Optimal dose finding of garenoxacin based on population pharmacokinetics/pharmacodynamics and Monte Carlo simulation

Abstract

PurposeGarenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens.MethodsAt the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once daily by the interim PK/PD analysis using phase I and phase II clinical data. The criteria used to determine an optimal dose were (1) the target attainment of the area under the unbound concentration–time curve divided by the minimum inhibitory concentration (fAUC0−24/MIC ratio) and (2) the maintenance of a trough concentration above the mutant prevention concentration. In a confirmatory phase III study, garenoxacin was administered 400 mg once daily to 136 patients infected with mild or moderate chronic respiratory diseases.ResultsLogistic regression analysis showed that fAUC0−24/MIC ratio was a significant variable that predicted clinical response (p = 0.0164). Of all subjects, 92.4% reached the target value of fAUC0−24/MIC ratio > 30 h, and the clinical efficacy rate of this population was 91.8%. On the other hand, there was no significant relationship between exposure values (AUC0−24 and maximum concentration) and the incidence of adverse events by the Mann–Whitney test.ConclusionsThe antimicrobial efficacy of the actual phase III study was consistent with the expectation from the Monte Carlo PD simulation. We were able to show that the optimal garenoxacin dosage regimens were successfully determined using prospective population PK/PD analysis and clinical trial simulations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-011-1095-3) contains supplementary material, which is available to authorized users.

Garenoxacin pharmacokinetics in patients undergoing maintenance hemodialysis

“…Plasma GRNX concentrations were expected to be >1 mg/mL above the MPC for common bacteria following the administration of 400 mg in healthy volunteers and patients with moderately impaired renal function. 20 In the current study, however, GRNX concentrations in some cases were below the MPC 24 hours after the start of administration, suggesting that it may not be possible to prevent the development of resistant mutants in some MH patients treated with 200 mg GRNX. Therefore, in addition to evaluating the treatment effects and preventing the development of resistant mutants, further research is needed to investigate the accumulation of GRNX and the impact of continuous administration on its pharmacokinetics.…”

“…A concentration of <1 µg/mL above the MPC has been calculated to inhibit the development of resistant mutants. Plasma GRNX concentrations were expected to be >1 µg/mL above the MPC for common bacteria following the administration of 400 mg in healthy volunteers and patients with moderately impaired renal function . In the current study, however, GRNX concentrations in some cases were below the MPC 24 hours after the start of administration, suggesting that it may not be possible to prevent the development of resistant mutants in some MH patients treated with 200 mg GRNX.…”

Applications of pharmacometrics in the clinical development and pharmacotherapy of anti-infectives

“…Population based pharmacokinetic M&S using Monte Carlo simulations helped in deciding on a dosage regimen by taking into account the between-subject variability in PK parameters and varying MIC distributions by various clinical isolates. This approach helped in determining the optimal dose for garenoxacin (400 mg) on the basis of (i) selecting AUC 0-24 /MIC as an appropriate PK/PD index derived from in vivo efficacy data, (ii) performing Monte Carlo Simulations using population PK parameters, MIC distributions and mutant prevention concentration (MPC), (iii) determining a recommended dose based on probability of target attainment, and (iv) validation of the recommended dose based on PK/PD data acquired from phase III studies for respiratory tract infection [27]. …”

Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin as a single injection for Pasteurellaceae respiratory infections in cattle using population pharmacokinetics and Monte Carlo simulations

“…Population pharmacokinetics associated with Monte Carlo simulations (MCSs) can contribute to optimization of antimicrobial drugs dosage regimen taking into account both the variability of the PK and the PD parameters. This approach is widely used in human medicine (DeRyke, Kuti, & Nicolau, ; Frei, Wiederhold, & Burgess, ; Roberts, Kirkpatrick, & Lipman, ; Tanigawara, Nozawa, & Tsuda, ; Turnidge & Paterson, ; Zelenitsky, Ariano, Harding, & Forrest, ). A growing interest in population pharmacokinetics and MCS applied to the assessment of anti‐infectives dosage regimens was recently shown in veterinary medicine (Black, Landersdorfer, Bulitta, Griffith, & Govendir, ; Rey et al., ; Vilalta, Giboin, Schneider, El Garch, & Fraile, ; Yuan et al., ).…”