Kuepfer, Lars (1); Niederalt, Christoph (1); Wendl, Thomas (1); Schlender, Jan-Frederik (1); Willmann, Stefan (2); Lippert, Jörg (2); Block, Michael (1); Eissing, Thomas (1); Teutonico, Donato (1)
(1) Bayer Technology Services, Leverkusen, Germany, (2) Bayer HealthCare, Wuppertal, Germany
Objectives: The objective of this study was to develop a full blown whole-body physiologically based pharmacokinetic (PBPK) model for the antibiotic ciprofloxacin to adequately describe the patient plasma concentration of this compound. The drug concentration predicted by the model was then coupled with an in vitro pharmacodynamic (PD) model to describe anti-bacterial drug effect as function of the ciprofloxacin target exposure.
Methods: A whole-body PBPK model was built with the PBPK software tool PK-Sim® (1) including both physiological information from the software database and ciprofloxacin physicochemistry. Relevant metabolisation (CYP1A2) and excretion processes (biliary, glomerular filtration rate (GFR) and tubular secretion) were explicitly included in the model and the clearance values were estimated from published plasma concentration profiles (2). To represent administration of solid dosage forms, a Weibull function was used to describe the dissolution process. An in vitro PD model describing E. coli (11775) microbial growth (3) and its antibiotic-mediated inhibition was coupled with the ciprofloxacin lung concentration predicted by the PBPK model established. Antimicrobial activity was simulated for two dosing regimens, 500 mg BID and 1000 mg OD.
Results: The PBPK model developed was able to adequately describe measured PK plasma concentration-time profiles after intravenous as well as after oral administration. Observed PK plasma profiles, AUCs and Cmax for iv and oral dosing regimens were within the 1.5-fold range for the simulations. Elimination and excretion processes described in the model are in agreement with mass balance information available for ciprofloxacin. Target site exposure in the lung was directly coupled to the antibacterial effect of ciprofloxacin. Comparison of expected kill curves with the two tested dosing regimen tested, 500 mg BID and 1000 mg OD, showed a similar outcome for E.coli (11775), with a decrease in CFU/ml > 5 log units over 24 h for both administrations, in agreement with reported literature data (3).
Conclusions:In conclusion, the PBPK/PD model developed was able to describe plasma concentration of ciprofloxacin after intravenous and oral administration, as well as to reproduce several treatment scenarios of antibacterial activity following ciprofloxacin administration.
References:
[1] Eissing T. et al. A computational system biology software platform for the multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front. Physio. (2011)
[2] Davis RL, Koup JR, Williams-Warren J, Weber A, Heggen L, Stempel D, et al. Pharmacokinetics of ciprofloxacin in cystic fibrosis. Antimicrobial agents and chemotherapy. 1987;31(6):915-9
[3] Schuck EL, Dalhoff A, Stass H, Derendorf H. Pharmacokinetic/pharmacodynamic (PK/PD) evaluation of a once-daily treatment using ciprofloxacin in an extended-release dosage form. Infection. 2005;33 Suppl 2:22-8
Reference: PAGE 25 () Abstr 5885 [www.page-meeting.org/?abstract=5885]
Poster: Drug/Disease modeling - Absorption & PBPK