Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers.
OBJECTIVE
Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non-small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg.


METHODS
Cohorts of NSCLC patients currently smoking > or = 10 cigarettes per day for > or = 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity.


RESULTS
Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 microg/mL for 150 mg and 300 mg, respectively.


CONCLUSIONS
The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.
Hughes
Andrew N
AN
Northern Centre for Cancer Treatment, Newcastle General Hospital, Westgate Rd, Newcastle upon Tyne, NE4 6BE. Andrew.Hughes@nuth.nhs.uk
O'Brien
Mary E R
ME
Petty
W Jeffrey
WJ
Chick
Jonathan B
JB
Rankin
Elaine
E
Woll
Penella J
PJ
Dunlop
David
D
Nicolson
Marianne
M
Boinpally
Ramesh
R
Wolf
Julie
J
Price
Allan
A
D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology*; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012907:Smoking / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C504573:CYP1A2 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2