Comparison of the probability of target attainment (PTA) of anidulafungin for antifungal prophylaxis against Candida species

Background: Intermittent dosing of anidulafungin is an attractive option for antifungal prophylaxis in patients with acute lymphoblastic leukaemia (ALL) due to anidulafungin’s long half-life and concentration-dependent killing [1]. At present there is a lack of information on the likely PK-PD outcomes of anidulafungin in ALL patients. This study evaluated the probability of target attainment (PTA) against Candida species with various dosing regimens of anidulafungin in adult patients with ALL using a Monte Carlo simulation platform.

Methods: Monte Carlo simulations were performed in Berkeley Madonna 8.3.18, using a published population PK model [2]. A two compartment model with zero order input was used. The population PK parameters and between-subject variability (CV%) were as follows: CL 1.12 L/h (26%), V1 30.7 L (25%), V2 23.2 L, and Q 0.94 L/h. The following dosing scenarios were simulated for 1000 subjects: 200 mg loading dose (LD) on day 1 then 100 mg daily (standard regimen), 200 mg LD on day 1 then 100 mg q48h, 200 mg q48h, 200 mg q72h, or 300 mg q72h. For each regimen, the free-drug (f) concentration was calculated to evaluate the effect of 84% [3] and 99% [4] protein binding. The PTA was determined as the percentage of the 1000 subjects who achieved a fAUC/MIC ratio of ≥ 13 or a fCmax/MIC ratio of ≥ 0.7 [1]. A PTA expectation value of ≥ 90% was considered optimal [5].

Results: When fAUC/MIC ratio was evaluated, the standard regimen and 200 mg LD followed by 100 mg q48h achieved target attainment for MICs ≤ 0.03 mg/L at 99% protein binding. The remaining regimens were effective for MICs ≤ 0.06 mg/L. At 84% protein binding, all regimens had PTA > 90% for MICs ≤ 0.5 mg/L. When fCmax/MIC ratio was evaluated, all regimens showed PTA > 90% for MICs ≤ 0.06 mg/L and ≤ 1 mg/L at 99% and 84% protein binding, respectively. All regimens failed to achieve the optimal PD targets at 99% protein binding. At 84% protein binding, the PTA expectation values of the standard regimen were 87% and 89.6% for fAUC/MIC and fCmax/MIC, respectively. At least 200 mg q72h was required to achieve optimal PD exposure.

Conclusions: The current model suggested that 200 mg LD followed by 100 mg daily with anidulafungin failed to achieve optimal PD targets in adult patients with ALL. Administering higher doses with longer dosing intervals may be needed to achieve better PD exposure.

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