Oral bioavailability of trovafloxacin with and without food in healthy ...

Journal of Antimicrobial Chemotherapy (1997) 39, Suppl. B, 87–92

JAC

Oral bioavailability of trovafloxacin with and without food in healthy volunteers Renli Teng, Lisa C. Dogolo, Susan A. Willavize, Hylar L. Friedman and John Vincent Central Research Division, Pfizer Inc., Groton, CT 06340, USA Two studies determined the oral bioavailability of trovafloxacin (CP-99,219) in healthy volunteers under fasted and fed conditions. In a randomized, two-way crossover study, 12 fasting subjects received two 100 mg tablets of trovafloxacin and an equivalent dose of alatrofloxacin (CP-116,517), administered by iv infusion over 1 h. Alatrofloxacin, the L-Ala-L-Ala prodrug of trovafloxacin, is rapidly converted in the body to trovafloxacin. After the oral dose of trovafloxacin, the mean Cmax and AUC were 2.2 mg/L and 30.4 mg·h/L, respectively. After the infusion of alatrofloxacin, the Cmax and AUC of trovafloxacin were 3.2 mg/L and 34.7 mg·h/L, respectively. The mean T1/2 after both treatments was about 11 h. The mean Cl and Vdss of trovafloxacin after the infusion of alatrofloxacin were 1.32 mL/min/kg and 1.13 L/kg, respectively. The mean oral bioavailability of trovafloxacin was estimated to be 87.6% (range 64.8–122.1%). Another randomized, open, three-way crossover study was conducted in 12 healthy male volunteers to investigate the effect of food in the gastrointestinal tract on the bioavailability of trovafloxacin. Each subject received three 100 mg tablets after fasting overnight (treatment A) or after a standard breakfast (treatment B), or 300 mg as oral aqueous suspension after fasting overnight (treatment C). Mean Tmax after treatment B occurred 2.2 h later (3.6 h vs 1.4 h) than after treatment A. Mean Cmax and AUC were 2.3 and 2.6 mg/L and 38.2 and 39.5 mg·h/L after B and A, respectively. About 5% of the administered dose was recovered unchanged in the 24 h urine sample after all three treatments. Thus, the food reduced mean Cmax by 12% but had no appreciable effect on mean AUC. The mean bioavailability of trovafloxacin administered as treatment regimen B was 96.6% relative to that of treatment A. The respective mean bioavailabilities of trovafloxacin as treatments B and A were 91.3% and 94.5% respectively of that of treatment C. The results of these studies indicate that trovafloxacin has good oral bioavailability and that the ingestion of food is unlikely to have a clinically significant effect on the bioavailability of trovafloxacin.

Introduction

organisms, Staphylococcus aureus and B. fragilis.3 The absolute oral bioavailability of trovafloxacin in rats, dogs and monkeys is 67%, 58% and 85%, respectively.6 Favourable pharmacokinetic features of trovafloxacin observed in healthy volunteers include rapid absorption (time to peak serum concentration (Tmax) about 1 h) and a long terminal-phase half-life (T1/2) of about 10 h.7 Maximum serum concentration (Cmax) and area under the serum concentration–time curve (AUC) increase in a dose-related manner.7,8 The mean unbound fraction in plasma was 22.0–28.3% and 95%.20–23 The mean bioavailability of trovafloxacin observed in the present study (87.6%) indicates that trovafloxacin is well 90

Oral bioavailability of trovafloxacin Table II. Pharmacokinetics of trovafloxacin (mean S.D.a] after 300 mg administered as tablets under fasted (A) and fed (B) conditions and as oral suspension under fasting conditions (C) Treatment

Cmaxa (mg/L)

A B C

2.6 2.3 3.0

0.6 0.4 0.4

Tmax (h) 1.4 3.6 1.1

0.7 1.6 0.5

AUCa (mg·h/L) 39.5 38.2 41.9

7.4 4.7 5.7

Cavgb (mg/L) 6.8 6.1 7.3

3.5 2.4 3.0

% Dose in urinec

Clr (mL/min)

T1/2 (h)

5.1 5.1 5.0

8.9 9.2 8.0

12.4 12.3 12.2

0.6 0.7 1.1

1.9 1.5 1.9

a

The means and standard deviations for Cmax and AUC are geometric. Concentration in pooled urine samples from 0 to 24 h. c Total amount of trovafloxacin excreted in 24 h urine sample, expressed as per cent of administered dose.

b

absorbed from the gastrointestinal tract. After the oral dose of trovafloxacin, the mean Cmax and AUC values were 2.2 mg/L and 30.4 mg·h/L, respectively. After alatrofloxacin the mean values of Cmax, AUC, Cl and Vdss were 3.2 mg/L, 34.7 mg·h/L, 1.32 mL/min/kg and 1.13 L/kg, respectively. The mean T1/2 after both trovafloxacin and alatrofloxacin (approximately 11 h) was similar to that observed in previous pharmacokinetic studies.7,8,10 In a previous single-dose study involving healthy male volunteers,10 the mean renal clearance of trovafloxacin after the iv infusion of a dose of alatrofloxacin equivalent to 200 mg of trovafloxacin was 0.16 mL/min/kg. Comparison of this value with the mean total body clearance observed in the present study (1.32 mL/min/kg) underscores the previous finding that the renal clearance of trovafloxacin is at least 15 times lower than that of ciprofloxacin, norfloxacin and ofloxacin). 7,8,21 The mean Vdss value of trovafloxacin (1.13 L/kg) suggests good tissue penetration. A change in the absorption of a drug from the gastrointestinal tract alters the rate at which and the extent to which the drug reaches the systemic circulation. The presence of food in the gastrointestinal tract is known to alter the absorption of many drugs by mechanisms that include altering the rate of gastric emptying, changing gastric pH or enzyme activity, and binding and chelation. 24 When the presence of food reduces the extent of drug absorption, therapeutic failure may result, so it is important to investigate the effect of food on the bioavailability of new drugs intended for oral use. Studies involving healthy volunteers have shown that standard carbohydrate and high-fat meals delay the absorption of currently used fluoroquinolones, including ciprofloxacin,12,14 enoxacin,13,14 lomefloxacin,16 ofloxacin14,17 and pefloxacin.15 Food in the gastrointestinal tract, however, has not been found to reduce significantly the extent of fluoroquinolone absorption. In Study I involving fasting healthy volunteers, the trovafloxacin tablet formulation was rapidly absorbed from the gastrointestinal tract (mean Tmax 2.3 h), and its absorption was nearly total. In Study II in which three 100 mg tablets of trovafloxacin were administered to 12

healthy subjects under fasting and fed conditions, a highfat breakfast containing milk prolonged the mean trovafloxacin Tmax by 2.2 h but, as the narrow confidence intervals show, had no clinically significant effect on overall drug exposure. The breakfast marginally lowered mean Cmax but had virtually no effect on the extent of absorption of trovafloxacin. The bioavailability of trovafloxacin after the breakfast was comparable to that under fasting conditions. The 300 mg dose of trovafloxacin was well tolerated by all the subjects. It was concluded that the slight delay in trovafloxacin absorption and modest reduction in Cmax caused by the presence of food is unlikely to be of clinical significance and that trovafloxacin, therefore, can be taken with or without food. Clinical trials are in progress to confirm the expected clinical utility of trovafloxacin.

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