PMID- 35165925
OWN - NLM
STAT- MEDLINE
DCOM- 20220719
LR  - 20220728
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 88
IP  - 8
DP  - 2022 Aug
TI  - Acalabrutinib CYP3A-mediated drug-drug interactions: Clinical evaluations and 
      physiologically based pharmacokinetic modelling to inform dose adjustment 
      strategy.
PG  - 3716-3729
LID - 10.1111/bcp.15278 [doi]
AB  - AIMS: Clinical drug interaction studies with itraconazole and rifampicin have 
      demonstrated that acalabrutinib is a sensitive substrate of CYP3A. A 
      physiologically based pharmacokinetic (PBPK) model was developed based on the 
      data of these studies. One of the active CYP3A metabolites, ACP-5862, was 
      identified but never studied in a drug interaction scenario. This study aims to 
      evaluate both parent and metabolite exposure change with coadministration of 
      moderate CYP3A inhibitors and its impact on safety and efficacy. METHODS: In an 
      open label, randomized, 2-period study, we investigated the effect of 
      coadministration of fluconazole or isavuconazole on the pharmacokinetics of 
      acalabrutinib. Bruton tyrosine kinase receptor occupancy and safety were compared 
      between different treatments. Experimental data were compared to PBPK simulation 
      results. RESULTS: Least square means of acalabrutinib maximum plasma 
      concentration and area under the curve increased 1.37 (1.14-1.64) and 1.60 
      (1.45-1.77)-fold in the presence of isavuconazole and 1.48 (1.10-1.98) and 2.16 
      (1.94-2.40)-fold in the presence of fluconazole, respectively. For ACP-5862, 
      these values are 0.72 (0.63-0.82) and 0.91 (0.86-0.97) fold for isavuconazole and 
      0.65 (0.49-0.87) and 0.95 (0.91-0.99) fold for fluconazole coadministration. The 
      PBPK model was able to recover acalabrutinib and ACP-5862 PK profiles in the 
      study. Bruton tyrosine kinase receptor occupancy change was minimal in the 
      presence of isavuconazole. There were no deaths, serious adverse events (AEs), or 
      subject discontinuation due to AEs in this study. Only mild (Grade 1) AEs were 
      reported during the study, by 17% of the study population. CONCLUSION: Our 
      results demonstrate the impact of fluconazole and isavuconazole on the 
      pharmacokinetics of acalabrutinib and ACP-5862, and suggest that no dose 
      adjustment is needed for concomitant administration with moderate CYP3A 
      inhibitors. the current PBPK model can be used to propose dose adjustment for 
      drug interactions via CYP3A.
CI  - (c) 2022 British Pharmacological Society.
FAU - Chen, Buyun
AU  - Chen B
AUID- ORCID: 0000-0001-8218-3063
AD  - Astrazeneca South San Francisco, CA, USA.
FAU - Zhou, Diansong
AU  - Zhou D
AUID- ORCID: 0000-0002-2673-1069
AD  - Astrazeneca Waltham, MA, USA.
FAU - Wei, Hua
AU  - Wei H
AD  - Astrazeneca South San Francisco, CA, USA.
FAU - Yotvat, Marmor
AU  - Yotvat M
AD  - Astrazeneca South San Francisco, CA, USA.
FAU - Zhou, Li
AU  - Zhou L
AD  - Astrazeneca Waltham, MA, USA.
FAU - Cheung, Jean
AU  - Cheung J
AD  - Astrazeneca South San Francisco, CA, USA.
FAU - Sarvaria, Nicole
AU  - Sarvaria N
AD  - Astrazeneca Mississauga, ON, Canada.
FAU - Lai, Richard
AU  - Lai R
AD  - Astrazeneca South San Francisco, CA, USA.
FAU - Sharma, Shringi
AU  - Sharma S
AUID- ORCID: 0000-0002-3120-225X
AD  - Astrazeneca South San Francisco, CA, USA.
FAU - Vishwanathan, Karthick
AU  - Vishwanathan K
AUID- ORCID: 0000-0002-6555-8131
AD  - Astrazeneca Waltham, MA, USA.
FAU - Ware, Joseph
AU  - Ware J
AD  - Astrazeneca South San Francisco, CA, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220328
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Benzamides)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Pyrazines)
RN  - 8VZV102JFY (Fluconazole)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - I42748ELQW (acalabrutinib)
SB  - IM
MH  - Area Under Curve
MH  - Benzamides
MH  - *Cytochrome P-450 CYP3A/metabolism
MH  - *Cytochrome P-450 CYP3A Inhibitors/pharmacology
MH  - Drug Interactions
MH  - Fluconazole/adverse effects
MH  - Humans
MH  - Models, Biological
MH  - Pyrazines
MH  - Receptor Protein-Tyrosine Kinases/metabolism
OTO - NOTNLM
OT  - CYP3A
OT  - acalabrutinib
OT  - drug interaction
OT  - pharmacokinetics
OT  - physiologically based pharmacokinetics
EDAT- 2022/02/16 06:00
MHDA- 2022/07/20 06:00
CRDT- 2022/02/15 05:39
PHST- 2022/01/25 00:00 [revised]
PHST- 2021/04/08 00:00 [received]
PHST- 2022/02/03 00:00 [accepted]
PHST- 2022/02/16 06:00 [pubmed]
PHST- 2022/07/20 06:00 [medline]
PHST- 2022/02/15 05:39 [entrez]
AID - 10.1111/bcp.15278 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2022 Aug;88(8):3716-3729. doi: 10.1111/bcp.15278. Epub 2022 
      Mar 28.