Pharmacokinetic properties of two erlotinib 150 mg formulations with a genetic effect evaluation in healthy Korean subjects.

BACKGROUND AND OBJECTIVE: Erlotinib is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor that acts on the epidermal growth factor receptor and inhibits cell proliferation, growth, migration, invasion and survival. This study was performed for the subsequent marketing of a test erlotinib formulation in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy adult volunteers. METHODS: A total of 46 healthy male subjects were enrolled in a single-dose, randomized, open-label, two-period, two-sequence, crossover, bioequivalence study. During each treatment period, subjects received 150 mg of erlotinib in either the test or reference formulation. There was a 2-week washout period between each period. Blood samples were obtained 15 times during each period, before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72 and 96 h after oral administration. Plasma concentrations of erlotinib were determined using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (C(max)), area under the plasma concentration-time curve to the last sampling time (AUC(t)), AUC from time zero to infinity (AUC(∞)), and time to reach C(max) (t(max)), were measured, and all treatment-emergent adverse events and their relationships with the study medications were recorded throughout the study. An additional analysis was performed to characterize the association between the cytochrome P450 (CYP) 1A1, CYP1A2 and CYP3A4 genotypes and the erlotinib pharmacokinetic parameters. RESULTS: A total of 41 subjects completed the study. There were no significant differences in the prevalence of adverse events between the two formulations, and there were no serious or unexpected adverse events during the study. Both formulations had very similar C(max), AUC, terminal half-life (t ½) and t(max) values. The 90% confidence intervals of the geometric least-squares mean ratios of the test to reference formulation were 1.09 (0.98-1.22) for C(max) and 1.10 (1.01-1.21) for AUCt. Statistical significance was observed between the CYP1A2*1M genotype and the erlotinib pharmacokinetic parameter, particularly C(max) (p = 0.015). CONCLUSIONS: This study suggests that the test and reference formulations of 150 mg erlotinib have similar pharmacokinetic characteristics. Both had no major safety issues and were well-tolerated. The test formulation met the regulatory criteria for assuming bioequivalence to the reference formulation for both AUCt and C max. The additional genetic analysis demonstrated that the major metabolic enzymes of erlotinib did not significantly affect erlotinib metabolism, with the exception of CYP1A2*1M.

Pharmacokinetics of a new orally soluble film formulation of sildenafil administered without water.

OBJECTIVE: To compare the pharmacokinetic profiles and to assess bioequivalence of a newly developed orally soluble film formulation of sildenafil, taken without water, with those of a conventional formulation of sildenafil. METHODS: This study was conducted in a population of healthy subjects as an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to 1 of 2 sequences of the two formulations: an orally soluble film (OSF) of 50 mg sildenafil as the test drug and a film-coated tablet (FCT) of 50 mg sildenafil as the reference drug. Blood samples were collected at intervals from 0 to 24 hours after administration. Plasma concentrations of sildenafil and its active metabolite N-desmethyl sildenafil were analyzed using a liquid chromatography/tandem mass spectrometry method. RESULTS: 48 healthy male subjects completed the study. The geometric mean (CV%) for Cmax in the OSF and FCT formulations were 267.21 (4.68%) ng/mL and 285.97 (5.32%) ng/mL, respectively. The geometric mean for AUClast in the OSF and FCT formulations were 664.48 (4.40%) ng x h/mL and 647.96 (4.63%) ng x h/mL, respectively. The geometric mean for AUCinf in the OSF and FCT formulations were 685.65 (4.37%) ng x h/mL and 666.28 (4.60%) ng x h/ mL, respectively. The 90% confidence intervals of the ratios of the geometric means of the Cmax, AUClast, and AUCinf were 0.844 - 1.030, 0.961 - 1.091, and 0.965 - 1.093, respectively. CONCLUSIONS: The OSF sildenafil formulation exhibited no significant differences in its pharmacokinetics compared with those of the FCT formulation. Therefore this convenient OSF sildenafil formulation, which can be taken without the need for water or chewing, offers physicians a novel and attractive treatment option for men with erectile dysfunction. *These authors contributed equally to this work.

UPLC-UV method for determination of risedronate in human urine.

This study was designed to develop a sensitive and rapid method for the quantitation of risedronate in human urine using ultra-performance liquid chromatography with ultra-violet detector (UPLC-UV) and to compare bioavailability parameter of 5, 35 and 150 mg risedronate. The mobile phase consisted of sodium phosphate buffer, 1 mM etidronate-acetonitrile (95:5, v/v), pH 9.0, and was pumped at a flow rate of 0.3 mL/min. Detection of risedronate in human urine by the UPLC-UV was accurate and precise from 20 ng/mL to 5 µg/mL (a correlation coefficient of 0.99) with 97.16% in mean recovery. The intra-day accuracy was 89.17-110.43% with precision of 0.04-3.16% and the inter-day accuracy was 89.23-110.19% with precision of 1.63-9.72%. Aet (accumulated excretion amount) of risedronate in the urine after 5, 35 and 150 mg administration was 35.08, 246.67 and 1.413.85 µg within 36 h and Umax (maximal excretion rate) was 12.11, 77.7 and 374.24 µg/h, respectively. The assessed dose proportionality of Umax and Aet with three single doses of risedronate was found in an approximately linear manner. These results indicate that the developed simple, rapid and robust assay enables the complete processing of large samples for pharmacokinetic studies of risedronate in biological fluid.