Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.

Institute of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Zentiva k s Prague Czech Republic

See more in PubMed

Rousselot P, Mollica L, Guilhot J, Guerci A, Nicolini FE, Etienne G, et al. Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients. Br J Haematol. 2021;194:393–402. doi: 10.1111/bjh.17654. PubMed DOI

Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharm Ther. 2012;92:203–13. doi: 10.1038/clpt.2012.73. PubMed DOI

European Medicines Agency. Sprycel: European public assessment report. First published: 18/08/2009. Last updated: 29/03/2019. https://www.ema.europa.eu/en/documents/overview/sprycel-epar-medicine-overview_en.pdf.

Eley T, Luo FR, Agrawal S, Sanil A, Manning J, Li T, et al. Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects. J Clin Pharm. 2009;49:700–9. doi: 10.1177/0091270009333854. PubMed DOI

Yago MR, Frymoyer A, Benet LZ, Smelick GS, Frassetto LA, Ding X, et al. The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria. AAPS J. 2014;16:1358–65. doi: 10.1208/s12248-014-9673-9. PubMed DOI PMC

European Medicines Agency. Sprycel: Summary of product characteristics. First authorisation: 20/11/2006. Latest renewal: 15/7/2016. https://www.ema.europa.eu/en/documents/product-information/sprycel-epar-product-information_en.pdf.

Christiansen PM. The incidence of achlorhydria and hypochlorhydria in healthy subjects and patients with gastrointestinal diseases. Scand J Gastroenterol. 1968;3:497–508. doi: 10.3109/00365526809179909. PubMed DOI

Smelick GS, Heffron TP, Chu L, Dean B, West DA, Duvall SL, et al. Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development. Mol Pharm. 2013;10:4055–62. doi: 10.1021/mp400403s. PubMed DOI

Zhang L, Wu F, Lee SC, Zhao H, Zhang L. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development. Clin Pharmacol Ther. 2014;96:266–277. doi: 10.1038/clpt.2014.87. PubMed DOI

European Medicines Agency. Guideline on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr**. 2010. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf.

European Medicines Agency. Guideline on bioanalytical method validation. EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2**. 2011. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf.

Yazdanian M, Briggs K, Jankovsky C, Hawi A. The “high solubility” definition of the current FDA guidance on biopharmaceutical classification system may be too strict for acidic drugs. Pharm Res. 2004;21:293–9. doi: 10.1023/B:PHAM.0000016242.48642.71. PubMed DOI

Faassen F, Vromans H. Biowaivers for oral immediate-release products: implications of linear pharmacokinetics. Clin Pharmacokinet. 2004;43:1117–26. doi: 10.2165/00003088-200443150-00004. PubMed DOI

Kuentz M, Nick S, Parrott N, Rothlisberger D. A strategy for preclinical formulation development using GastroPlus as pharmacokinetic simulation tool and a statistical screening design applied to a dog study. Eur J Pharm Sci. 2006;27:91–9. doi: 10.1016/j.ejps.2005.08.011. PubMed DOI

van Leeuwen RWF, Jansman FGA, Hunfeld NG, Peric R, Reyners AKL, Imholz ALT, et al. Tyrosine kinase inhibitors and proton pump inhibitors: an evaluation of treatment options. Clin Pharmacokinet. 2017;56:683–8. doi: 10.1007/s40262-016-0503-3. PubMed DOI PMC

Hunfeld NG, Touw DJ, Mathot RA, van Schaik RH, Kuipers EJ. A comparison of the acid-inhibitory effects of esomeprazole and rabeprazole in relation to pharmacokinetics and CYP2C19 polymorphism. Aliment Pharm Ther. 2012;35:810–8. doi: 10.1111/j.1365-2036.2012.05014.x. PubMed DOI

Blum RA, Hunt RH, Kidd SL, Shi H, Jennings DE, Greski-Rose PA. Dose-response relationship of lansoprazole to gastric acid antisecretory effects. Aliment Pharmacol Ther. 1998;12:321–7. doi: 10.1046/j.1365-2036.1998.00306.x. PubMed DOI

Habet S. Narrow therapeutic index drugs: clinical pharmacology perspective. J Pharm Pharmacol. 2021;73:1285–91. doi: 10.1093/jpp/rgab102. PubMed DOI

Ishida Y, Murai K, Yamaguchi K, Miyagishima T, Shindo M, Ogawa K, et al. Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia. Eur J Clin Pharmacol. 2016;72:185–93. doi: 10.1007/s00228-015-1968-y. PubMed DOI

He S, Bian J, Shao Q, Zhang Y, Hao X, Luo X, et al. Therapeutic drug monitoring and individualized medicine of dasatinib: focus on clinical pharmacokinetics and pharmacodynamics. Front Pharmacol. 2021;12:797881. doi: 10.3389/fphar.2021.797881. PubMed DOI PMC

Sharma M, Holmes HM, Mehta HB, Chen H, Aparasu RR, Shih YT, et al. The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer. Cancer. 2019;125:1155–62. doi: 10.1002/cncr.31917. PubMed DOI PMC

Chu MP, Ghosh S, Chambers CR, Basappa N, Butts CA, Chu Q, et al. Gastric acid suppression is associated with decreased erlotinib efficacy in non-small-cell lung cancer. Clin Lung Cancer. 2015;16:33–9. doi: 10.1016/j.cllc.2014.07.005. PubMed DOI

Larfors G, Lennernäs H, Liljebris C, Brisander M, Jesson G, Andersson P, et al. Comedication of proton pump inhibitors and dasatinib is common in CML but XS004, a novel amorphous solid dispersion formulation of dasatinib, provides improved uptake and low pH-dependency, minimizing unwanted drug-drug interactions. Blood. 2022;140:6769–70. doi: 10.1182/blood-2022-156487. DOI