Pharmacokinetics-pharmaco dynamics of a sordarin derivative (GM 237354) ina murine model of lethal candidiasis

Sordarins are a new class of antifungal agents which selectively inhibit fu ngal protein synthesis (FPS) by impairing the function of elongation factor 2, The present study investigates possible correlations between sordarin p harmacokinetic (PK) properties and therapeutic efficacy, based on a murine model of invasive systemic candidiasis, and provides a rationale for dose s election in the first study of efficacy in humans. A significant correlatio n between PK parameters and the in vivo activity of GM 237354, taken as a r epresentative FPS inhibitor, was demonstrated in a murine model of lethal s ystemic candidiasis. Area under the concentration-time curve (AUC) and maxi mum concentration of drug in serum (C-max) over 24 h were determined after a single GM 237354 subcutaneous (s.c.) dose (50 mg/kg of body weight) in he althy animals (no significant PK changes with infection were observed for o ther sordarin derivatives). These results have been used to simulate PK pro files obtained after several doses and/or schedules in animal therapy. A PK -pharmacodynamic (PD) parameter such as the time that serum drug concentrat ions remain above the MIC (t > MIG) was also determined, Treatment efficaci es were evaluated in terms of the area under the survival time curve (AUSTC ), using Kaplan-Meier survival analysis and in terms of kidney fungal burde n (log CFU/gram) after s.c. doses of 2.5, 5, 10, 20, and 40 mg/kg every 4, 8, or 12 h (corresponding to total daily doses of 5 to 240 mg/kg), The resu lts show all treatments to significantly prolong survival versus that of in fected and nontreated controls (P < 0.05), Relationships between simulated PK and PK-PD parameters and efficacy were explored. A good correlation inde pendent of the dosing interval was observed with AUC (but not C-max or t > MIG) and both AUSTC and kidney burden. Following repeated dosing every 8 h, AUG,, (AUC at which 50% of the maximum therapeutic efficacy is obtained) w as estimated as 21.7 and 37.1 mu g h/ml (total concentrations) for AUSTC an d kidney burden using a sigmoid E-max and an inhibitory sigmoid E-max PK-PD model, respectively. For an efficacy target of 90% survival, AUC was predi cted as 67 mu g h/ml, We conclude that the PK-PD approach is useful for eva luating relationships between PK parameters and efficacy in antifungal rese arch. Moreover, the results obtained with this approach could be successful ly applied to clinical studies.