Clinical Implications of the Pharmacokinetics of Crizotinib in Populations of Patients with Non-Small Cell Lung Cancer.
OBJECTIVE
We assessed the effect of baseline patient demographic and disease characteristics on the crizotinib pharmacokinetic parameters oral clearance (CL/F), volume of distribution (V2/F), and area under the curve at steady state (AUCss) following multiple crizotinib 250-mg twice-daily dosing in patients with ALK-positive cancer.


METHODS
A pharmacokinetic model was fit to data from 1,214 patients. We identified statistically significant covariates (P ≤ 0.001) by evaluating their effects on CL/F and V2/F and estimated their magnitudes.


RESULTS
Age, Eastern Cooperative Oncology Group performance status, aspartate aminotransferase (AST) levels, albumin levels, and smoking status had no effect on CL/F or V2/F. Statistically significant covariates were Asian race and female sex for CL/F and V2/F and body weight, creatinine clearance (CLcr), and total bilirubin for CL/F only. The model predicted that CL/F would be 9% lower or higher in a 40-kg or a 100-kg patient, respectively; 16% lower in patients with CLcr 30 mL/minute; 23% lower in Asians; and 11% lower in females than the reference patient (65-kg non-Asian male; baseline CLcr, 91.6 mL/minute; total bilirubin, 0.41 mg/dL). The effect of total bilirubin on CL/F was small. V2/F was 23% lower in Asians than non-Asians and females than males. Effects of all significant covariates on AUCsswere not predicted to be clinically relevant.


CONCLUSIONS
Crizotinib at a 250-mg twice-daily starting dose appears to be appropriate for all patients irrespective of age, sex, race, body weight, mild or moderate renal impairment, or hepatic function (in the range evaluated: bilirubin ≤ 2.1 mg/dL or AST ≤124 U/L). Clin Cancer Res; 22(23); 5722-8. ©2016 AACR.
Pfizer Oncology, La Jolla, California. Erjian.Wang@pfizer.com.
Erjian
E
Wang
Pfizer Pharmacometrics, La Jolla, California.
Dana J
DJ
Nickens
Pfizer Oncology, New York, New York.
Akintunde
A
Bello
Pfizer Oncology, La Jolla, California.
Reza
R
Khosravan
Pfizer Pharmacometrics, La Jolla, California.
Michael
M
Amantea
Pfizer Oncology, La Jolla, California.
Keith D
KD
Wilner
Pfizer Oncology, La Jolla, California.
Kourosh
K
Parivar
Pfizer Oncology, La Jolla, California.
Weiwei
W
Tan
D000368:Aged; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D000077547:Crizotinib; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib