and safety of the NSAID, ketoprofen (KTP), in gel formulations. Forty-two subjects, ages 35 to 57 years, with generalized, moderate to advanced adult periodontitis were recruited and randomized to one of 5 treatments over a 14½-day treatment period: (1) 0.5% KTP gel; (2) 1.0% KTP gel; (3) 1.0% KTP alternate gel; (4) 2.0% KTP gel; and (5) 25 mg KTP capsule (positive control). Plasma samples were obtained on days 1 (pre-dosing, 0.5, 1, 2, 3, 6 hr), 8 (pre-dosing, 2 hr), 15 (pre-dosing, 2 hr), and 22 (7 days post-treatment). Plasma KTP concentrations were determined by means of high-performance liquid chromatography. Significant differences in mean area under the plasma concentration vs. time curve (AUC_0-∞ ) among the groups were detected (p < 0.001), with the 25 mg p.o. capsule exhibiting the largest value (5054 ng-hr/mL), the 2.0% gel exhibiting an intermediate value (2244 ng-hr/mL), the 1.0% gels exhibiting lower but comparable values (1516 for the alternate formulation vs. 1461 ng-hr/mL), and the 0.5%. gel showing the lowest value (736 ng-hr/mL). Significant differences in dose- and weight-adjusted maximum plasma concentration (C_max/dose/kg) were detected overall such that the 25 mg p.o. capsule demonstrated higher values as compared with the 4 gel formulations (p = 0.001). The 5 treatments exhibited similar mean times of maximum plasma concentration (t_max) values ranging from 0.6 to 1 hr. Systemic exposures relative to dose and body weight were lower for the gel formulations than for the capsule. The relative systemic bioavailability of the gels compared with peroral administration ranged from 54% to 69%.

Keywords

ketoprofen pharmacokinetics periodontal diseases/therapy plasma bioavailability non-steroidal anti-inflammatory agents drug administration (topical/ intra-oral).

Get full access to this article

View all access options for this article.

References

Abranson MM , Wolff LF , Offenbacher S. , Aeppli DM , Hardie ND , Friedman HM (1992). Flurbiprofen effect on gingival crevicular fluid prostaglandin and thromboxane levels in humans. J Periodont Res 27:539-543.

Forland SC , Wechter WJ , Witchwoot S. , Clifford KH , Arnett RL , Cutler RE (1996). Human plasma concentrations of R, S, and racemic flurbiprofen given as a toothpaste. J Clin Pharmacol 36:546-553.

Heasman PA , Seymour RA , Boston PF (1989). The effect of a topical non-steroidal anti-inflammatory drug on the development of experimental gingivitis in man. J Clin Periodontol 16:353-358.

Jamali F. , Brocks DR (1990). Clinical pharmacokinetics of ketoprofen and its enantiomers. Clin Pharmacokinet 19:197-217.

Jeffcoat MK , Reddy MS , Haigh S. , Buchanan W. , Doyle MJ , Meredith MP , et al. (1995). A comparison of topical ketorolac, systemic flurbiprofen, and placebo for the inhibition of bone loss in adult periodontitis . J Periodontol 66:329-338.

Jusko WJ (1992). Guidelines for the collection and analysis of pharmacokinetic data. In: Applied pharmacokinetics: princi-ples of therapeutic drug monitoring. Evans WE , Schentag JJ , Jusko WJ , Lelling MV , editors. Vancouver, WA: Applied Therapeutics, Inc., Chapter 2.

Kelm GR , Buchanan W. , Meredith MP , Offenbacher S. , Mankodi SM , Dobrozsi DJ , et al. (1996). Evaluation of ketorolac concen-trations in plasma and gingival crevicular fluid following topical treatment with oral rinses and dentifrices. J Pharm Sci 85 :842-847.

Li KL , Vogel R. , Jeffcoat MK , Alfano MC , Smith MA , Collins JG , et al. (1996). The effects of ketoprofen creams on periodontal disease in rhesus monkeys. J Periodont Res 31:525-531.

Loe H. , Silness J. (1963). Periodontal disease in pregnancy. I. Prevalence and severity. Acta Odontol Scand 21:533-551.

10.

Offenbacher S. , Odle BM , Gray RC , Van Dyke TE (1984). Crevicular fluid prostaglandin E levels as a measure of the periodontal disease status of adult and juvenile periodontitis patients . J Periodont Res 19:1-13.

11.

Offenbacher S. , Odle BM , Van Dyke TE (1986). The use of crevicular fluid prostaglandin E2 levels as a predictor of periodontal attachment loss. J Periodont Res 21:101-102.

12.

Offenbacher S. , Odle BM , Green MD , Mayambala CS , Smith MA , Fritz ME , et al. (1990). Inhibition of human periodontal prostaglandin E2 synthesis with selected agents. Agents Actions 29:232-238.

13.

Offenbacher S. , Heasman PA , Collins JG (1993). Modulation of host PGE2 secretion as a determinant of periodontal disease expression. J Periodontol 64:432-444.

14.

Papas A. , Samiei S. , Arbree N. , Konnikov N. , Troullos E. , Binder T. , et al. (1997). Reduction of alveolar bone loss under denture with ketoprofen gel (abstract). J Dent Res 76(Spec Iss):383.

15.

Paquette DW , Lawrence HP , Wilder R. , Maynor G. , Binder T. , Troullos E. , et al. (1997a). Pharmacodynamic effects of keto-profen on crevicular fluid prostanoids in adult periodontitis (abstract). J Dent Res 76(Spec Iss):233.

16.

Paquette DW , Fiorellini JP , Martuscelli G. , Oringer RJ , Howell TH , McCullough JR , et al. (1997b). Enantiospecific inhibition of ligature-induced periodontitis in beagles with topical (S)-ketoprofen. J Clin Periodontol 24:521-528.

17.

Salvi GE , Williams RC , Offenbacher S. (1997). Non-steroidal anti-inflammatory drugs as adjuncts in the management of periodontal diseases and peri-implantitis. Curr Opin Periodontol 4:51-58.

18.

Shah AK , Wei G. , Lanman RC , Bhargava VO , Weir SJ ( 1996). Percutaneous absorption of ketoprofen from different anatomical sites in man. Pharm Res 13:168-172.

19.

Silness J. , Loe H. (1964). Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 24:747-759.

20.

Stalker DJ , Pollock SR (1991). Bioavailability of flurbiprofen following buccal administration. Pharm Res 8:605-607.

21.

United States. Food and Drug Administration ( 1970). National Adverse Drug Reaction Directory: "COSTART" (coding symbols for thesaurus of adverse reaction terms). Rockville, MD: United States Department of Health, Education, and Welfare. Public Health Service. Food and Drug Administration.

22.

Upton RA , Buskin JN , Guentert TW , Williams RL , Riegelman S. (1980). Convenient and sensitive high-performance liquid chromatography assay for ketoprofen, naproxen and other allied drugs in plasma and urine. J Chromatogr 190:119-128.