Population pharmacokinetic analysis of ciprofloxacin in intensive care unit adult patients
Dalia Khachman (1,2), Jean-Marie Conil (3,4), Bernard Georges (3,4), Sylvie Saivin (2,4), Georges Houin (2) and Celine M. Laffont (1)
(1) UMR181 Physiopathologie et Toxicologie Expérimentales, INRA, ENVT, Toulouse, France; (2) Laboratoire de Pharmacocinétique et Toxicologie Clinique, Hôpital Purpan, Institut Fédératif de Biologie, Toulouse, France; (3) Pôle d’Anesthésie-Réanimation, Hôpital Rangueil, Toulouse, France; (4) GRCB 48, IFR 150 Institut Fédératif de Recherche Biomédicale de Toulouse, Université Paul Sabatier, Toulouse, France.
Objectives: To propose optimal dosage regimens for Intensive Care Unit (ICU) patients in order to achieve relevant PK/PD targets. It is the largest ciprofloxacin population PK analysis performed to date in this population of patients.
Methods: Serum ciprofloxacin concentrations of 119 ICU patients were determined at various times after i.v. infusion at standard doses and on several occasions using a validated HPLC method. Two-thirds of the patients were used for model building (N=79, 453 concentrations) and one-third for model evaluation (N=40, 242 concentrations). Population PK analysis was carried out with NONMEM 6 (FOCE-I). In contrast to previous studies [1,2], interoccasion variability was assessed. Evaluation of the model was performed using visual predictive checks and normalised prediction distribution errors [3]. AUC24h/MIC and Cmax/MIC ratios were calculated for each patient to assess whether the respective targets of 100 h and 8 were reached for the dosage regimens given in the study (mainly 400 mg b.i.d.). PK/PD simulations were further carried out to assess other dosage regimens of ciprofloxacin with respect to the AUC24h/MIC target.
Results: A 2-compartment model was found to best fit concentration data. Creatinine clearance using Cockcroft and Gault formula and total protein concentration in blood were identified as relevant covariates on ciprofloxacin clearance and explained a large part of interindividual variability. Only moderate interoccasion variability on clearance could be estimated (26%). Finally, PK/PD assessment showed that the dosage regimen of 400 mg b.i.d. used in 83% of patients did not allow to reach the PK/PD target for P. aeruginosa nor Enterobacteriaceae. The percentage of patients reaching the target was much higher with other tested dosage regimens (400 mg t.i.d., 600 mg b.i.d or 1200 mg o.d.) with small differences between them.
Conclusions: The present analysis confirms previous findings i.e. a large interindividual variability on ciprofloxacin clearance which is partly explained by creatinine clearance [1,2]. More importantly, PK/PD assessment support the use of ciprofloxacin dosages higher than the one currently used in the majority of our ICU patients. More complex PK/PD simulations are on the way to account for the whole distribution of MIC and other PK/PD targets.
References:
[1] Forrest A et al. Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin. Antimicrob Agents Chemother 1993; 37:1065-1072.
[2] Conil J-M et al. Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches. Int J Antimicrob Agents 2008; 32:505-510.
[3] Brendel K et al. Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 2006; 23(9):2036-2049.
Acknowledgment: Dalia Khachman was supported by a fellowship from the Lebanese National Council for Scientific Research (Beirut, Lebanon).
