Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers.

PURPOSE: To investigate the pharmacokinetics, metabolism and tolerability of afatinib (BIBW 2992), an oral irreversible ErbB family blocker, in healthy male volunteers. METHODS: In this open-label, single-center study, 8 healthy male volunteers received a single oral dose of 15 mg [(14)C]-radiolabeled afatinib (equivalent to 22.2 mg of the dimaleinate salt) as a solution. Blood, urine and fecal samples were collected for at least 96 hours (h) after dosing. Plasma and urine concentrations of afatinib were analyzed using high-performance liquid chromatography-tandem mass spectrometry. [(14)C]-radioactivity levels in plasma, whole blood, urine and feces were measured by liquid scintillation counting methods. Metabolite patterns were assessed by high-performance liquid chromatography. RESULTS: [(14)C]-radioactivity was mainly excreted via feces (85.4%). Overall recovery of [(14)C]-radioactivity was 89.5%, indicative of a complete mass balance. Afatinib was slowly absorbed, with maximum plasma concentrations achieved at a median of 6 h after dosing, declining thereafter in a biexponential manner. The geometric mean terminal half-life of afatinib was 33.9 h in plasma and longer for [(14)C]-radioactivity in plasma and whole blood. Apparent total body clearance for afatinib was high (geometric mean 1,530 mL/min). The high volume of distribution (4,500 L) in plasma may indicate a high tissue distribution. Afatinib was metabolized to only a minor extent, with the main metabolite afatinib covalently bound to plasma proteins. Oxidative metabolism mediated via cytochrome P-450 was of negligible importance for the elimination of afatinib. Afatinib was well tolerated. CONCLUSIONS: Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism.

Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A2 receptor and synthase inhibitor, in healthy subjects.

AIMS: To characterize the pharmacokinetics of terbogrel, a new combined thromboxane A2 (TxA2) receptor and synthase inhibitor, in healthy human subjects after single or multiple oral administration. METHODS: Forty-eight healthy male subjects received a single oral dose (10, 25, 50, 100, 150 or 200 mg) of terbogrel or placebo and 32 different subjects received one of the following treatments twice daily for 7 days: 50, 100 or 150 mg terbogrel, placebo, or once-a-day 330 mg acetylsalicylic acid. RESULTS: Terbogrel was well tolerated without obvious adverse effects following either a single oral dose or administration over 7 days. Plasma drug concentrations were dose-linear and there was no accumulation over 7 days. There was a dose-dependent blockade of TxA2 receptors and of inhibition of thromboxane synthase activity with values for IC50 of 12 ng ml(-1) and 6.7 ng ml(-1), respectively. At the highest dose tested (150 mg) there was almost complete inhibition of thomboxane synthase and thromboxane receptor occupancy. Even at trough concentrations, receptor occupancy remained above 80% and thromboxane synthase was still completely inhibited. These two activities were associated with a dose-dependent inhibition of platelet aggregation (>80% at the 150 mg dose of terbogrel) and enhanced prostacyclin production. CONCLUSIONS: Terbogrel is a potent agent having two distinct, complimentary pharmacodynamic actions, namely inhibition of thromboxane synthase and antagonism of the TxA2 receptor. The antithrombotic effect of terbogrel was dose-dependent and was associated with enhanced prostacyclin production. Terbogrel is an attractive candidate for long-term antithrombotic therapy.

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.