Assessment of pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers.

Objective: Levofloxacin and cyclosporine show different pharmacokinetic properties, but are known to be dose proportional within the therapeutic range. The authors evaluated the pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Methods: Two independent, randomized, crossover studies were performed. For levofloxacin, eight volunteers were randomly assigned in a 1:1 ratio to receive a low dose (7.5 mg) orally or intravenously, followed by a 1-week washout period and administration via the alternate route. After another 1-week washout period, a therapeutic dose (750 mg) was administered to all eight subjects. For cyclosporine, another eight volunteers received a low dose (2 mg) or a therapeutic dose (200 mg) orally with a 1-week washout period. Drug concentrations were determined by LC-MS/MS. Results: For levofloxacin, the mean values for dose-normalized C-max and AUC(last) with the two doses were as follows: therapeutic dose, 15.2 +/- 4.6 ng/ml/mg and 103.6 +/- 15.5 ng.h/ml/mg, respectively; low dose, 17.1 +/- 6.5 ng/ml/mg and 72.6 +/- 8.7 ng.h/ml/mg, respectively. For cyclosporine, the mean values for dose-normalized C-max and AUC(last) were as follows: therapeutic dose, 4.9 +/- 1.5 ng/ml/mg and 15.4 +/- 4.9 ng.h/ml/mg, respectively; low dose, 1.6 +/- 0.6 ng/ml/mg and 9.3 +/- 7.3 ng.h/ml/mg, respectively. Conclusion: In this study levofloxacin, which is completely absorbed and primarily eliminated renally without modification, showed better pharmacokinetic proportionality than cyclosporine, which is poorly absorbed and extensively metabolized.