Safety, pharmacokinetics and pharmacodynamics of BI 135585, a selective 11ß-hydroxysteroid dehydrogenase-1 (HSD1) inhibitor in humans: liver and adipose tissue 11ß-HSD1 inhibition after acute and multiple administrations over 2 weeks.

AIMS: To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitor, after single- and repeated-dose administration. METHODS: The single-dose study included open-label administration of 200 mg BI 135585 in healthy volunteers, while in the multiple-dose study, we carried out randomized, double-blind administration of 5-200 mg BI 135585 or placebo once daily over 14 days in patients with type 2 diabetes (T2DM). Assessments included 11ß-HSD1 inhibition in the liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) and in subcutaneous adipose tissue (AT) ex vivo and determination of hypothalamus-pituitary-adrenal (HPA) axis hormone levels. RESULTS: No major safety issues occurred with BI 135585 administration. The HPA axis was mildly activated with slightly increased, but still normal adrenocorticotropic hormone levels, increased total urinary corticoid excretion but unchanged plasma cortisol levels. After multiple doses of 5-200 mg BI 135585, exposure (area under the curve) increased dose-proportionally and half-life was 55-65 h. The urinary THF/THE ratio decreased, indicating liver 11ß-HSD1 inhibition. Median 11ß-HSD1 enzyme inhibition in the AT reached 90% after a single dose of BI 135585, but was low (31% or lower) after 14 days of continuous treatment. CONCLUSIONS: BI 135585 was safe and well tolerated over 14 days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11ß-HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.

Bioequivalence of Linagliptin 5 mg once daily and 2.5 mg twice daily: pharmacokinetics and pharmacodynamics in an open-label crossover trial.

Linagliptin is an oral antihyperglycemic drug that acts by inhibiting the dipeptidyl peptidase-4 enzyme. A 5-mg once-daily regimen is available, but an alternative regimen was needed for twice-daily fixed-dose combinations. Although linagliptin has non-linear pharmacokinetics, simulation suggested 2.5 mg twice-daily would provide bioequivalent exposure and comparable plasma dipeptidyl peptidase-4 inhibition to 5 mg once-daily.This crossover study compared steady-state pharmacokinetics and pharmacodynamics of linagliptin 5 mg once-daily and 2.5 mg twice-daily, both administered for 7 days.In total, 16 healthy volunteers entered the study, and 15 completed both treatment periods. Exposure over 24-h at steady state (AUC0-24,ss) was similar for linagliptin 5 mg once-daily and 2.5 mg twice-daily (132 vs. 124 nmol · h/L), and the 90% confidence interval of the adjusted geometric mean ratio of AUC0-24,ss was well within the acceptance range for bioequivalence (ratio 93.9%; 90% confidence interval 89.5, 98.5). Median dipeptidyl peptidase-4 inhibition over a 24-h interval at steady state was 85.9% with linagliptin 5 mg once-daily and 86.5% with 2.5 mg twice-daily, and median dipeptidyl peptidase-4 inhibition values were approximately 80.0% at trough. Most subjects had no adverse events and there were no serious adverse events.Linagliptin 5 mg once-daily and 2.5 mg twice-daily provided bioequivalent exposure and similar inhibition of dipeptidyl peptidase-4 over the whole dosing interval.

Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers.

OBJECTIVE: Co-administration of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) with pioglitazone may improve glycemic control in patients with Type 2 diabetes due to their complementary mechanisms of action. This study aimed to investigate any potential pharmacokinetic interaction between linagliptin and pioglitazone, a CYP 2C8 substrate. METHODS: 20 (10 male and 10 female) healthy subjects, between 22 and 65 years of age with a BMI range of > = 18.5 and < =29.9 kg/m2, took part in this single center open-label, randomized,two-way cross-over study. The subjects were administered linagliptin 10 mg/day and/orpioglitazone 45 mg/day until steady state was reached. RESULTS: Co-administration of pioglitazone did not significantly affect linagliptin Cmax,ss (geometric mean ratio(GMR) 107.3; 90% confidence interval (CI);92.3 ­ 124.8) or AUC tau,ss (GMR 113.4; 90%CI 103.0 ­ 124.9). Co-administration of linagliptin did not significantly affect pioglitazoneAU tau,ss (GMR 94.4; 90% CI 87.1 ­102.2), but reduced Cmax,ss by 14% (GMR85.6; 90% CI 78.1 ­ 93.8). As expected, linagliptin and pioglitazone were well tolerated,whether administered alone or concomitantly.There were no reported serious adverse events. The investigator defined 5 adverse events as drug-related with linagliptin,and 4 with pioglitazone. CONCLUSIONS: Linagliptinand pioglitazone have no clinically relevant pharmacokinetic interaction and may be co-administered without dose adjustment.These data further confirm that linagliptin is not an inhibitor of CYP2C8 in vivo.As the pharmacokinetic profiles of linagliptin and pioglitazone are similar in Type 2 diabetes patients and healthy subjects, it is reasonable to assume that they may be administered together to Type 2 diabetes patients without dose adjustment.