CLINICAL PHARMACOLOGY & THERAPEUTICS 1 2 2 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 1999

I1-19

LACK OF PHARMACOKINETIC INTERACTION BETWEEN MORPHINE AND DEXTROMETHORPHAN IN HEALTHY VOLUNTEERS. F.S. Caruso, PhD, 1 D.A. Johnson, PhD, .1 and P.K. Noonan, PhD, 2 Algos Pharmaceutical Corporation,1 Neptune NJ, PPD Pharmaco, Inc.,2 Richmond, VA.

Previous studies have demonstrated that a morphine sulfate (MS)/dextromethorphan HBr (DM) combination product pro- vides superior analgesic activity over MS alone. This study shows the increased efficacy is not due to a pharmacokinetic (PK) interaction. The interaction study was an open-label, single-dose, three-way crossover in fasted healthy subjects comparing the 1:1 combination with each component drug: I) 60 mg MS with 60 mg DM, ii) 60 mg MS, and iii) 60 mg DM. Plasma concentra- tion/time profiles for dextromethorphan, dextrorphan, morphine, morphine-3-13-glucuronide (M-3-G), and morphine-6-13- glucuronide were analyzed. Twenty-four subjects were included in the analyses. No significant differences were observed for the PK parameters AUC[0_241, AUC[0_~], Cma x, Tma x, K e, and Tt/2 for any drug or metabolite except for the inactive metabolite M-3-G. Minimal differences in Tma x and TI/2 between treatments for M-3-G were not considered clinically relevant. Thus, a PK or metabolic interaction cannot account for the increased anal- gesic efficacy of MS in the presence of DM. A combination prod- uct of MS/DM is in late stage clinical development for treatment of moderate to severe pain.

PI-21

EVALUATING THE EFFECTS OF TOPICALLY APPLIED PRODUCTS ON SUPERFICIAL SKIN WOUNDS. A.M. Kligman,* MD, PhD, M. Stoudemayer, BS,* L. DeShields, MS,* R. Maas-Irslinger, MD,* S.K.I.N., Inc., Conshohocken, PA, and Beiersdorf, Inc., Norwalk, CT.

Superficial skin wounds are common and can be troublesome. The key to evaluating products designed to treat these wounds is a reliable human model system with sensitivity to distinguish between potentially active and control sites. Ten subjects had two sites treated on the back with 1% cantharidin i n #3 filter paper discs (0.5cm). The discs were moistened and affixed to the skin for 24 hours. The resulting blisters were de-roofed leaving intact a bed of basal cell epithelium. One wound served as the untreated control. The treated sites had an ointment (petrolatum, mineral oil, ceresin, lanolin alcohol, panthenol, glycerin, and bisabolol) applied daily for ten days. The sites were then evaluated daily for re-epithelialization (nearest 10%). Photographs and skin sur- face replicas were also done. The percent of re-epithelialization of treated versus non-treated sites was statistically significant beginning at day 6. This method is sensitive enough to identify effective treatments for superficial wounds.

PI-20 POPULATION PHARMACOKINETICS OF TRAMADOL

AND ACETAMINOPHEN GIVEN ORALLY AS A SINGLE DOSE COMBINATION TABLET IN HEALTHY VOLUNTEERS. S. Liao, PhD, and X. Li, MS, K. Larson, MS, The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA.

Objective: To determine whether any demographic covariates (gender, race, body weight, creatinine clearance, smokers, and CYP2D6 genotyping) may significantly affect the pharmacoki- netics (PK) of tramadol and acetaminophen (APAP) given as a combination.

Methods: APAP, tramadol and its metabolite M 1 plasma data collected in four phase I PK studies (50 male and 34 female sub- jects with age and body weight ranged from 19 to 40 years and 49 to 94 kg, respectively) were analyzed by a population approach using the NONMEM program. A one-compartment PK model with first-order absorption was used in the analysis.

Results: The optimal population PK model for APAP indi- cated that the most important determinant of APAP clearance and volume of distribution is body weight. There was no gender effect on APAP clearance. The optimal model for tramadol and M1 indicated no clinically significant gender effect. There were 8 CYP2D6 poor metabolizers and 11 smokers included in these studies. CYP2D6 poor metabolizers have slightly decreased tra- madol clearance and a 70% decrease in M1 formation. PK of APAP, tramadol and M1 in smokers were not significantly dif- ferent from nonsmokers.

PI-22

A COMPARISON OF THE EFFICACY OF t~- KETOBUTYRIC ACID (KBA), NORDIHIDRO-GUAIARETIC ACID (NDGA), SALICYLIC ACID (SA), AND PLACEBO (P) IN THE ACCELERATED REMOVAL OF CORNS. K.M. Williams, R.O. Day, L.K. Roberts, J.A. Harbin, Dept. Of Clin. Pharmacol., St. Vincent's Hosp., Sydney, and Schering-Plough Healthcare Products, Memphis, TN.

Forty-four patients were randomized to treatment (twice daily, 5 consecutive days) of a single hard corn with either KBA (4%), NDGA (12%), SA (12.6%), or P ('Arlasolve-Klucel,' the NDGA vehicle). Forty-one patients were included in the efficacy analy- sis. All were included in the safety analysis. SA had equal total keratolytic activity to KBA based on investigator subjective assessment of cumulative amount of tissue removed. These data also indicated that the rate of removal was greater with SA. Daily photographic records were consistent with histological findings that KBA and SA had similar keratolytic activity. There was no evidence that either NDGA or P had keratolytic activity. How- ever, no difference between treatments was apparent for corn diameter or thickness based on quantitative micrometer measures. Clinical assessment (pain, maceration, erythema, blood chem- istry, reported adverse events) indicated that no treatment was toxic, or caused systemic or dermatologic changes. (Sponsored by Schering-Plough Healthcare Products. The assis- tance of D. Gengos, S. Duffy and other St. Vincent's Clinical Tri- als Centre staff is gratefully acknowledged.)