PMID- 37503797
OWN - NLM
STAT- MEDLINE
DCOM- 20230918
LR  - 20230918
IS  - 1600-0609 (Electronic)
IS  - 0902-4441 (Linking)
VI  - 111
IP  - 4
DP  - 2023 Oct
TI  - Despite warnings, co-medication with proton pump inhibitors and dasatinib is 
      common in chronic myeloid leukemia, but XS004, a novel oral dasatinib 
      formulation, provides reduced pH-dependence, minimizing undesirable drug-drug 
      interactions.
PG  - 644-654
LID - 10.1111/ejh.14059 [doi]
AB  - BACKGROUND: Dasatinib and other tyrosine kinase inhibitors (TKI) have 
      revolutionized the treatment of chronic myeloid leukemia (CML). However, as a 
      lipophilic weak base, crystalline monohydrate, dasatinib (Sprycel(R)) is poorly 
      soluble, rendering a pH-dependent absorption and a highly variable 
      bioavailability. Thus, co-medication with proton pump inhibitors (PPI) profoundly 
      impairs dasatinib uptake and is clearly recommended against. XS004 is a novel 
      oral immediate release and amorphous solid dispersion (ASD) formulation of 
      dasatinib and is bioequivalent to the original crystalline dasatinib at 30% lower 
      dosages. XS004 is designed to mitigate gastric pH dependency, thus optimizing 
      absorption and bioavailability. METHODS: We investigated the prevalence of 
      dasatinib and PPI co-medication among chronic-phase CML patients in a real-world 
      setting and assessed the plasma pharmacokinetics (PK) of XS004 with and without 
      PPI co-medication (omeprazole) in healthy volunteers. RESULTS: Using the Swedish 
      CML and Prescribed Drug Registers, we identified 676 TKI-treated CML patients; 
      320 (47%) had been prescribed PPI at some point after CML diagnosis. Among 
      dasatinib-treated patients, the 2-year cumulative PPI co-medication was 24%. 
      Interestingly, the 5-year overall survival was significantly lower for 
      TKI-treated CML patients with versus without PPI co-medication (79% vs. 94%; 
      hazard ratio 3.5; 95% confidence interval, 2.1-5.3; p < .0001). When assessing PK 
      of XS004, neither C(max) nor area under the plasma concentration curve levels in 
      plasma were significantly altered by the PPI co-medication. CONCLUSION: In 
      conclusion, despite warnings, PPI co-medication is common among dasatinib-treated 
      CML patients in a real-world setting. The new XS004 ASD formulation of dasatinib 
      provided, in contrast to original crystalline dasatinib, superior pH independence 
      with stable bioavailability, thereby minimizing drug-drug interactions. This may 
      improve the long-term efficacy and tolerability of dasatinib in CML.
CI  - (c) 2023 The Authors. European Journal of Haematology published by John Wiley & 
      Sons Ltd.
FAU - Larfors, Gunnar
AU  - Larfors G
AUID- ORCID: 0000-0002-1549-8695
AD  - Unit of Hematology, Department of Medical Sciences, Uppsala University, Uppsala, 
      Sweden.
FAU - Andersson, Per
AU  - Andersson P
AD  - Xspray, Solna, Sweden.
FAU - Jesson, Gerald
AU  - Jesson G
AD  - Xspray, Solna, Sweden.
FAU - Liljebris, Charlotta
AU  - Liljebris C
AD  - Xspray, Solna, Sweden.
FAU - Brisander, Magnus
AU  - Brisander M
AD  - Xspray, Solna, Sweden.
FAU - Lennernas, Hans
AU  - Lennernas H
AD  - Department of Pharmaceutical Biosciences, Translational Drug Discovery and 
      Development, Uppsala University, Uppsala, Sweden.
FAU - Stenke, Leif
AU  - Stenke L
AD  - Karolinska University Hospital and Karolinska Institutet, Department of 
      Hematology, Theme Cancer and Department of Medicine Solna, Stockholm, Sweden.
LA  - eng
GR  - Xspray/
GR  - Nordic CML Study Group/
PT  - Journal Article
DEP - 20230728
PL  - England
TA  - Eur J Haematol
JT  - European journal of haematology
JID - 8703985
RN  - RBZ1571X5H (Dasatinib)
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
SB  - IM
MH  - Humans
MH  - Dasatinib/adverse effects
MH  - *Proton Pump Inhibitors/adverse effects
MH  - Protein Kinase Inhibitors/adverse effects
MH  - *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis/drug 
      therapy/epidemiology
MH  - Drug Interactions
MH  - Hydrogen-Ion Concentration
OTO - NOTNLM
OT  - CML
OT  - PPI
OT  - XS004
OT  - dasatinib
OT  - drug-drug interactions
OT  - pharmacokinetics
EDAT- 2023/07/28 13:10
MHDA- 2023/09/18 12:43
CRDT- 2023/07/28 06:35
PHST- 2023/07/10 00:00 [revised]
PHST- 2023/04/06 00:00 [received]
PHST- 2023/07/11 00:00 [accepted]
PHST- 2023/09/18 12:43 [medline]
PHST- 2023/07/28 13:10 [pubmed]
PHST- 2023/07/28 06:35 [entrez]
AID - 10.1111/ejh.14059 [doi]
PST - ppublish
SO  - Eur J Haematol. 2023 Oct;111(4):644-654. doi: 10.1111/ejh.14059. Epub 2023 Jul 
      28.