Effect of erlotinib on CYP3A activity, evaluated in vitro and by dual probes in patients with cancer.

In vitro, erlotinib (0-30 µmol/l) and C-labelled midazolam (MDZ) (5 µmol/l) were incubated with human liver microsomes; separately, microsomes were preincubated with erlotinib (10 µmol/l) before the addition of MDZ. Results showed a time-dependent inhibition of MDZ metabolism by erlotinib, with a Ki of 7.5 µmol/l and an inactivation rate constant of 0.009/min. Patients with cancer (n=24) received a single oral dose of 7.5 mg MDZ and a single intravenous dose of 3 µCi [C-N-methyl] erythromycin on days 1, 8, 14 and 21. Patients also received 150 mg oral erlotinib daily from day 8 to day 14. Plasma concentrations of erlotinib and OSI-420 were determined on days 8 and 14; MDZ and 1'-hydroxymidazolam were determined on days 1, 8, 14 and 21. Coadministration of erlotinib resulted in a 4 and a 16% increase in CO2 on days 8 and 14, respectively, after the administration of erythromycin. The mean AUC0-last of MDZ decreased 17 and 34% after erlotinib treatment on day 8 and day 14, respectively. The half-life of MDZ and the AUC ratio of 1'-hydroxymidazolam to MDZ were not significantly changed. Although erlotinib may be a weak mechanism-based irreversible inhibitor of CYP3A4 in vitro, in vivo, erlotinib did not inhibit CYP3A-mediated metabolism, as determined by the erythromycin breath test and the MDZ pharmacokinetics. The mechanism for reduced exposure of MDZ is unclear, but may be because of an increase in intestinal metabolism or decreased absorption. These findings suggest that coadministration of erlotinib may not result in clinically relevant increases in exposure of CYP3A substrates.

Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration.

Subcutaneous (SC) delivery is a common route of administration for therapeutic monoclonal antibodies (mAbs) with pharmacokinetic (PK)/pharmacodynamic (PD) properties requiring long-term or frequent drug administration. An ideal in vivo preclinical model for predicting human PK following SC administration may be one in which the skin and overall physiological characteristics are similar to that of humans. In this study, the PK properties of a series of therapeutic mAbs following intravenous (IV) and SC administration in Göttingen minipigs were compared with data obtained previously from humans. The present studies demonstrated: (1) minipig is predictive of human linear clearance; (2) the SC bioavailabilities in minipigs are weakly correlated with those in human; (3) minipig mAb SC absorption rates are generally higher than those in human and (4) the SC bioavailability appears to correlate with systemic clearance in minipigs. Given the important role of the neonatal Fc-receptor (FcRn) in the PK of mAbs, the in vitro binding affinities of these IgGs against porcine, human and cynomolgus monkey FcRn were tested. The result showed comparable FcRn binding affinities across species. Further, mAbs with higher isoelectric point tended to have faster systemic clearance and lower SC bioavailability in both minipig and human. Taken together, these data lend increased support for the use of the minipig as an alternative predictive model for human IV and SC PK of mAbs.

Pharmacokinetics and metabolism of the dipeptidyl peptidase IV inhibitor carmegliptin in rats, dogs, and monkeys.

The pharmacokinetics and excretion of carmegliptin, a novel dipeptidyl peptidase IV inhibitor, were examined in rats, dogs, and cynomolgus monkeys. Carmegliptin exhibited a moderate clearance, extensive tissue distribution, and a variable oral bioavailability of 28-174%. Due to saturation of intestinal active secretion, the area under the plasma concentration-time curve (AUC) in dogs and monkeys increased in a more than dose-proportional manner over an oral dose range of 2.5-10 mg/kg. Following oral administration of [(14)C]carmegliptin at 3 mg/kg, > 94% of the radioactive dose was recovered in 72-h post-dose from Wistar rats and Beagle dogs. Virtually, the entire administered radioactive dose was excreted unchanged in urine, intestinal lumen, and bile. Approximately 36%, 29%, and 19% of the dose were excreted by respective routes. Consistently, in vitro, carmegliptin was highly resistant to hepatic metabolism in all species tested. Based on in vitro studies, carmegliptin is a good substrate for Mdr1/MDR1. Breast cancer resistance protein (Bcrp) is not expected to be involved in the transport of carmegliptin since in vitro carmegliptin was not significantly transported by this transporter. The very high extravascular distribution of carmegliptin in the intestinal tissues, as demonstrated in Wistar rats and Beagle dogs, could play a significant role in its therapeutic effect.

The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition.

BACKGROUND: Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed that erlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2. METHODS: A computer-based simulation model, SimCYP, predicted that CYP3A4 contributed to approximately 70% of the metabolic elimination of erlotinib, with CYP1A2 being responsible for the other approximately 30%. A drug-drug interaction study was therefore conducted for erlotinib and a potent CYP3A4 inhibitor, ketoconazole, in healthy male volunteers to evaluate the impact of CYP3A4 inhibition on erlotinib exposure. RESULTS: Ketoconazole caused an almost two-fold increase in erlotinib plasma area under the concentration curve and in maximum plasma concentration. This is consistent with the SimCYP prediction of a two-fold increase in erlotinib AUC, further validating a primary (approximately 70%) role of CYP3A4 in erlotinib elimination. CONCLUSION: Prediction of clinically important drug-drug interaction with SimCYP using in vitro human metabolism data can be a powerful tool during early clinical development to ensure safe administration of anticancer drugs, which are often co-administered at maximum tolerated doses with other drugs as part of a palliative treatment regimen.

Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers.

Metabolism and excretion of erlotinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, were studied in healthy male volunteers after a single oral dose of [14C]erlotinib hydrochloride (100-mg free base equivalent, approximately 91 microCi/subject). The mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The majority of the total administered radioactivity was excreted in feces (83+/-6.8%), and only a low percentage of the dose was recovered in urine (8.1+/-2.8%). Only less than 2% of what was recovered in humans was unchanged erlotinib, which demonstrates that erlotinib is eliminated predominantly by metabolism. In plasma, unchanged erlotinib represented the major circulating component, with the pharmacologically active metabolite M14 accounting for approximately 5% of the total circulating radioactivity. Three major biotransformation pathways of erlotinib are O-demethylation of the side chains followed by oxidation to a carboxylic acid, M11 (29.4% of dose); oxidation of the acetylene moiety to a carboxylic acid, M6 (21.0%); and hydroxylation of the aromatic ring to M16 (9.6%). In addition, O-demethylation of M6 to M2, O-demethylation of the side chains to M13 and M14, and conjugation of the oxidative metabolites with glucuronic acid (M3, M8, and M18) and sulfuric acid (M9) play a minor role in the metabolism of erlotinib. The identified metabolites accounted for >90% of the total radioactivity recovered in urine and feces. The metabolites observed in humans were similar to those found in the toxicity species, rats and dogs.