Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double‐blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10–400 mg (n = 40) or at multiple doses of 50–400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half‐lives of 8–10 h and 14–17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose‐proportional increases observed in maximum plasma concentration and area under the curve. Steady‐state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430–2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min−1 (range 1480–2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration–time curves with values increasing rapidly and in a dose‐dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5‐fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild‐to‐moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted.

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Background and ObjectivesIdarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy.MethodsIn this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45–64 years; 16 elderly, 65–80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state.ResultsDabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses ≥2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects.ConclusionsImpaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab.Clinical Trial Registration http://www.clinicaltrials.gov. Unique identifier: NCT01955720.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0417-0) contains supplementary material, which is available to authorized users.

Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism.

This article reports the clinical investigation of a probe drug cocktail containing substrates of key drug transporters. Single oral doses of 0.25 mg digoxin (P‐gp), 5 mg furosemide (OAT1 and OAT3), 500 mg metformin (OCT2, MATE1, and MATE2‐K), and 10 mg rosuvastatin (OATP1B1, OATP1B3, and BCRP) were administered separately or as a cocktail in a randomized six‐period crossover trial in 24 healthy male volunteers. As a cocktail, relative bioavailabilities of digoxin and metformin and furosemide AUC0‐tz were similar to separate dosing. However, when administered as a cocktail the Cmax of furosemide was 19.1% lower and the Cmax and AUC0‐tz of rosuvastatin were 38.6% and 43.4% higher, respectively. In addition, the effects of increased doses of metformin or furosemide on the cocktail were investigated in 11 and 12 subjects, respectively. The cocktail explored in this trial has the potential to be used for the in vivo screening of transporter‐mediated drug–drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics