In vitro feasibility studies for clinical microdialysis with lipophilic compounds: A case study with the antifungal...

To guide optimal dosing, knowledge about target-site drug exposure is essential and is commonly determined using the sampling technique of clinical microdialysis. The extent of target-site pharmacokinetic variability for posaconazole, a highly lipophilic azole antifungal with widely varying plasma pharmacokinetics between patients, is currently unknown. Microdialysis of posaconazole is considered challenging due to high unspecific binding and feasibility should be carefully evaluated in vitro, prior to clinical application. The objective of this study was to foster clinical in vivo applicability through in vitro evaluation of perfusate additives to suppress nonspecific binding of posaconazole. Supporting this aim, a bioanalytical method using mass spectrometry was developed for posaconazole in microdialysate with a lower limit of quantification of 10.0 ng/mL. The investigations addressing compatibility with the microdialysis system were exhausted without accomplishing feasibility of posaconazole for clinical microdialysis, as relative recovery was unfavourably low (<4%) and not congruent with relative delivery values in retrodialysis setting, which were misleadingly high (>82%). An unspecific binding assay suggested that up to 100% of the compound were retained in the tubing material, confirming the hypothesis of unspecific binding. Thus, reliable quantification of unbound posaconazole concentrations at target site was deemed infeasible with currently available catheter materials and clinically acceptable perfusate additives; advances in low-adsorption catheter materials and in-vivo-compatible perfusate formulations are required to enable clinical microdialysis of posaconazole. Utilizing the knowledge gained from exploring microdialysis with posaconazole, an efficient in vitro workflow for feasibility studies on clinical microdialysis with highly lipophilic compounds including early stop criteria was proposed.