A Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic (WBPBPK-PD) Model for Colistin in Critically Ill Patients
(English)Manuscript (preprint) (Other academic)
Objectives: Colistin is used as a salvage therapy for multidrug-resistant Gram-negative bacterial infections and administered as a prodrug, colistimethate sodium (CMS). Characterizing distribution of colistin at the site of infection is important to optimize bacterial killing. The aims of this analysis were (i) to apply a whole-body physiologically based pharmacokinetic (WPBPK) model structure to describe the pharmacokinetics (PK) of CMS and colistin in critically ill patients and (ii) to predict colistin concentration-time courses and bacterial killing in target tissues combining the WBPBPK model with a semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model.
Methods: 27 critically ill patients treated with colistin were included in the analysis. A WBPBPK model previously developed in rat was applied to describe CMS and colistin PK data. The model was used to predict tissue concentrations in lungs, skin, blood and kidneys to drive a semi-mechanistic PKPD model on a wild-type (ATCC 27853) or a meropenem-resistant (AUR552) clinical strain P. aeruginosa to predict bacterial killing following the original dosing regimen and by replacing the original initial dose with a loading dose of 9MU.
Results: The plasma data were reasonably well described by the WBPBPK model for both CMS and colistin with a slight overprediction at the 1st occasion. High exposure was predicted in kidneys comparable to what had been predicted in previous studies, in rat and healthy subjects. Bacterial load was quickly cleared for both the ATCC 27853 and ARU552 strains in all tissues and at a higher extend in kidney tissue, for all dosing scenarios.
Conclusion: The WPBPK model was able to adequately describe the PK of CMS and colistin in critically ill patients. The combination of the predicted PK profiles in tissues of interest with a PKPD model was able to predict the bactericidal effect of colistin at target sites.
WBPBPK-PD model, colistin, critically ill patient, bacterial killing, site of infection
IdentifiersURN: urn:nbn:se:uu:diva-280002OAI: oai:DiVA.org:uu-280002DiVA: diva2:909419