Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma

Abstract

This report summarizes a totality-of-evidence approach supporting recommendation of a 320mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

A two‐part, single‐arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B‐cell malignancies

“…No marked difference in response rates was observed between the two dose regimens in the current study. This is consistent with results of the global study in which both doses led to clinically meaningful and comparable response rates in patients with MCL, WM and CLL/SLL, and durable responses across tumour types 12,13 …”

“…The present study showed that comparable total daily AUC was achieved between 160 mg BID and 320 mg QD regimens. Based on a pooled analysis of phase I/II/III studies 12 and exposure–response analyses, 2 the differences in C max and trough concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety end‐points. Given the comparable safety, efficacy, and daily AUC between the two regimens, and the convenience of once‐daily dosing, which may improve treatment adherence, 320 mg QD has been approved together with 160 mg BID in the United States, Europe and other countries/regions.…”

The safety of Bruton's tyrosine kinase inhibitors in B‐cell malignancies: A systematic review

“…Further, zanubrutinib, a second-generation BTK, did not affect the action of ITK and TEC. It should be noted, that zanubrutinib may be dosed at 320 mg once a day or 160 mg twice a day with a half-life of 6 h. 85 The review by Chuck 84 also indicated a reduction of the cardiotoxicities associated with the administration of the second-generation BTK inhibitors, compared to the first generation. Acalabrutinib was also shown to improve the survival and adherence rates of the patients than ibrutinib, and the continued use of the drugs was linked to reduced cardiotoxicities.…”

The Ascension of Targeted Covalent Inhibitors

“…For all the approved BTK drugs, the occupancy assay has been used to define the frequency of dosing and the dose amount used. For example, using 12 , the occupancy assay made it possible to compare occupancy at the 160 mg twice a day (bid) and 320 mg once a day (qd) doses and also demonstrated that target occupancy in PBMCs was consistent with that seen in target tissues such as lymph nodes. Similarly, for 13 , the occupancy assays demonstrated that the 100 mg bid dose showed higher occupancy than the 200 mg qd …”