Effect of esomeprazole on the oral absorption of dasatinib in a patient with Philadelphia‐positive acute lymphoblastic leukemia

We describe herein the first reported case of a drug–drug interaction between dasatinib and esomeprazole in a patient with Philadelphia‐positive acute lymphoblastic leukemia leading to a decrease in dasatinib oral absorption.

The patient was a 16‐year‐old man (1.76 m, 61.5 kg) who benefited from allogeneic stem cell transplantation after a myeloablative conditioning regimen based on 12‐Gy total body irradiation and etoposide (60 mg kg^–1). This case is presented in the context of progression of imatinib‐resistant chronic myelogenous leukemia (CML) in acute lymphoblastic leukemia (ALL) with B‐cell lineage. One month after stem cell transplantation, Bcr/Abl transcripts were undetectable and chimerism (on total leucocytes) was assessed at 98% donor cells in blood. Two months later, the patient experienced a molecular relapse with 0.06% and 0.03% Bcr/Abl transcripts in blood and bone marrow, respectively. The degree of chimerism was assessed at 99% donor cells in bone marrow. Immunosuppressive treatment was quickly diminished and dasatinib was introduced at a daily dose of 100 mg but was thereafter decreased to 70 mg day^–1 because of a severe leukopenia (white blood cells at 690 mm^{– 3}). At this dose, the plasma trough concentration of dasatinib was 5.1 ng.ml^–1 (normal value <2.5 ng ml^–1 1) suggesting a suspected role of dasatinib in the occurrence of leukopenia. Despite the decrease in dasatinib dosing, a severe pancytopenia in the context of staphylococcus bacteraemia was observed and dasatinib was stopped. One week later, dasatinib was restarted at a daily dose of 50 mg then increased to 60 mg. Four months after transplantation, as the immunosuppressive drugs were withdrawn, the degree of chimerism reached 100% donor cells in blood, and Bcr/Abl transcripts were still detectable but not quantifiable. Despite a prolonged mild pancytopenia, the patient was treated with 50 mg day^–1 of dasatinib to limit molecular relapse. In this context, a study of plasma concentrations of dasatinib was performed as previously described by Bouchet et al. using liquid chromatography–tandem mass spectrometry (limit of quantification of 0.1 ng.ml^–1) 2. This revealed a maximal concentration (C _max) of 23.1 ng ml^–1 (normal value >50.0 ng ml^–1 1) 4 h after the administration of dasatinib (Figure 1). The estimated area under the curve between 0 and 6.5 h (AUC(0,6.5 h)) using the trapezoidal rule was 89.6 ng ml^–1 h. The terminal elimination half‐life (t _1/2) was estimated to be 4.9 h. From these results, we concluded that there was a decrease in dasatinib absorption, probably related to a drug–drug interaction influencing dasatinib pharmacokinetics. Drugs concomitantly taken with dasatinib by the patient included prednisolone (15 mg once daily), valaciclovir (500 mg twice daily), cefuroxime (250 mg twice daily), ursodeoxycholic acid (200 mg twice daily), itraconazole (200 mg twice daily), human immunoglobulins (25 g monthly), pentamidine (300 mg monthly) and esomeprazole (40 mg once daily). As itraconazole was simultaneously used with dasatinib, an increase could have been expected due to an inhibition of CYP3A4 by itraconazole 3 but it was not observed. This result could be explained by a limited absorption of itraconazole due to the effect of esomeprazole on gastric acidity 4. Thus, esomeprazole was considered as the main suspected drug in the decrease of dasatinib absorption and its dosing was first decreased from 40 mg to 20 mg once daily but finally stopped. A second drug concentration–time profile of dasatinib was established 4 days after esomeprazole discontinuation (Figure 1). This revealed an increase of C _max and the estimated AUC(0,6.5 h) from 23.1 to 52.0 ng ml^–1 and from 89.6 to 130.6 ng ml^–1 h, respectively. The increase of these two pharmacokinetics parameters with an unmodified estimated t _1/2 (4.7 vs. 4.9 h) and a 1 h earlier t _max (3 vs. 4 h) after esomeprazole discontinuation confirmed the influence of esomeprazole on the oral absorption of dasatinib. The influence of esomeprazole on the pharmacokinetics of dasatinib resulting in a 56% decrease of C _max and a 32% decrease of AUC(0,6.5 h) was in the same order of magnitude as the study led by Bristol‐Myers Squibb. This study found a decrease in C _max and AUC(0,∞) of 41% and 42%, respectively, when dasatinib was concomitantly used with omeprazole 5. Besides omeprazole, the efficacy of dasatinib was also described to be encumbered by a decrease of its absorption when used and administered simultaneously with gastric acid pH modulators such as lansoprazole 6, famotidine or aluminium‐magnesium hydroxides 7. In the case of CML or ALL with no resistance to imatinib, imatinib remains an excellent first choice and presents the advantage of being relatively spared by the influence of proton pump inhibitors (PPIs) (pKa value of 7.7). In alternative first line therapies such as dasatinib or nilotinib with an absorption encumbered by a concomitant use of PPIs, PPIs could be replaced by aluminium‐magnesium hydroxides or H₂‐receptor antagonists administered 2 h before or 2 h after the administration of tyrosine kinase inhibitors (TKIs), respectively 7. In case of concomitant use of PPIs with TKIs, the current available pharmacokinetic and pharmacodynamic studies seem to describe dexlansoprazole, esomeprazole and rabeprazole as the three most potent PPIs to modify the pH of the gastric medium (intragastric pH value above 4 for significantly longer periods of time (>12–16 h)) 8, 9. Furthermore, considering the study of Röhss et al., the administration of PPIs in a once daily regimen during a 24 h period revealed for all the tested PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) the two lowest values of intragastric pH measured around 16 h and 24 h after PPI intake, respectively 10. In consequence, the administration of PPIs in a once daily dose regimen 2 or 3 h after the TKI intake (as advised for H₂‐receptor agonists 7) could probably constitute an alternative option to explore limiting the decrease in TKI absorption due to concomitant use of PPI therapy.

Figure 1.

Dasatinib blood concentrations in the presence () and the absence () of esomeprazole after an administration of a 50 mg daily dose

Finally, dasatinib was stopped 3 weeks after esomeprazole discontinuation because of a pancytopenia and severe acute hepatitis suspected to be attributable to the treatment toxicity, but was attributed to hepatic grade 3 chronic graft vs. host disease (GVHD) after liver biopsy. Nine months after transplantation, our patient is still alive and he has not received any TKI since, with no relapse of his leukemia at this time. Immunosuppressive treatment for hepatic GVHD is still on‐going. Informed consent was obtained from the patient.

Competing Interests

All authors have completed the Unified Competing Interest form and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Pape, E. , Michel, D. , Scala‐Bertola, J. , Schiestel, T. , Harlé, A. , Bouchet, S. , Contet, A. , Pochon, C. , and Gambier, N. (2016) Effect of esomeprazole on the oral absorption of dasatinib in a patient with Philadelphia‐positive acute lymphoblastic leukemia. Br J Clin Pharmacol, 81: 1195–1196. doi: 10.1111/bcp.12895.