PHARMACOKINETIC DEVELOPMENT OF QUINOLONE ANTIBIOTICS

A prerequisite for the pharmacokinetic development of quinolone antibi otics is a sensitive and accurate method for the quantification of the drug in biological fluids, Both, a drug specific (e.g. HPLC) and a dr ug non-specific but effect related assay (e.g. bioassay) should be use d during early clinical development to detect major active metabolites , The basic pharmacokinetic behavior of the drug is investigated as pa rt of the early phase I program, where single and multiple ascending d ose studies are performed to characterize the safety and tolerability of the quinolone in healthy volunteers. Further pharmacokinetic studie s are performed to describe the absolute bioavailability, dose proport ionality, pharmacokinetics in young and elderly, male and female volun teers, The suitability of the clinical dosage form must be evaluated i n comparison to an oral solution and by quantification of the effect o f food on bioavailability. The characterization of the absorption in d ifferent parts of the gastrointestinal tract may be valuable for dosag e form optimization, In order to start phase IIb clinical trials, the potential of possible drug-drug interactions with antacids, cimetidine , theophylline and warfarin has to be evaluated, This can be done by i n vitro and in vivo preclinical experiments, before formal clinical-ph armacology studies are performed. Further pharmacokinetic characteriza tion (e.g. studies in special subpopulation, extended interaction stud ies, total recovery using C-14-labelled compound blister fluid penetra tion) will be done parallel to the phase II/III development program. D uring these efficacy and safety trials blood samples should be obtaine d and PK-parameters can be calculated using sparse data analysis metho ds like non-linear mixed effect modeling (NONMEM) or Bayesian methods to characterize the pharmacokinetics in the target population.