Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species

Abstract

Abstract The pharmacokinetics of moxifloxacin was investigated in NMRI mice, Wistar rats, rhesus monkeys, beagle dogs, Göttingen minipigs and healthy human volunteers after iv and oral administration of moxifloxacin-HCl (single doses of moxifloxacin 9.2 mg/kg bodyweight) in animals and 100 mg moxifloxacin (1.4 mg/kg bodyweight po and 1.2 mg/kg bodyweight iv) in humans. The plasma concentration vs time courses of the unchanged compound (determined by HPLC) and the derived pharmacokinetic parameters were used to evaluate the absorption process, to compare the pharmacokinetics in these species and to perform an interspecies scaling. The results of the pharmacokinetic investigations indicate a clear dependence on the species. Moxifloxacin is absorbed quickly (rats, dogs, humans > monkeys): the major portion of the dose reached the systemic circulation within the first 2 h. In the minipig absorption was slower. Bioavailability was high to moderate (91–52%) in all species. Protein binding ( fu ) was low (55–71%) in all species. The volume of distribution at steady state ( Vss ) was medium to large (2.0–4.9 L/kg) in all species. There were considerable differences in maximum concentrations ( Cmax,norm , 0.430–0.070 kg/L) and in AUC norm values (oral, 6.18–0.184 kg·h/L; iv, 7.51–0.237 kg·h/L). Total body clearance ( CL ) decreased with increasing bodyweight (4.21–0.132 L/(h·kg)). The mean residence time (MRT) decreased with decreasing bodyweight (15–0.88 h). The half-life ( t½ ) decreased with decreasing bodyweight (oral, 12–1.3 h, iv, 13–0.93 h). There was moderate to low renal excretion (iv, 20–6.2%), the renal clearance, ( CLR ) was in the range 0.615–0.0222 L/(h·kg). Regarding the pharmacokinetic parameters determined after oral administration, the dog was most similar to the human in terms of Cmax , AUC and t½ . There was good correlation between bodyweight and CL (coefficient of correlation ( r ) = 0.959), Vss ( r = 0.990) and MRT ( r = 0.943). On the basis of preclinical studies a terminal half-life appropriate for once-daily dosing in humans was predicted and confirmed by Phase I data.