The effect of rifampicin, a prototypical CYP3A4 inducer, on erlotinib pharmacokinetics in healthy subjects.

PURPOSE: 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.

Trends in intake and outcome data for animal shelters in Colorado, 2000 to 2007.

OBJECTIVE: To measure trends in animal shelter intake and outcome data for dogs and cats in Colorado on a statewide, urban, and rural basis from 2000 through 2007. DESIGN: Retrospective cohort study. SAMPLE POPULATION: A group of 104 animal shelters and rescue organizations from Colorado representing 92% and 94% of statewide dog and cat intake, respectively, in 2007. PROCEDURES: Annual animal shelter data were analyzed for trends by use of linear regression analysis. Trends in urban and rural subgroups of shelters were compared by use of Student t tests. RESULTS: Statewide, the number of intakes/1,000 residents decreased by 10.8% for dogs during the 8-year study period, but increased by 19.9% for cats. There was no change in the dog euthanasia rate at 3.7/1,000 residents/y, but the rate for cats increased by 35.7% to 3.9/1,000 residents/y. There was no change in the statewide live release rate for dogs or cats, but there was a decrease of 12.6% for cats in the urban subgroup. CONCLUSIONS AND CLINICAL RELEVANCE: The trends suggested that the number of unwanted dogs in Colorado decreased during the study period, whereas the number of unwanted cats in animal shelters increased. There were clear differences in the trends in the urban and rural data, suggesting different needs in each type of community. At the current level of resource allocation, the shelter dynamics for dogs appeared to have reached equilibrium with respect to euthanasia. Transfers were increasingly being used within all regions of the state to optimize the chances of adoption.

Effects of smoking on the pharmacokinetics of erlotinib.

PURPOSE: To compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150 or 300 mg dose of erlotinib. EXPERIMENTAL DESIGN: This was a single-center, open-label pharmacokinetic study in healthy male subjects. Subjects were enrolled into two treatment cohorts based on smoking status (current smokers and nonsmokers). The pharmacokinetic profile for erlotinib and its metabolite, OSI-420, was determined for each subject following each treatment. RESULTS: Current smokers achieved significantly less erlotinib exposure following a single 150 or 300 mg dose than nonsmokers. Following the 150 mg dose, the geometric mean erlotinib AUC(0-infinity) in smokers was 2.8-fold lower than in nonsmokers and similar to that of nonsmokers at the 300 mg dose. C(max) in smokers was two-thirds of that in nonsmokers, and C(24h) in smokers was 8.3-fold lower than in nonsmokers. The median C(24h) of smokers at the 300 mg dose was slightly less than the C(24h) of smokers at the 150 mg dose. The median C(max) was greater in smokers at the 300 mg dose than in nonsmokers at the 150 mg dose. CONCLUSION: This study confirms that the pharmacokinetics of erlotinib is different in current smokers and nonsmokers. The observation that AUC(0-infinity) and C(24h) were significantly decreased in smokers compared with nonsmokers, and a smaller decrease in C(max) was observed, is consistent with increased metabolic clearance of erlotinib in current smokers.