Population pharmacokinetics of finafloxacin in healthy volunteers and patients with complicated urinary tract infections [PublishAheadOfPrint]

Background: Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTI) while pharmacokinetics was characterized by highly variable concentration vs. time profiles, suggesting the need for an elaborated pharmacokinetic model.

Methods: Data from three clinical trials were evaluated; 127 healthy volunteers were dosed orally (N=77) or intravenously (N=50) and 139 patients with cUTI received finafloxacin intravenously. Plasma (2824 samples in volunteers, 414 in patients) and urine (496 samples in volunteers, 135 in patients) concentrations were quantified by LC/MS-MS. NONMEM was used to build a population pharmacokinetic model and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression.

Results: A two-compartment model with first-order elimination described the data best (central [Vc] and peripheral [Vp] volumes: 47L [20%] and 43L [67%]; elimination clearance and inter-compartmental clearance: 21L/h [54%] and 2.8L/h [57%]) (median bootstrap estimates, coefficients of variation). Vc increased with body surface area and clearance was reduced in patients (-29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens.

Conclusions: Despite the inter-individual variability, the present dataset does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited.

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