1. Christina Howlett, Pharm.D., BCOP Assistant Clinical Professor, Ernest Mario School of Pharmacy Oncology Pharmacy Specialist, Hackensack University Medical Center May 14, 2016 TACKLING TKI INTERACTIONS

2.  Nothing to disclose CONFLICTS OF INTEREST

3.  Pharmacist  Explain the impact of common drug-drug interactions on the safety and efficacy of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)  Technician  Identify common drug-drug interactions of tyrosine kinase inhibitors OBJECTIVE

4.  AZ is a 57 year old man admitted to the hospital with fevers and shortness of breath. His past medical history includes hypertension, chronic myeloid leukemia (CML) and acid reflux symptoms for the past few months.  Home medications  Lisinopril 20 mg PO daily  Dasatinib (Sprycel ® ) 100 mg PO daily  Esomeprazole 20 mg PO daily  Further workup  WBC - 130,000, differential – 18% blasts  Bone marrow biopsy - progressive CML in blast phase PATIENT CASE

5.  While performing medication reconciliation, you learn AZ has been taking esomeprazole OTC for the past three months due to new acid reflux symptoms  You alert medical team of interaction between dasatinib and esomeprazole  Interaction can result in significant decreases in dasatinib exposure  Plasma concentrations of TKIs correlate with efficacy and safety  Discuss alternative options to manage AZ’s acid reflux… PATIENT CASE Haouala A, et al. Blood 2011; 117(8):e75-87.

6. DASATINIB & ACID SUPPRESSIVE THERAPY Mechanism Solubility of dasatinib - pH dependent Dasatinib concentrations decrease significantly with pH > 4 Acid suppressive therapy (AST) can decrease dasatinib’s bioavailability Data Dasatinib dose- adjusted AUC reduced by 58% with concomitant AST (lansoprazole and famotidine) Coadministration with Al/Mag antacids decreases AUC by 55-58%, but AUC unchanged if antacids given 2 hours before or after dasatinib Dasatinib 22 hours after omeprazole  dasatinib AUC reduced by 43% Dasatinib 10 hours after famotidine  dasatinib AUC reduced by 61% Timing Dasatinib (Sprycel ® ) package insert. Bristol Myers Squibb: Princeton, NJ; 2015. Eley T, et al. J Clin Pharmacol 2009; 29:700-709.

7.  Longer-term ASTs significantly reduce dasatinib exposure, which can lead to inadequate treatment and disease progression  Do not administer H 2 -receptor antagonists (H 2 RAs) or proton pump inhibitors (PPIs) with dasatinib  Patients requiring AST may use Al/Mag containing antacids if given two hours before or two hours after dasatinib dose RECOMMENDATIONS Dasatinib (Sprycel ® ) package insert. Bristol Myers Squibb: Princeton, NJ; 2015. Eley T, et al. J Clin Pharmacol 2009; 29:700-709.

8.  TKIs used to treat CML include –  Imatinib, dasatinib, nilotinib, bosutinib, ponatinib  Common interactions  H 2 RAs/PPIs  Dasatinib, nilotinib, bosutinib  CYP3A4 substrates  Imatinib, dasatinib, nilotinib, bosutinib, ponatinib (minor)  QTc prolongation  Dasatinib, nilotinib TKI INTERACTIONS Nilotinib (Tasigna ® ) package insert. Novartis Pharmaceuticals: East Hanover, NJ; 2015. Bosutinib (Bosulif ® ) package insert. Pfizer Inc.: New York, NY; 2015. Haouala A, et al. Blood 2011; 117(8):e75-87.

9.  Pharmacists play a key role in identifying TKI drug interactions that can significantly impact response to therapy  Drug information resources should be used to check for potential interactions at every transition of care  Communicating significance of interaction and recommended plan to both the medical team and the patient is essential for continued compliance SUMMARY

10.  The following drug interaction occurs between pantoprazole and dasatinib therapy: A.Due to CYP3A4 inhibition, pantoprazole will cause an increase in dasatinib concentrations B.Pantoprazole and dasatinib both prolong the QTc interval C.Pantoprazole increases gastric pH, which can significantly reduce dasatinib concentrations D.There is no drug interaction as long as pantoprazole is taken 12 hours after dasatinib E.None of the above PHARMACIST QUESTION

11. TECHNICIAN QUESTION  Which of the following drugs interacts with dasatinib? A.Pantoprazole B.Omeprazole C.Famotidine D.All of the above