Which Analysis Approach Is Adequate to Leverage Clinical Microdialysis Data? A Quantitative Comparison to Investigate Exposure and Response Exemplified by Levofloxacin

PURPOSE: Systematic comparison of analysis methods of clinical microdialysis data for impact on target-site drug exposure and response. METHODS: 39 individuals received a 500 mg levofloxacin short-term infusion followed by 24-h dense sampling in plasma and microdialysate collection in interstitial space fluid (ISF). ISF concentrations were leveraged using non-compartmental (NCA) and compartmental analysis (CA) via (ii) relative recovery correction at midpoint of the collection interval (midpoint-NCA, midpoint-CA) and (ii) dialysate-based integrals of time (integral-CA). Exposure and adequacy of community-acquired pneumonia (CAP) therapy via pharmacokinetic/pharmacodynamic target-attainment (PTA) analysis were compared between approaches. RESULTS: Individual AUC(ISF) estimates strongly varied for midpoint-NCA and midpoint-CA (≥52.3%CV) versus integral-CA (≤32.9%CV) owing to separation of variability in PK parameters (midpoint-CA = 46.5%–143%CV(PK), integral-CA = 26.4%–72.6%CV(PK)) from recovery-related variability only in integral-CA (41.0%–50.3%CV(recovery)). This also led to increased variability of AUC(plasma) for midpoint-CA (56.0%CV) versus midpoint-NCA and integral-CA (≤33.0%CV), and inaccuracy of predictive model performance of midpoint-CA in plasma (visual predictive check). PTA analysis translated into 33% of evaluated patient cases being at risk of incorrectly rejecting recommended dosing regimens at CAP-related epidemiological cut-off values. CONCLUSIONS: Integral-CA proved most appropriate to characterise clinical pharmacokinetics- and microdialysis-related variability. Employing this knowledge will improve the understanding of drug target-site PK for therapeutic decision-making. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11095-021-02994-1.