Imatinib
Imatinib. First-in-class targeted-cancer drug — competitive ATP-site inhibitor of BCR-ABL tyrosine kinase (chronic myeloid leukemia) plus c-Kit… Oral half-life 18 h.
First-in-class targeted-cancer drug — competitive ATP-site inhibitor of BCR-ABL tyrosine kinase (chronic myeloid leukemia) plus c-Kit (GIST) and PDGFR. Transformed CML from a fatal disease into a chronic condition. CYP3A4 substrate + moderate inhibitor.
PK: A TWO-COMPARTMENT CENTRAL VOLUME IN A ONE-COMPARTMENT RECORD. The cited paper is explicit — "a two-compartment open model with sequential zero- then first-order absorption ... oral clearance of 19 L/h ... central volume of distribution (V c/F) of 139 L ... apparent peripheral volume of distribution (V p/F) of 130 L" — and the stored triple implied 5.46 L/h, 3.48x below that paper own clearance. The replacement is chosen for its MODEL SHAPE as much as its numbers: "A ONE-COMPARTMENT MODEL with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l", which lands within 5% and is internally consistent with the stored half-life. THE PHYSICAL CHECK IS DECISIVE AND SHOWS THE OLD VALUE WAS A STATE ERROR: at 139 L the model put steady-state peak at 4.08 mg/L against a measured "2.6 +/- 0.8" and trough at 1.93 against "1.2 +/- 0.8" — it reproduced the STEADY-STATE peak on the FIRST dose. MY PRIOR THAT IMATINIB BIOAVAILABILITY IS GENUINELY MEASURED IS CONFIRMED, verbatim twice, and class 6 is therefore immaterial: at 98% apparent and true are indistinguishable. Its active metabolite has "comparable pharmacological activity to the parent drug" and is not modelled.
Pharmacokinetics
- Oral — t½ 18 h · F 98% · ka 0.94 h⁻¹ · Vd 347 L
Sources: PMID:26189007, PMID:16842382, PMID:16122278, PMID:14747424