Ibrutinib tablet splitting as a practical strategy for dose reduction in the management of drug–drug interactions

Background Ibrutinib exposure is strongly affected by cytochrome P450 3A4 (CYP3A4) activity. Drug-drug interactions (DDIs) can substantially increase ibrutinib plasma concentrations, requiring major dose reductions in DDI management. This study aimed to assess whether splitting ibrutinib 140 mg tablets is a practical and feasible strategy to adjust ibrutinib dosing in case of DDIs. Methods Ibrutinib 140 mg tablets were split into quarters using a tablet splitter aiming at 35 mg dose units. The obtained quarters were evaluated according to the European Pharmacopoeia requirements for Uniformity of Dosage Units. In addition, Uniformity of Mass, Uniformity of Content, loss of mass, stability of quartered tablets, reproducibility of splitting, usability of the splitting device, and patient instructions were assessed. The expected effects of tablet splitting on ibrutinib exposure were calculated. Results A strong correlation between tablet mass and ibrutinib content was observed ( r = 0.896; p < 0.0001), indicating uniform distribution of ibrutinib throughout the tablets. Loss of mass was <3% for all tablets, indicating that quartering did not lead to substantial material loss. The mean ibrutinib content was 34.4 mg (range 28.2–40.3 mg). Uniformity of Dosage Units of ibrutinib quarters complied with the European Pharmacopoeia requirements, with an acceptance value of 7.5% against a requirement of ≤15%. Split tablets were stable for at least two weeks under outpatient storage conditions. Patient instructions were considered sufficient and the splitting device was rated user-friendly. The impact of splitting variation on exposure is within the range of interindividual variation in ibrutinib exposure. Conclusion Splitting ibrutinib 140 mg tablets may provide a practical, clinically feasible and patient-friendly strategy to obtain 35 or 70 mg doses of ibrutinib when dose reduction is required in the management of DDIs. The expected exposure variation due to dose variations introduced by tablet splitting is unlikely to be of clinical relevance.