rifampin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of this study were to 1) develop physiologically based pharmacokinetic (PBPK) models of bosutinib; 2) verify and refine the PBPK models based on clinical study results of bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, as well as single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment; 3) apply the PBPK models to predict DDI outcomes in patients with weak and moderate CYP3A inhibitors; and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration. Results showed that the PBPK models adequately predicted bosutinib oral exposures in patients after single- and multiple-dose administrations. The PBPK models also reasonably predicted changes in bosutinib exposures in the single-dose DDI and DDZI results, suggesting that the PBPK models were sufficiently developed and verified based on the currently available data. Finally, the PBPK models predicted 2- to 4-fold increases in bosutinib exposures by moderate CYP3A inhibitors, as well as comparable increases in bosutinib exposures in renally and hepatically impaired patients between single- and multiple-dose administrations. Given the challenges in conducting numerous DDI and DDZI studies of anticancer drugs in patients, we believe that the PBPK models verified in our study would be valuable to reasonably predict bosutinib exposures under various scenarios that have not been tested clinically.

Topics: Administration, Oral; Aniline Compounds; Area Under Curve; Computer Simulation; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Ketoconazole; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Models, Biological; Nitriles; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Quinolines; Rifampin; src-Family Kinases; Treatment Outcome

A 10-year-old girl with chronic myelogenous leukemia began receiving cyclosporine the day before bone marrow transplant surgery Three days after the transplant, she developed fever and neutropenia due to a Staphylococcus aureus bacteremia. Despite treatment with various antibiotics, the patient's fever persisted over the next 4 days. Intravenous rifampin was added to her antibiotic regimen of piperacillin, tobramycin, cloxacillin, and amphotericin. On day 12, the patient's blood cultures were negative and her fever had resolved; rifampin was discontinued. On day 16, the patient engrafted; she subsequently developed a grade II graft-versus-host disease of the skin and gastrointestinal tract, which responded to methylprednisolone. Her cyclosporine blood levels, which had been subtherapeutic since day 5 despite increasing intravenous dosages, were within the therapeutic range on day 21, and she was discharged 12 days later. To our knowledge, this is the first documented case of an intravenous cyclosporine-rifampin interaction that resulted in subtherapeutic cyclosporine concentrations in a child receiving a bone marrow transplant who subsequently developed acute graft-versus-host disease.

Topics: Antibiotics, Antitubercular; Bacteremia; Bone Marrow Transplantation; Child; Cyclosporine; Drug Interactions; Female; Fever; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infusions, Intravenous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neutropenia; Rifampin; Staphylococcal Infections; Staphylococcus aureus

Topics: Chemical and Drug Induced Liver Injury; Fever of Unknown Origin; Humans; Isoniazid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Liver Function Tests; Male; Middle Aged; Rifampin; Time Factors