The effect of rifampicin, a prototypical CYP3A4 inducer, on erlotinib pharmacokinetics in healthy subjects.
OBJECTIVE
Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib.


METHODS
Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8-14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8-18. The primary endpoint in each study was the ratio of exposure (AUC0-∞ and C max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only.


RESULTS
In Study 1, the geometric mean ratios of AUC0-∞ and C max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC0-∞ and C max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1.


CONCLUSIONS
Erlotinib exposure (AUC0-∞ and C max) was reduced after pre- or concomitant dosing with rifampicin. Doses of ≥450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect.
The Hamilton Consulting Group, Boulder, CO, USA.
Marta
M
Hamilton
Julie L
JL
Wolf
Daniel W
DW
Drolet
Scott H
SH
Fettner
Ashok K
AK
Rakhit
Karsten
K
Witt
Bert L
BL
Lum
D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D000069347:Erlotinib Hydrochloride; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin