Therapeutic drug monitoring-guided individualized dosing of multiple BTK inhibitors combined with voriconazole: Real-world evidence on managing drug-drug interactions

Abstract Introduction: Bruton's tyrosine kinase inhibitors (BTKis) have transformed the treatment landscape of B-cell malignancies, demonstrating both proven efficacy and an acceptable safety profile. BTKis are primarily metabolized by cytochrome P450 (CYP) 3A4, making it susceptible to drug-drug interactions (DDIs) with CYP3A4 inhibitors or inducers like voriconazole.Therapeutic drug monitoring (TDM) quantifies drug concentrations in patient samples using modern analytical techniques and computational methods, enabling individualized dosing that has significantly improved patient outcomes. This study aimed to describe the effect of voriconazole on BTKis concentrations and guide dose adjustment based on TDM when used in combination. Methods: Four patients with B-cell malignancies received BTKis in combination with voriconazole [200 mg twice a day (BID)] for the treatment of fungal or respiratory infections. The regimens included ibrutinib [560 mg once a day (QD), reduced to 140 mg QD], zanubrutinib (160 mg BID, reduced to 80 mg QD), orelabrutinib (150 mg QD, reduced to 50 mg QD), and acalabrutinib (100 mg BID, reduced to 100 mg QD). Dose reductions for ibrutinib and zanubrutinib followed prescribing information, while adjustments for orelabrutinib and acalabrutinib-lacking formal recommendations-were based on clinical judgment. TDM of BTKis was carried out by liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: TDM revealed that trough concentrations of BTKis remained within a comparable range before and after dose adjustments. Trough concentrations of BTKis before and after dose reduction were as follows: ibrutinib, 4.28 mg/L and 5.27 mg/L; zanubrutinib, 15.85 mg/L and 18.96 mg/L; orelabrutinib, 21.91 mg/L and 25.05 mg/L; and acalabrutinib, 12.89 mg/L and 13.61 mg/L. These findings support the appropriateness of dose reduction in the presence of CYP3A4 inhibition. And no adverse drug events (ADEs) were observed during the treatment with BTKis in combination with voriconazole. Conclusion: The study suggests that coadministration of BTKis with CYP3A inhibitors can significantly affect its pharmacokinetic properties, and TDM has been shown to optimize the individualized dose adjustments of BTKis in the presence of DDIs. We are currently conducting a prospective real-world study to further elucidate exposure-response relationships, aiming to transition BTKi therapy from empirical to precision medicine. These efforts will provide valuable insights for optimizing dosing regimens, guiding personalized treatment decisions, and improving clinical outcomes.