PMID- 37837178
OWN - NLM
STAT- MEDLINE
DCOM- 20231226
LR  - 20240417
IS  - 1752-8062 (Electronic)
IS  - 1752-8054 (Print)
IS  - 1752-8054 (Linking)
VI  - 16
IP  - 12
DP  - 2023 Dec
TI  - Impact of posaconazole and diltiazem on pharmacokinetics of encorafenib, a BRAF 
      V600 kinase inhibitor for melanoma and colorectal cancer with BRAF mutations.
PG  - 2675-2686
LID - 10.1111/cts.13662 [doi]
AB  - Encorafenib is a potent and selective ATP competitive inhibitor of BRAF 
      V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal 
      cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro 
      and may be susceptible to drug-drug interactions when co-administered with CYP3A 
      inhibitors or inducers. The primary objective was to assess the impact of the 
      strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp 
      inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy 
      volunteers following a single 50-mg dose. A total of 32 participants were 
      enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to 
      infinity (AUC(inf) ) and maximum plasma concentration (C(max) ) geometric mean 
      for encorafenib increased by 183% and 68.4%, respectively, when co-administered 
      with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h 
      when coadministered with posaconazole, and plasma terminal half-life (t((1/2)) ) of 
      encorafenib increased from 4.3 to 7.3 h. The AUC(inf) and C(max) geometric mean 
      for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered 
      with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 
      to 16.0 L/h when co-administered with diltiazem, and plasma t((1/2)) of encorafenib 
      increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), 
      or patient discontinuations due to AEs in parts 1 or 2. The most frequently 
      reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 
      69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study 
      indicate that co-administration of encorafenib with strong or moderate CYP3A4 
      inhibitors should be avoided.
CI  - (c) 2023 Pfizer Inc. Clinical and Translational Science published by Wiley 
      Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Hahn, Erik
AU  - Hahn E
AUID- ORCID: 0000-0001-6061-1442
AD  - Global Product Development, Pfizer Inc., Boulder, Colorado, USA.
FAU - Chavira, Renae
AU  - Chavira R
AUID- ORCID: 0009-0008-3634-0249
AD  - Global Product Development, Pfizer Inc., Boulder, Colorado, USA.
FAU - Wollenberg, Lance
AU  - Wollenberg L
AUID- ORCID: 0009-0002-4791-8655
AD  - Early Clinical Development, Pfizer Inc., Boulder, Colorado, USA.
FAU - Tan, Weiwei
AU  - Tan W
AD  - Global Product Development, Pfizer Inc., La Jolla, California, USA.
FAU - Reddy, Micaela B
AU  - Reddy MB
AUID- ORCID: 0000-0002-2721-3714
AD  - Early Clinical Development, Pfizer Inc., Boulder, Colorado, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231104
PL  - United States
TA  - Clin Transl Sci
JT  - Clinical and translational science
JID - 101474067
RN  - 0 (Antineoplastic Agents)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - EE92BBP03H (Diltiazem)
RN  - 8L7891MRB6 (encorafenib)
RN  - 6TK1G07BHZ (posaconazole)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
SB  - IM
MH  - Humans
MH  - *Antineoplastic Agents/therapeutic use
MH  - *Colorectal Neoplasms/drug therapy/genetics
MH  - Cytochrome P-450 CYP3A Inhibitors/pharmacology
MH  - Diltiazem/therapeutic use
MH  - Drug Interactions
MH  - Headache/chemically induced
MH  - *Melanoma/drug therapy/genetics
MH  - Mutation
MH  - Protein Kinase Inhibitors/pharmacokinetics
MH  - Proto-Oncogene Proteins B-raf/genetics/therapeutic use
PMC - PMC10719479
COIS- All authors are employees of Pfizer Inc. and may own Pfizer stock.
EDAT- 2023/10/14 10:47
MHDA- 2023/12/17 09:41
PMCR- 2023/11/04
CRDT- 2023/10/14 01:22
PHST- 2023/09/08 00:00 [revised]
PHST- 2023/07/11 00:00 [received]
PHST- 2023/09/22 00:00 [accepted]
PHST- 2023/12/17 09:41 [medline]
PHST- 2023/10/14 10:47 [pubmed]
PHST- 2023/10/14 01:22 [entrez]
PHST- 2023/11/04 00:00 [pmc-release]
AID - CTS13662 [pii]
AID - 10.1111/cts.13662 [doi]
PST - ppublish
SO  - Clin Transl Sci. 2023 Dec;16(12):2675-2686. doi: 10.1111/cts.13662. Epub 2023 Nov 
      4.