PMID- 34532877 OWN - NLM STAT- MEDLINE DCOM- 20220412 LR - 20220731 IS - 1365-2125 (Electronic) IS - 0306-5251 (Print) IS - 0306-5251 (Linking) VI - 88 IP - 5 DP - 2022 May TI - Exposure-response analysis of acalabrutinib and its active metabolite, ACP-5862, in patients with B-cell malignancies. PG - 2284-2296 LID - 10.1111/bcp.15087 [doi] AB - 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. CI - (c) 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. FAU - Edlund, Helena AU - Edlund H AUID- ORCID: 0000-0002-4036-0831 AD - Clinical Pharmacology & Quantitative Pharmacology (CPQP), Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden. FAU - Buil-Bruna, Nuria AU - Buil-Bruna N AD - Clinical Pharmacology & Quantitative Pharmacology (CPQP), Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK. FAU - Vishwanathan, Karthick AU - Vishwanathan K AUID- ORCID: 0000-0002-6555-8131 AD - Clinical Pharmacology & Quantitative Pharmacology (CPQP), Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Boston, Massachusetts, USA. FAU - Wei, Helen AU - Wei H AD - Biostatistics, AstraZeneca, South San Francisco, California, USA. FAU - Raman, Rakesh AU - Raman R AD - Medical Safety Science, AstraZeneca, South San Francisco, California, USA. FAU - de Kock, Mine AU - de Kock M AD - Clinical Pharmacology & Quantitative Pharmacology (CPQP), Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK. FAU - He, Zhongqing AU - He Z AD - Quantitative Clinical Pharmacology Data Services, R&D, AstraZeneca, Boston, Massachusetts, USA. FAU - Liu, Huan AU - Liu H AD - Clinical Pharmacology & Quantitative Pharmacology (CPQP), Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Boston, Massachusetts, USA. FAU - Baek, Marshall AU - Baek M AD - Biostatistics, AstraZeneca, South San Francisco, California, USA. FAU - Ware, Joseph AU - Ware J AD - Quantitative Clinical Pharmacology, AstraZeneca, South San Francisco, California, USA. FAU - Patel, Priti AU - Patel P AD - Clinical Development, AstraZeneca, South San Francisco, California, USA. FAU - Tomkinson, Helen AU - Tomkinson H AD - Clinical Pharmacology & Quantitative Pharmacology (CPQP), Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK. FAU - Sharma, Shringi AU - Sharma S AUID- ORCID: 0000-0002-3120-225X AD - Quantitative Clinical Pharmacology, AstraZeneca, South San Francisco, California, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211017 PL - England TA - Br J Clin Pharmacol JT - British journal of clinical pharmacology JID - 7503323 RN - 0 (Benzamides) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazines) RN - I42748ELQW (acalabrutinib) SB - IM MH - Benzamides/adverse effects/pharmacokinetics MH - Humans MH - *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy MH - Progression-Free Survival MH - Protein Kinase Inhibitors/therapeutic use MH - Pyrazines PMC - PMC9298019 OTO - NOTNLM OT - ACP-5862 OT - B-cell OT - BTK inhibitor OT - Calquence OT - acalabrutinib OT - chronic OT - exposure-efficacy OT - exposure-response OT - exposure-safety OT - leukaemia OT - lymphocytic OT - obinutuzumab OT - pharmacokinetics COIS- Helena Edlund, Karthick Vishwanathan, Mine de Kock, Zhongqing He, Huan Liu and Helen Tomkinson are employees of AstraZeneca. Priti Patel and Shringi Sharma are employees and stockholders of AstraZeneca. Helen Wei, Marshall Baek and Nuria Buil-Bruna are former employees of AstraZeneca. Rakesh Raman and Joseph Ware are former employees of AstraZeneca and retain AstraZeneca stock. The study was funded by Acerta Pharma, South San Francisco, CA, a member of the AstraZeneca Group. EDAT- 2021/09/18 06:00 MHDA- 2022/04/13 06:00 PMCR- 2021/10/17 CRDT- 2021/09/17 07:31 PHST- 2021/07/29 00:00 [revised] PHST- 2021/02/01 00:00 [received] PHST- 2021/08/11 00:00 [accepted] PHST- 2021/09/18 06:00 [pubmed] PHST- 2022/04/13 06:00 [medline] PHST- 2021/09/17 07:31 [entrez] PHST- 2021/10/17 00:00 [pmc-release] AID - BCP15087 [pii] AID - 10.1111/bcp.15087 [doi] PST - ppublish SO - Br J Clin Pharmacol. 2022 May;88(5):2284-2296. doi: 10.1111/bcp.15087. Epub 2021 Oct 17.