Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg. Absorption of bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94 %) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction data on bosutinib in healthy subjects, patients with CML, and special populations.
Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA. richat.abbas-borhan@pfizer.com.
Richat
R
Abbas
Pfizer Inc, San Diego, CA, USA.
Poe-Hirr
PH
Hsyu
D000814:Aniline Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D044466:Asian People; D002986:Clinical Trials as Topic; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004562:Electrocardiography; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D017093:Liver Failure / Q000378:metabolism; D008657:Metabolic Clearance Rate; D009570:Nitriles / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000378:metabolism
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human