Pharmacokinetics and Bioavailability of a New Formulation of Teicoplanin following Intravenous and Intramuscular Administration to Humans KELLY K. ANTONY,ERICW. LEWIS, MICHAELT. KENNY,JACQUELINE K. DULWORTH, MARCIAB. BRACKMAN, RON KUZMA, LIANNGYUH, MARK G. ELLER,AND GARYA. THOMPSON~ Received June 11, 1990, from Merrell Dow Research Institute, Cincinnati. OH 45215 and Indianapolis, IN 46268. September 7, 1990. Abstract 0 Pharmacokinetics,bioavailability, and local tolerance (at the

site of intramuscular administration) of a new formulation of teicoplanin (400mg/3 mL) were investigated in 24 normal, healthy, male volunteers. A single dose of 6 mglkg was administered intravenously and intramuscularly using a randomized crossover design. Volunteers and investigator were blinded as to the route of administration;placebo was administered by the other route. Blood and urine samples were collected for 21 days and were analyzed for microbiologicalactivity. The median (range) pharmacokinetic parameters of teicoplanin following single-dose iv administration were as follows: steady-statevolume of distribution of 1.6 (1.2-2.8) Ukg; total clearance of 10.2 (8.G15.1)mUh/kg; renal clearance of 10.0 (7.9-1 3.8)mUh/kg;and terminal disposition half-lifeof 168 (1 1 1-278) h. Following single-dose im administration, significantly more subjects complained of pain following administration of teicoplanin (58%) compared with placebo (4%).Teicoplanin was completely absorbed with a median (range) peak serum concentration of 12.3 (6.6-37.5) @/mL occurring at a median (range) time of 4.1 (0.7-6.1)h. Since the 90% confidence interval for the ratio of areas under the serum concentrationtime curve falls within the range of 80 to 120%,the extent of systemic absorption of teicoplanin following im administration is equivalent to that following iv administration.

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study,s 200 mg of teicoplanin was administered intramuscularly every 12 h for three doses, followed by 200 mg every 24 h for three doses. A mean peak plasma concentration of 7.1 pg/mL was achieved after the first dose, and a mean peak plasma concentration of 12.1 pg/mL was obtained following the last dose. Time to reach the peak concentration ranged from 2 to 4 h. Comparing these results to a previous study, the bioavailability (based on area analysis following the last dose) was -95%. In current clinical trials, doses up to 30 mg/kg are being administered. As a result of this increase in dose, a new formulation containing 400 mg/3 mL was developed. Except for the concentration of teicoplanin, this formulation is identical to the earlier formulation containing 200 mg/3 mL. The purpose of this study was to determine the pharmacokinetics and bioavailability of teicoplanin following singledose iv and im administration of 6 mg/kg using the new formulation. In addition, local tolerance at the site of im administration was assessed.

Experimental Section Teicoplanin is a new glycopeptide antibiotic that is chemically related to vancomycin and ristocetin. It is active against aerobic and anaerobic gram-positive bacteria.14 Its effect on susceptible organisms is bactericidal and, like vancomycin, it interferes with cell wall synthesis.5 The pharmacokinetics of teicoplanin has been studied in normal, healthy volunteers following single- and multipledose iv administration. Following iv administration, the plasma concentration-time profiles were described by a sum of three to four exponentials. The pharmacokinetics following multiple-dose administration was linear from 3 to 6 mg/kg.6 Over this range, the median pharmacokinetic parameters were as follows: total clearance of 13.6 mL/h/kg; renal clearance of 10.9 m L h k g ; steady-state volume of distribution of 1.2 Wkg; and terminal disposition half-life of 147 h. These results indicate that total clearance is predominantly a function of renal clearance, and that dosage regimen adjustments may be necessary in patients with impaired renal function. Upon multiple dosing, steady-state would be obtained in 2 to 3 weeks if no loading dose(s) was administered. Upon iv administration of 6 mg/kg every 24 h, a steady-state trough serum concentration of -14 pglmL would be obtained. Teicoplanin is not absorbed following oral administration, but is well absorbed following im administration. The bioavailability of teicoplanin has been previously investigated following single- and multiple-dose im administration (200 mg/3 mL formulation). Following single-dose im administration of 3 mg/kg,7.s the bioavailability of teicoplanin (compared with iv administration) was -90%. In the multiple-dose 0022-3549/9 1/0600-0605$0 1.00/0 0 1991, American Pharmaceutical Association

Study Design-This study was conducted in 24 normal, healthy, male volunteers using a randomized, double-blind, balanced, twoperiod (21days per period) crossover design. Periods were separated by 1week. Institutional Review Board approval and informed consent was obtained prior to the start of the study. In each period, placebo (normal saline) and 6 mg/kg of teicoplanin (lot IC-4068)were administered to each subject. Teicoplanin or placebo was administered as a 30-min constant rate iv infusion subsequent to im administration. Blood samples were obtained a t 0,30,35,45, and 60 min, and at 2, 3, 4, 5, 6, 8, 12,24,36, and 48 h after the start of the iv infusion. Additional blood samples were obtained every 24 h for an additional 19 days. Urine was pooled every 24 h for 21 days following im administration (teicoplanin or placebo). Local tolerance at the site of im administration was assessed at the time of administration and 4,8,12,and 24 h after administration of teicoplanin or placebo. The severity of intolerance was rated on a scale of 0 to 3 (where 0 = absent, 1 = mild, 2 = moderate, and 3 = severe symptoms). Analytical M e t h o d s S e r u m (harvested from blood) and urine samples were analyzed for teicoplanin using a validated microbiological assay.9 Within- and between-day coefficients of variation were

Pharmacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans.

Pharmacokinetics, bioavailability, and local tolerance (at the site of intramuscular administration) of a new formulation of teicoplanin (400 mg/3 mL)...
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