Urinary dipeptidyl peptidase-4 protein is increased by linagliptin and is a potential predictive marker of urine albumin-to-creatinine ratio reduction in patients with type 2 diabetes.

Results of a post hoc analysis of urinary dipeptidyl peptidase-4 (DPP-4) protein as a predictor of urine albumin-to-creatinine ratio (UACR) response to linagliptin treatment based on MARLINA-T2D trial data are described. MARLINA was a 24-week, phase 3b, multinational, placebo-controlled clinical trial, in which patients with type 2 diabetes (T2D), HbA1c 6.5%-10.0% and UACR 30-3000 mg/g (n = 360) were treated with linagliptin or placebo. After 24 weeks of treatment, linagliptin significantly inhibited urinary DPP-4 activity and increased urinary DPP-4 protein. Furthermore, medium urinary DPP-4 protein levels (between 5.5 and 7.5 natural logarithmic [ln] µg/g creatinine) at baseline allowed for prediction of improved UACR in linagliptin-treated individuals. In patients with lower or higher levels of urinary DPP-4 protein at baseline, no association between linagliptin treatment and improved UACR was present. This might suggest a varying degree of importance of DPP-4 as a pathophysiological factor in T2D-associated kidney disease. In summary, urinary DPP-4 might be a useful predictive biomarker for UACR improvement by linagliptin.

Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers.

PURPOSE: To 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. METHODS: This 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. RESULTS: Bioavailability 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 AUC(τ,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 (AUC(τ,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 AUC(0-24) was 103%; 90% CI 80.3-131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation. CONCLUSIONS: When 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.

Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI 187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety, Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14 Days.

OBJECTIVE: To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with the selective 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in male and female patients with type 2 diabetes and overweight or obesity. METHODS: Randomized, double-blind, parallel-group, placebo-controlled multiple rising dose study, with 10-360 mg BI 187004 once daily over 14 days in 71 patients. Assessments included 11beta-HSD1 inhibition in the liver and subcutaneous adipose tissue ex vivo (clinical trial registry number NCT01874483). RESULTS: BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 51.8% (n=29) for BI 187004 and 35.7% (n=5) for placebo. There were no clinically relevant deviations in laboratory or electrocardiogram parameters besides one patient on 360 mg discontinuing treatment due to moderate supraventricular tachycardia.BI 187004 was rapidly absorbed within 2 h; exposure increased non-proportionally. The oral clearance was low, apparent volume of distribution was moderate to large, and terminal half-life with 106-124 h was rather long. Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies was 87.9-99.4% immediately after the second dose and 73.8-97.5% 24 h after the last dose of BI 187004. CONCLUSIONS: BI 187004 was safe and well tolerated over 14 days and could be dosed once daily. Targeted 11beta-HSD1 enzyme inhibition of≥80% could be shown for BI 187004 doses≥40 mg. This dose should be targeted in further studies to test blood glucose lowering in patients with type 2 diabetes and overweight or obesity.

Safety and tolerability of linagliptin in Asians with type 2 diabetes: a pooled analysis of 4457 patients from 21 randomized, double-blind, placebo-controlled clinical trials.

BACKGROUND: Safety and tolerability of glucose-lowering drugs is a key consideration for use in type 2 diabetes (T2D). We evaluated the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in Asian patients with T2D. RESEARCH DESIGN AND METHODS: This was a post-hoc, descriptive pooled analysis of 21 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2D patients lasting ≤52 weeks. We evaluated adverse events (AEs) and laboratory parameters in Asian participants living in Asia, both overall and in the East Asian subgroup. RESULTS: This analysis included 4457 Asian patients overall (2712 receiving linagliptin; 1745 receiving placebo) and 3057 (68.6%) East Asians. AEs were reported in 1510 (55.7%) Asian patients receiving linagliptin and 1032 (59.1%) receiving placebo but were considered drug-related in only 13.0% of each group. Serious AEs occurred in 109 (4.0%) linagliptin patients and 90 (5.2%) placebo patients. The most common AEs were nasopharyngitis (6.4% linagliptin, 7.3% placebo), upper respiratory tract infection (5.7% linagliptin, 6.5% placebo), and hypoglycemia (7.3% linagliptin, 6.3% placebo). One linagliptin patient had pancreatitis; none had bullous pemphigoid. No clinically relevant mean changes in laboratory parameters occurred. These findings were consistent in East Asians. CONCLUSIONS: Linagliptin is well tolerated in Asian T2D patients, including East Asians, with low risk for AEs.

Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity.

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.

Early Combination Therapy with Linagliptin and Metformin in People with Type 2 Diabetes Improves Glycemic Control to HbA1c ≤ 6.5% without Increasing Hypoglycemia: Pooled Analysis of Two Randomized Clinical Trials.

INTRODUCTION: Clinical guidelines suggest a glycated hemoglobin A1c (HbA1c) target of ≤ 6.5% for type 2 diabetes patients with short duration of disease, few comorbidities and/or long life expectancy-provided this goal can be achieved safely. We explored whether initial combination treatment with the dipeptidyl peptidase-4 inhibitor linagliptin and metformin could provide better glycemic control (HbA1c ≤ 6.5%) than metformin alone without increasing hypoglycemia. METHODS: We pooled and analyzed individual patient data from two randomized clinical trials of early combination therapy with linagliptin and metformin versus metformin monotherapy. The primary outcome in both trials was the change in HbA1c from baseline to week 24. We evaluated the percentage of patients who achieved HbA1c ≤ 6.5% at week 24 and the incidence of adverse events. RESULTS: Most (> 70%) of the 1160 patients analyzed were treatment naive, and more than half had had diabetes for ≤ 1 year; mean baseline HbA1c was approximately 8.7%. Combination therapy with linagliptin and metformin resulted in more patients achieving HbA1c ≤ 6.5% than metformin alone, both for a metformin dose of 500 mg (40.1 vs. 22.9%, respectively, odds ratio [OR] 2.84, 95% confidence interval [CI] 1.87-4.32) and 1000 mg (49.5 vs. 35.4%, respectively, OR 2.28, 95% CI 1.54-3.40). Hypoglycemia occurred in < 3% of patients, with a comparable incidence between treatment groups. Other adverse events were also balanced between groups. CONCLUSION: Early combination treatment with linagliptin and metformin can improve the chances of achieving tight glycemic control (HbA1c ≤ 6.5%) without increasing the risk of hypoglycemia or other adverse events. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00798161 and NCT01708902.

Pharmacokinetic Properties of Ibuprofen (IBU) From the Fixed-Dose Combination IBU/Caffeine (400/100 mg; FDC) in Comparison With 400 mg IBU as Acid or Lysinate Under Fasted and Fed Conditions-Data From 2 Single-Center, Single-Dose, Randomized Crossover Studies in Healthy Volunteers.

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.

Pharmacokinetics of a once-daily extended-release formulation of pramipexole in healthy male volunteers: three studies.

BACKGROUND: Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily. OBJECTIVES: These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation. METHODS: Three Phase I studies were conducted, all in healthy adult men aged