Clinical Pharmacokinetics

, Volume 40, Issue 4, pp 307–315 | Cite as

Population Pharmacokinetics of Clinafloxacin in Healthy Volunteers and Patients with Infections

Experience with Heterogeneous Pharmacokinetic Data
  • Bill Frame
  • Jeffrey Koup
  • Raymond Miller
  • Richard Lalonde
Original Research Article

Abstract

Objective: Clinafloxacin is a new fluoroquinolone antibacterial with inhibitory activity against aerobic, anaerobic and atypical bacterial pathogens. The objectives of this study are to evaluate the pharmacokinetics of clinafloxacin in healthy volunteers and patients with infections and to describe our experience with mixed-effects modelling using heterogeneous pharmacokinetic data.

Design and setting: Retrospective analysis of data from phase I to III trials.

Patients and participants: 204 healthy volunteers and 221 patients with infections.

Methods: Nonlinear mixed-effects modelling (MEM) was used to evaluate 3437 clinafloxacin plasma concentrations collected in 15 phase I to III trials. Models were developed separately for the healthy volunteers and patients, and then for the combined study population.

Results: The phase I data were best described with a 2-compartment linear model with first-order absorption. The absorption lag-time and absorption rate constant were 0.24h and 1.17h−1, respectively. The volumes of distribution were found to be nonlinear functions of body surface area. Estimated creatinine clearance was the most important covariate for systemic clearance (CL). Interoccasion variability (IOV) in CL was observed in the patients in the phase II trial. In the combined study population, the variability in CL was best described by a model including IOV and distinct variabilities for healthy volunteers and patients.

Conclusion: MEM was useful for evaluating data collected during different phases of drug development for this new fluoroquinolone agent.

Keywords

Mixed Effect Modelling Interindividual Variability Intraindividual Variability Clinafloxacin Combine Phase 

References

  1. 1.
    Pans XS, Fisher LM. DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrob Agents Chemother 1998; (42) 11: 2810–6Google Scholar
  2. 2.
    Ednie LM, Jacobs MR, Appelbaum PC. Comparative activities of clinafloxacin against gram-positive and -negative bacteria. Antimicrob Agents Chemother 1998; (42) 5: 1269–73PubMedGoogle Scholar
  3. 3.
    Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13(10): 818–29PubMedCrossRefGoogle Scholar
  4. 4.
    Brodfuehrer JI, Preibe S, Guttendorf R. Achiral high-performance liquid chromatographic methods for clinafloxacin, a fluoroquinolone antibacterial, in human plasma. J Chromatogr B 1998; 709: 265–72CrossRefGoogle Scholar
  5. 5.
    Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analysis. J Pharmacokinet Biopharmaceut 1993; 21: 735–50Google Scholar
  6. 6.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41PubMedCrossRefGoogle Scholar
  7. 7.
    Robert S, Zarowitz BJ, Peterson EL, et al. Predictability of creatinine clearance in critically Ill patients. Crit Care Med 1993; 12(10): 1487–95CrossRefGoogle Scholar
  8. 8.
    Facca BF, Frame B, Treisenberg S. Population pharmacokinetics of ceftizoxime administered by continuous infusion in clinically ill adult patients. Antimicrob Agents Chemother 1998; 42: 1783–7PubMedGoogle Scholar
  9. 9.
    Frame B, Facca BF, Nicolau DP, et al. Population pharmacokinetics of continuous infusion ceftazidime. Clin Pharmacokinet 1999; 37(4): 343–50PubMedCrossRefGoogle Scholar
  10. 10.
    Beal SL, Sheiner LB. NONMEM users guides. San Francisco (CA): NONMEM Project Group, University of California at San Francisco, 1992Google Scholar
  11. 11.
    Mendenhall W, Wackerly DD, Scheaffer RL. Mathematical statistics with applications. 4th ed. Boston (MA): PWS-KENT, 1990Google Scholar
  12. 12.
    Ette EI. Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 1997; 37: 486–95PubMedGoogle Scholar
  13. 13.
    Beal SL, Sheiner LB. NONMEM users guide VII: conditional estimation methods. San Francisco (CA): NONMEM Project Group, University of California at San Francisco, 1997Google Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  • Bill Frame
    • 1
  • Jeffrey Koup
    • 1
  • Raymond Miller
    • 1
  • Richard Lalonde
    • 1
  1. 1.Department of Clinical Pharmacokinetics and PharmacodynamicsPfizerGlobal Research and DevelopmentAnn ArborUSA

Personalised recommendations