No abstract

Rapid onset of analgesic action is linked with rapid absorption of analgesics (high maximum concentration [Cmax] and short time to maximum concentration [tmax]). After overnight fasting, ibuprofen lysinate reaches higher peak plasma levels (Cmax) earlier than ibuprofen acid (tmax) with comparable exposure (area under the plasma concentration–time curve [AUC]); however, subjects usually take ibuprofen with or within a short time of a meal. Therefore, pharmacokinetic (PK) studies under fed conditions may better characterize properties under real‐life conditions. We investigated a new fixed‐dose combination (FDC) of ibuprofen acid 400 mg and caffeine 100 mg in 2 single‐dose, randomized, crossover PK studies in healthy subjects (both N = 36). The FDC was compared with ibuprofen 400 mg as acid and as lysinate after an overnight fast in Study 1, and with ibuprofen lysinate after a meal in Study 2. After fasting, results for ibuprofen in the FDC were comparable with those from ibuprofen acid alone. Caffeine did not affect the Cmax, tmax, and AUC. As expected, a higher Cmax and shorter tmax were observed with ibuprofen lysinates vs the FDC. Compared with administration after fasting, Cmax and tmax for ibuprofen lysinate administered postprandially were markedly different, while with FDC, these parameters were less sensitive to food intake. Taken after a meal, ibuprofen in the FDC reached tmax earlier than ibuprofen lysinate (median 1.25 vs 1.63 hours), and Cmax was approximately 13% higher, with comparable AUC, suggesting that the profile of ibuprofen was in favor of the FDC compared with ibuprofen lysinate. Thus, under real‐life conditions, ibuprofen lysinate had no PK advantage over the FDC. All preparations were well tolerated.

Background The study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity. Methods This was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5–360 mg BI 187004 or placebo once daily as single dose in 72 healthy male volunteers with overweight or obesity. Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocortisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus–pituitary–adrenal axis hormones. Results BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n = 9) for all 9 BI 187004 dose groups and 5.9% (n = 1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non-proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5 h (5 mg) to 14.5 h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3–5%). Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10 h and from 59.4% (10 mg) to 98.6% (360 mg) after 24 h. Conclusions BI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. Trial registration ClinicalTrials.gov, NCT01587417, registered on 26-Apr-2012.

PurposeTo evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate.MethodsThis was an open-label trial in healthy male subjects. In part 1 (pilot, n = 8) and part 3 (n = 12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran.ResultsBioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUCτ,ss were 135% (90% CI 107–169%) and 132% (90% CI 112–156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUCτ,ss ratio test/reference: 91.9%, 90% CI 78.7–107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC0−24 was 103%; 90% CI 80.3–131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation.ConclusionsWhen given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-012-1304-8) contains supplementary material, which is available to authorized users.

BackgroundThe study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity.MethodsThis was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5-360 mg BI 187004 or placebo once daily as single dose in 72 healthy volunteers with overweight or obesity.Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocotisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus-pituitary-adrenal axis hormones.ResultsBI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n=9) for all 9 BI 187004 dose groups and 5.9% (n=1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non‑proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5h (5 mg) to 14.5h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3-5%). Urinary tetrahydrocortisol/tetrahydrocotisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10h and from 59.4% (10 mg) to 98.6% (360 mg) after 24h. ConclusionsBI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. Trial registry number: ClinicalTrials.gov, NCT01587417, registered on 26-Apr-2012, https://clinicaltrials.gov/ct2/show/study/NCT01587417