I.K. Minichmayr (1,2), M. Zeitlinger (3), C. Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Dept. of Clinical Pharmacology, Medical University Vienna, Austria.
Objectives: Doripenem is a broad-spectrum carbapenem antibiotic indicated for the empirical therapy of serious bacterial infections. Adequate drug concentrations at the site of infection are imperative to ensure successful and safe treatment. To quantify these, the method of microdialysis has proven beneficial, particularly if infections are located in peripheral soft tissues. The present analysis sought to characterise plasma and target site pharmacokinetics of doripenem and to assess its distribution characteristics into interstitial space fluid (ISF) by population pharmacokinetic modelling.
Methods: Data originated from the first part of a study in six healthy volunteers following a single 1‑h infusion of 500 mg doripenem. Rich sampling was performed over a period of eight hours in plasma (n=66) and, by means of microdialysis, in the ISF of subcutaneous adipose tissue (n=65) and muscle tissue (n=66) [1]. Model development was performed in NONMEM 7.3 (FOCE Interaction). The observed dialysate concentrations were analysed using an integrated model enabling the differentiation between pharmacological drug distribution processes and methodological microdialysis-specific aspects (e.g. retrodialysis as the method of in vivo calibration) [2,3].
Results: A two-compartment disposition model with linear elimination was best suited to describe doripenem pharmacokinetics (V=26.6 L, CL=22.3 L/h). Penetration into peripheral tissues was found to be rapid and more pronounced into the ISF of subcutaneous adipose tissue than of muscle tissue. Despite the homogeneity of the population, considerable interindividual variability was observed, especially in clearance.
Conclusions: A combined population model for doripenem concentrations measured in plasma and ISF of skeletal muscle and subcutaneous adipose tissue was successfully developed. The established model will form the basis for simulating and evaluating target site pharmacokinetics for different administration schedules advocated for doripenem (e.g. prolonged infusion, continuous infusion). Furthermore, the translatability of the observed results from a healthy male population to patient populations will be investigated.
References:
[1] Burian B et al. Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers. Antimicrob Agents Chemother 56: 532–5 (2012).
[2] Boström E et al. In vivo blood-brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics. Drug Metab Dispos 34: 1624-31 (2006).
[3] Minichmayr IK et al. A microdialysate-based integrated model with nonlinear elimination for determining plasma and tissue pharmacokinetics of linezolid in four distinct populations. PAGE 22, Abstr 2930 (2013).
Reference: PAGE 23 (2014) Abstr 3240 [www.page-meeting.org/?abstract=3240]
Poster: Drug/Disease modeling - Infection