Evaluation of the Absolute Oral Bioavailability and Bioequivalence of Erlotinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in a Randomized, Crossover Study in Healthy Subjects

Abstract

A randomized, open-label, 2-period crossover study was conducted to evaluate the bioequivalence of 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg (arm A, n = 42) and the oral bioavailability of the 150-mg tablet versus a 25-mg intravenous infusion (arm B, n = 20) in healthy subjects. The washout period was 2 weeks between treatments. Plasma concentrations of erlotinib and its active metabolite, OSI-420, were measured after each dose. The ratios of geometric means for AUC(0-infinity) and Cmax of erlotinib following 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg were (1 and 0.95) within the predefined bioequivalence range of 0.80 to 1.25. The mean absolute oral bioavailability, using compartmental analysis, was estimated as 59% (95% confidence interval, 55%-63%). Overall, 6 tablets of erlotinib 25 mg are bioequivalent to a single 150-mg tablet. Both intravenous and oral erlotinib were generally well tolerated with an estimated bioavailability of 59% following oral administration.

Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100

“…The bioavailability of erlotinib in mice has not been published. However, assuming it is similar to that observed in humans (59%; Frohna et al, 2006), one would not expect a modulator of its metabolism and/or transport to increase its exposure more than two-fold. Indeed, a 2.5-fold increase in the dose of BAS 100 (to 25 mg kg À1 ) did not result in a further increase in erlotinib exposure in the current study.…”

“…It is approved for the treatment of advanced nonsmall cell lung cancer as a single agent and advanced pancreatic cancer in combination with gemcitabine. Erlotinib has an average oral bioavailability in humans of 59% (Frohna et al, 2006), but exhibits substantial (up to eight-fold) interindividual pharmacokinetic variability (Hidalgo et al, 2001;Tan et al, 2004), which may result in variable treatment outcomes. Erlotinib is extensively metabolised into multiple products , including an active O-desmethyl metabolite, OSI-420.…”

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

“…Indeed, considering that recently expression of CYP3A in the intestine has been shown to affect drug absorption (38) and that erlotinib has been reported to be susceptible to CYP3A-mediated metabolism (22,39,40), an altered expression/ activity of CYP3A in our mice model might affect the magnitude of our findings. However, the bioavailability observed in WT mice is of the same magnitude as observed in humans (41) and the experimental condition in this model may thus reflect the pharmacokinetic condition in patients. It has been reported previously that food can significantly increase the bioavailability of erlotinib.…”

Oral erlotinib, but not rapamycin, causes modest acceleration of bladder and hindlimb recovery from spinal cord injury in rats

“…13 Thus, Erlotinib was given to rats in a clinically relevant dose equivalent to a dose that could be tolerated without major adverse events (EMA Tarceva report) if administered to humans for several consecutive days, with bioavailability taken into account. 14 Higher doses would not be recommended unless combined with a vehicle that reduces toxicity, such as nanoencapsulation. 15 In summary, the local administration, the difference in length of the administration period, the difference in potency, and the difference in concentration may all explain the increased efficacy of PD168393 as compared with that of Erlotinib.…”