Systematic review of antimicrobial pharmacokinetic/pharmacodynamic indices in murine thigh and hollow fibre dose fractionation studies analysed with a standard method.

Abstract

BACKGROUND: Pre-clinical models are commonly used to determine human antibiotic dosage regimens using pharmacokinetic/pharmacodynamic (PKPD) indices. The murine thigh infection model (MTIM) is most commonly used for PKPD index determination, while the hollow fibre infection model (HFIM) may be a viable alternative. However, there is no standardized method for determining the PKPD index and R2 may not be the ideal metric to determine goodness of fit for nonlinear models. This study aimed to reanalyse PKPD indices published in MTIM and HFIM, using a standardized modelling approach. METHODS: Systematic literature review was conducted to identify MTIM and HFIM dose fractionation studies. Searches covered databases including PubMed, MEDLINE, BIOSIS, SCOPUS and EMBASE. Data were extracted and modelled using eight variations of Emax model, with model selection based on the lowest Akaike information criterion (AIC) and parameter plausibility in terms of precision and interpretability. RESULTS: A total of 53 studies were included: 50 MTIM (of 1138) and 3 HFIM (of 316). Among the 53 studies, reporting issues included an infrequent use of AIC for model selection as applied in only one paper, and a lack of methodological transparency in 29 papers. Remodelling revealed some disagreement in optimal PKPD indices in six studies. CONCLUSIONS: This study suggests a standard method for PKPD index model selection and provides a database on PKPD index analysis. Building the Emax model from one to four estimated parameters and assessing them with AIC is recommended to avoid over fitting. Too few HFIM dose fractionation studies were found to allow comparison of PKPD index with MTIM.