Isavuconazole and Calcium Channel Blocker for Invasive Fungal Disease Accompanied With Hypertension: Evidence From the FAERS and PBPK/PD Model

Patients with invasive fungal disease (IFD) frequently present with hypertension, necessitating polypharmacy and increasing the risk of drug–drug interactions (DDIs). This study evaluated the safety of combining isavuconazole (ISA), a triazole antifungal drug (TAD), and calcium channel blockers (CCBs) in hypertensive patients with IFD using the FDA Adverse Event Reporting System (FAERS) and physiologically based pharmacokinetic/pharmacodynamic models. FAERS data on hypertension and hypotension involving TADs from 2015 (first quarter) to 2023 (fourth quarter) were used. Disproportionality analysis was performed using the reporting odds ratio (ROR) and information component (IC) methods. DDI models were developed and validated using the Simcyp simulator and in vitro experiments. Dose regimen evaluation and optimization were conducted using the established DDI model. ISA was not associated with hypertension or hypotension. Nifedipine and amlodipine were frequently associated with hypotension induced by CYP3A4 inhibition. The simulated regimens showed that ISA doubled plasma exposure to nifedipine immediate-release (IR) and controlled-release (CR) formulations, increased the maximum concentration by 1.51-fold for nifedipine IR and 2.15-fold for nifedipine CR, and caused a 3.5- to 4.09-fold increase in maximum systolic blood pressure reduction for nifedipine IR. The effects of amlodipine were negligible. Dose optimization, such as halving the nifedipine dose, effectively managed the overexposure. ISA appears safe for use in hypertensive patients with IFD when combined with CCBs, with minimal risk of significant DDIs. Personalized dosing adjustments can mitigate DDI risk. These findings support the clinical use of ISA to enhance dosing precision and patient safety.