Acalabrutinib received approval for treatment of adult patients with mantle cell lymphoma who received at least one prior therapy and adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. This study investigated the impact of hepatic impairment (HI) on acalabrutinib PK and safety at a single 50-mg dose in fasted subjects. This study was divided into two studies: study 1, an open-label, parallel-group study in Child-Pugh Class A or B subjects and healthy subjects, and study 2, an open-label, parallel-group study in Child-Pugh Class C subjects and healthy subjects.

Baseline characteristics and safety profiles were similar across groups. Acalabrutinib exposure (area under the curve [AUC]) increased slightly (1.90- and 1.48-fold) in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) HI compared with healthy subjects. In severe HI (Child-Pugh Class C), acalabrutinib exposure (AUC and maximum concentration [Cmax]) increased approximately 5.0-fold and 3.6-fold, respectively. Results were consistent across total and unbound exposures. Severe HI did not impact total/unbound metabolite (ACP-5862) exposures; metabolite to parent ratio decreased to 0.6 - 0.8 (versus 3.1 - 3.6 in healthy subjects).

In summary, single oral dose of 50 mg acalabrutinib was safe and well tolerated in subjects with mild, moderate and severe HI and in healthy control subjects. In subjects with severe HI, mean acalabrutinib exposure increased by up to 5-fold and should be avoided. Acalabrutinib does not require dose adjustment in patients with mild or moderate HI.

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