(T-049) Monte-Carlo simulations to assess isavuconazole probability of pharmacokinetic-pharmacodynamic target attainment (PTA) for Chinese pediatric patients with invasive aspergillosis (IA) or invasive mucormycosis (IM)

Shuangchen Cong – Pfizer Pharmaceutical Ltd., Development China, Beijing, China.; Susan R Raber – Pfizer R&D, Pfizer Inc, La Jolla, CA, USA; Phylinda LS Chan – Pfizer R&D UK Ltd. Sandwich, Kent, UK; Jian Liu – Pfizer Pharmaceutical Ltd., Development China, Beijing, China.

Objectives: Isavuconazole (Cresemba®), a triazole antifungal targeting ergosterol biosynthesis, is approved globally for invasive aspergillosis (IA) and mucormycosis (IM) management in adults, with pediatric indications only in Western markets. This study aimed to 1) characterize the pharmacokinetic (PK) profile in Chinese pediatric patients (1 to < 18 years) using population PK modelling, and 2) PTA for proposed dosing regimens through simulations.

Methods: A validated Western-derived population PK model was employed for Monte Carlo simulations (N=1000/year of age) incorporating Chinese pediatric demographic data. Body weights followed a truncated normal distribution (3rd – 97th percentiles) to minimize outlier effects. PK/Pharmacodynamic (PD) targets were derived from a preclinical study establishing total drug Area Under Concentration-Time Curve at Steady State/Minimum Inhibitory Concentration (AUCss/MIC) as the primary driver of efficacy1. Using MIC determined with Clinical and Laboratory Standards Institute (CLSI) method, the 50% survival effective AUCss/MIC ratio for isavuconazole was 50.48 (95% confidence interval, 44.90 to 56.74)1. MIC distributions from the China Fungal Surveillance Study2 informed PTA calculations across Aspergillus and Mucorales isolates in China. The dose regimen used for simulation is the approved pediatric dose regimen in EU Summary of Product Characteristics (SmPC) 3.

Results: The proposed dose regimen achieved ≥90% PTA against Aspergillus species (83.8% coverage) and Mucorales species (90.33% coverage) at MIC ≤ 1 mg/L, for all Chinese pediatric patients, regardless of age groups, weight groups and administration route. Conservative modelling incorporating potential ethnic-specific PK differences (40% lower clearance in Chinese adult and 50% higher AUCss, not clinically meaningful) enhanced PTA to ≥98% at MIC =1 mg/L. Current simulations based on existing population PK would provide the most rational and conservative results that support the sufficient efficacy in Chinese pediatric patients. Comparative exposure analysis revealed Chinese pediatric AUCss values remained within established adult therapeutic windows, aligning with global safety and efficacy benchmarks.

Conclusions: Population PK simulations demonstrate robust PTA (≥90%) for isavuconazole in Chinese pediatric patients, with exposure comparable to approved adult regimens across ethnicities. These findings support the proposed dosing strategy’s clinical validity and its alignment with international regulatory standards for pediatric antifungal therapy.

Citations: [1] Seyedmousavi, Seyedmojtaba et al. “Pharmacodynamics of isavuconazole in an Aspergillus fumigatus mouse infection model.” Antimicrobial agents and chemotherapy vol. 59,5 (2015): 2855-66. doi:10.1128/AAC.04907-14
[2] Jing, Ran et al. “In vitro Activity of Isavuconazole and Comparators Against Clinical Isolates of Molds from a Multicenter Study in China.” Infection and drug resistance vol. 15 2101-2113. 22 Apr. 2022, doi:10.2147/IDR.S360191
[3] Cresemba | European Medicines Agency (EMA); https://www.ema.europa.eu/en/medicines/human/EPAR/cresemba#product-info

Keywords: Chinese pediatric, anti-fungal, Monte-Carlo simulation