Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects

Hsyu, Poe‐Hirr; Pignataro, Daniela Soriano; Matschke, Kyle

doi:10.1007/s00228-016-2108-z

Cited by 13 publications

(17 citation statements)

References 24 publications

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“…Additional information about bosutinib pharmacokinetics is also available on the FDA website (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/ 203341Orig1s000ClinPharmR.pdf). Briefly, bosutinib pharmacokinetics were determined in HVs (n = 12) and CPs (n = 3) after a single oral administration of a clinically recommended dose at 500 mg (Cortes et al, 2011;Hsyu et al, 2017). Bosutinib steady-state pharmacokinetics were determined in CPs (n = 3) after multiple-dose oral administration at 500 mg once daily (Cortes et al, 2011).…”

Section: Clinical Pharmacokinetic Datamentioning

confidence: 99%

Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug–Drug and Drug–Disease Interactions

et al. 2017

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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.

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Section: Clinical Pharmacokinetic Datamentioning

confidence: 99%

Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug–Drug and Drug–Disease Interactions

et al. 2017

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“…Sample collection timing could be within ±10% of the nominal time (eg, ±6 minutes for a 60‐minute sample interval). K 3 ‐ethylenediaminetetraacetic acid plasma samples were prepared by a liquid–liquid extraction procedure and analyzed for bosutinib concentrations (InVentiv Health Clinical Lab, Inc. East Princeton, New Jersey) using a validated, sensitive, and specific high‐performance liquid chromatography (HPLC)–tandem mass spectrometry (MS/MS) method . Briefly, 50 μL of internal standard (d 8 ‐bosutinib) was added to 100 μL of plasma, followed by 100 μL of carbonate buffer (pH 10) at ∼4°C and 1 mL of methyl tert‐butyl ether.…”

Section: Methodsmentioning

confidence: 99%

“…The between‐day assay accuracy, expressed as percent relative error, for quality control (QC) concentrations, ranged from −2% to 9% for the low, medium, high, and diluted QC samples. Assay precision, expressed as the between‐day percent coefficients of variation (%CV) of the mean estimated concentrations of QC samples, was ≤8.58% for low (3 ng/mL), medium (30 ng/mL), high (150 ng/mL), and diluted (2000 ng/mL) concentrations . Sample collection times were used for the PK analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Bosutinib is a substrate of the cytochrome P450 3A4 (CYP3A4) enzyme, which is the principal mechanism of bosutinib clearance; therefore, concurrent use of a strong or moderate CYP3A4 inhibitor or CYP3A4 inducer should be avoided to avert altered exposure to bosutinib due to drug–drug interactions (DDIs). This recommendation is based on several DDI studies performed in healthy subjects . Following administration of oral bosutinib (400 mg, on day 1) and the gastric proton pump inhibitor (PPI) lansoprazole (60 mg [2 × 30 mg] on day 14) followed by concomitant administration of bosutinib and lansoprazole (same respective doses on day 15 after an overnight fast) in 24 healthy subjects, mean C max and area under the curve (AUC) for bosutinib were reduced by 46% and 26%, respectively; in addition, mean apparent total body clearance (CL/F) from plasma increased, and the median time to reach C max was prolonged, demonstrating the potential for reduced absorption probably due to reduced solubility .…”

mentioning

confidence: 99%

“…This recommendation is based on several DDI studies performed in healthy subjects. 7,11,13,14 Following administration of oral bosutinib (400 mg, on day 1) and the gastric proton pump inhibitor (PPI) lansoprazole (60 mg [2 × 30 mg] on day 14) followed by concomitant administration of bosutinib and lansoprazole (same respective doses on day 15 after an overnight fast) in 24 healthy subjects, mean C max and area under the curve (AUC) for bosutinib were reduced by 46% and 26%, respectively; in addition, mean apparent total body clearance (CL/F) from plasma increased, and the median time to reach C max was prolonged, demonstrating the potential for reduced absorption probably due to reduced solubility. 15 Given this possibility, it is recommended that short-acting antacids or H2 blockers be used in place of PPIs to circumvent an inadvertent reduction in bosutinib exposure.…”

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confidence: 99%

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Absolute Bioavailability of Bosutinib in Healthy Subjects From an Open‐Label, Randomized, 2‐Period Crossover Study

Hsyu

Pignataro

Matschke

2017

Clinical Pharm in Drug Dev

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This study evaluated the absolute bioavailability of bosutinib and assessed its safety and tolerability after single-dose oral and intravenous administration. In this phase 1 open-label, 2-sequence, 2-period crossover study, healthy, fed subjects aged 18-55 years were randomized to 1 of 2 treatment sequences (n = 7/sequence): oral bosutinib (100 mg × 5) followed by intravenous bosutinib (120 mg in approximately 240 mL over 1 hour), with a ≥14-day washout, or intravenous bosutinib and then oral bosutinib. Results of plasma pharmacokinetics analyses demonstrated that exposure to intravenous bosutinib was 3-fold higher than for oral bosutinib (16.2 and 5.5 ng·h/mL/mg, respectively), and mean terminal half-life was similar (35.5 and 31.7 hours). The ratio of adjusted geometric means (90%CI) for the dose-normalized area under the plasma concentration-time profile (AUC /D) was 33.85% (30.65%-37.38%). Most treatment-emergent adverse events (AEs) were mild in severity. Gastrointestinal (GI) AEs occurred in 9 of 13 subjects given oral bosutinib, whereas no subjects given intravenous bosutinib experienced GI AEs, suggesting bosutinib present in the GI tract had an effect. Bosutinib exhibited an absolute bioavailability of 33.85% based on the ratio of AUC /D. Both oral and intravenous bosutinib were safe and well tolerated in healthy, fed adult subjects.

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Bosutinib: A Potent Second-Generation Tyrosine Kinase Inhibitor

Isfort¹,

Crysandt²,

Gezer³

et al. 2018

Small Molecules in Hematology

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Bosutinib is one of the five tyrosine kinase inhibitors which are currently approved for the treatment of chronic myeloid leukemia. By its dual inhibition of Src and ABL kinase and also targeting further kinases, it creates a unique target portfolio which also explains its unique side effect profile. The approval of bosutinib in 2013 made the drug available for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. As initially the first-line clinical trial comparing bosutinib with imatinib in CML patients in chronic phase did not reach its primary endpoint and therefore the product was not licensed for first-line therapy, a second first-line trial, the so-called BFORE study, was performed and just recently the promising results have been published predicting a quick expansion of the existing label. In comparison with the other approved TKIs, bosutinib harbors a distinct side effect profile with only very few cardiovascular and thromboembolic events and minimal long-term safety issues with most adverse events happening during the first months of treatment. On the other hand, gastrointestinal side effects are very common (e.g., diarrhea rates in more than 80% of the patients) with bosutinib surprising some of the investigators during the early clinical trials evaluating bosutinib. Until then, several approaches have been used to face this problem resulting in extensive supportive efforts (such as early loperamid treatment) as well as new trials testing alternative dosing strategies with early dose adjustment schedules. This article reports preclinical and clinical data available for bosutinib both in hematologic diseases such as CML or ALL and solid tumours as well as other diseases and envisions future perspectives including additional patient groups in which bosutinib might be of clinical benefit.

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Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects

Cited by 13 publications

References 24 publications

Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug–Drug and Drug–Disease Interactions

Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug–Drug and Drug–Disease Interactions

Absolute Bioavailability of Bosutinib in Healthy Subjects From an Open‐Label, Randomized, 2‐Period Crossover Study

Bosutinib: A Potent Second-Generation Tyrosine Kinase Inhibitor

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