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Exposure–response analysis of acalabrutinib and its active metabolite, ACP‐5862, in patients with B‐cell malignancies
Author(s) -
Edlund Helena,
BuilBruúria,
Vishwanathan Karthick,
Wei Helen,
Raman Rakesh,
Kock Miné,
He Zhongqing,
Liu Huan,
Baek Marshall,
Ware Joseph,
Patel Priti,
Tomkinson Helen,
Sharma Shringi
Publication year - 2022
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.15087
Subject(s) - cmax , medicine , pharmacology , metabolite , active metabolite , adverse effect , population , pharmacokinetics , oncology , environmental health
Aims Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next‐generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP‐5862) vs . efficacy and safety responses in patients with B‐cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab. Methods For exposure–efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression‐free survival and tumour regression. For exposure–safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B‐cell malignancies. Acalabrutinib and ACP‐5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP‐5862 to overall efficacy/safety. Results A total of 573 patients were included (exposure–efficacy analyses, n = 274; exposure–safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration–time curve (AUC 24h,ss ) and total active maximal concentration at steady‐state (C max,ss ) were similar for patients who received acalabrutinib as monotherapy or in combination with obinutuzumab, and for responders and nonresponders. No relationship was observed between AUC 24h,ss /C max,ss and progression‐free survival or tumour regression. Acalabrutinib AUC 24h,ss and C max,ss were generally comparable across groups regardless of AE incidence. Conclusion No clinically meaningful correlations between acalabrutinib PK exposure and efficacy and safety outcomes were observed. These data support the fixed acalabrutinib dose of 100 mg twice daily in the treatment of patients with B‐cell malignancies.