Aim: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor with a primarily non‐renal route of excretion, ...in subjects with type 2 diabetes mellitus (T2DM).
Methods: Linagliptin pharmacokinetics was studied under single‐dose and steady‐state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end‐stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM).
Results: Renal excretion of unchanged linagliptin was <7% in all groups. Under single‐dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration–time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20–60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady‐state AUC and Cmax values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half‐life of linagliptin ranged from 14–15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r2 = 0.18) was seen between creatinine clearance and steady‐state exposure.
Conclusions: Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.
Aims: To investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin (BI 1356) in patients ...with type 2 diabetes mellitus.
Methods: Forty‐seven male type 2 diabetic patients received linagliptin 1, 2.5, 5 or 10 mg, or placebo, once daily for 12 days.
Results: Linagliptin exposure area under the plasma concentration–time curve and maximum plasma concentration (Cmax) increased less than proportionally with dose. Accumulation half‐life was short (8.6–23.9 h), resulting in rapid attainment of steady state (2–5 days) and little accumulation (range: 1.18–2.03). The long terminal half‐life (113–131 h) led to a sustained inhibition of DPP‐4 activity. Renal excretion was below 1% on day 1 in all dose groups. Inhibition of plasma DPP‐4 activity correlated well with linagliptin plasma concentrations, resulting in DPP‐4 inhibition >90% in the two highest dose groups; even 24 h postdose, DPP‐4 inhibition was >80%. Following an oral glucose tolerance test, 24 h after the last dose, statistically significant reductions of glucose excursions were observed with linagliptin (2.5, 5 and 10 mg doses) compared with placebo. Linagliptin was well tolerated. The frequency of adverse events (AEs) was not higher with linagliptin (54%) than with placebo (75%). No serious AEs and no episodes of hypoglycaemia were reported.
Conclusions: In type 2 diabetic patients, multiple rising doses of linagliptin were well tolerated and resulted in significant improvements of glucose parameters. Together with the favourable pharmacokinetics, these results confirm the unique profile of linagliptin in the DPP‐4 inhibitor class.
Diabet. Med. 27, 1409–1419 (2010)
Aims The efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, linagliptin, added to ongoing metformin therapy, were assessed in patients with Type 2 ...diabetes who had inadequate glycaemic control (HbA1c≥ 7.5 to ≤ 10%; ≥58.5 to ≤85.8 mmol/mol) with metformin alone.
Methods Patients (n = 333) were randomized to receive double‐blind linagliptin (1, 5 or 10 mg once daily) or placebo or open‐label glimepiride (1–3 mg once daily). The primary outcome measure was the change from baseline in HbA1c at week 12 in patients receiving combination therapy compared with metformin alone.
Results Twelve weeks of treatment resulted in a mean (sem) placebo‐corrected lowering in HbA1c levels of 0.40% (± 0.14); 4.4 mmol/mol (± 1.5) for 1 mg linagliptin, 0.73% (± 0.14); 8.0 mmol/mol (± 1.5) for 5 mg, and 0.67% (± 0.14); 7.3 mmol/mol (± 1.5) for 10 mg. Differences between linagliptin and placebo were statistically significant for all doses (1 mg, P = 0.01; 5 mg and 10 mg, P < 0.0001). The change in mean (sem) placebo‐corrected HbA1c from baseline was −0.90% (± 0.13); −9.8 mmol/mol (± 1.4) for glimepiride. Adjusted and placebo‐corrected mean changes in fasting plasma glucose were −1.1 mmol/l for linagliptin 1 mg (P = 0.002), −1.9 mmol/l for 5 mg and −1.6 mmol/l for 10 mg (both P < 0.0001). One hundred and six (43.1%) patients reported adverse events; the incidence was similar across all five groups. There were no hypoglycaemic events for linagliptin or placebo, whereas three patients (5%) receiving glimepiride experienced hypoglycaemia.
Conclusions The addition of linagliptin to ongoing metformin treatment in patients with Type 2 diabetes was well tolerated and resulted in significant and clinically relevant improvements in glycaemic control, with 5 mg linagliptin being the most effective dose.
This randomized, double‐blind, parallel, placebo‐controlled, single rising‐dose study investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of BI 1356 (once‐daily, ...given orally) in healthy men. BI 1356 was well tolerated and safe up to and including a dose of 600 mg. The incidence of drug‐related adverse events was equal in subjects receiving BI 1356 (30%) or placebo (31%). No clinically relevant deviations in laboratory or ECG parameters were reported. Exposure of BI 1356 increased less than proportionally from 2.5 mg to 5 mg, more than proportionally from 25 mg to 100 mg and approximately proportionally for doses from 100 mg to 600 mg. The geometric mean terminal half‐life was up to 184 hours. Renal excretion was low. All doses of BI 1356 inhibited plasma dipeptidyl peptidase 4 activity. Single doses of 2.5 mg and 5 mg inhibited dipeptidyl peptidase 4 activity by 72.7% and 86.1% from baseline, respectively. The time to achieve maximum inhibition shifted with increasing doses from 3 hours (2.5 mg) to <0.7 hours (≥200 mg). Within the dose range tested, a direct pharmacokinetic/pharmacodynamic relationship was observed. The pharmacokinetic and pharmacodynamic profile results demonstrate the potency and full 24‐hour duration of action of BI 1356. Based on an estimated therapeutic dose of 5 mg, the therapeutic window of BI 1356 is expected to be >100‐fold.
Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of linagliptin in patients with type 2 diabetes mellitus (T2DM).
Methods: After screening and a 14‐day washout, ...subjects received linagliptin 2.5, 5 or 10 mg or placebo once‐daily for 28 days in this randomized, double‐blind, parallel, placebo‐controlled within‐dose groups study.
Results: Seventy‐seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose‐proportionally. Rapid and sustained inhibition of dipeptidyl peptidase‐4 reached 91–93% across linagliptin doses at steady state. At the end of the 24‐h dosing interval, inhibition was still high (82–90%). There were marked increases in plasma glucagon‐like peptide‐1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo‐corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was −0.31% (2.5‐mg dose), −0.37% (5‐mg dose) and −0.28% (10‐mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns.
Conclusions: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.
Aims
To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11β‐hydroxysteroid dehydrogenase‐1 (11β‐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 11β‐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 11β‐HSD1 inhibition. Median 11β‐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 11β‐HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.
Aims To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11 beta -hydroxysteroid dehydrogenase-1 (11 beta -HSD1) inhibitor, after single- and ...repeated-dose administration. Methods The single-dose study included open-label administration of 200mg BI 135585 in healthy volunteers, while in the multiple-dose study, we carried out randomized, double-blind administration of 5-200mg BI 135585 or placebo once daily over 14days in patients with type 2 diabetes (T2DM). Assessments included 11 beta -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 5-200mg BI 135585, exposure (area under the curve) increased dose-proportionally and half-life was 55-65h. The urinary THF/THE ratio decreased, indicating liver 11 beta -HSD1 inhibition. Median 11 beta -HSD1 enzyme inhibition in the AT reached 90% after a single dose of BI 135585, but was low (31% or lower) after 14days of continuous treatment. Conclusions BI 135585 was safe and well tolerated over 14days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11 beta -HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.
Abstract Background The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations ...it showed potential as a once-daily oral antidiabetic drug. Objectives In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM. Methods In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA1c ) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis. Results Baseline demographic characteristics were well balanced across the 4 treatment groups (mean SD age, 59.7 6.4 years in the placebo group, 60.8 9.2 years in the 0.5 mg group, 60.2 6.4 years in the 2.5 mg group, and 59.1 8.6 years in the 10 mg group; mean SD weight, 67.2 10.0 kg in the placebo group, 64.5 9.0 kg in the 0.5 mg group, 69.6 9.4 kg in the 2.5 mg group, and 63.5 12.2 kg in the 10 mg group; mean SD duration of T2DM diagnosis, 5.1 4.2 years in the placebo group, 5.2 4.7 years in the 0.5 mg group, 5.9 4.8 years in the 2.5 mg group, and 2.6 2.3 years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and Cmax (which occurred at 1.25–1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223–260 hours) but did not reflect the accumulation half-life (10.0–38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (–11.5, –13.6, and –25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (–29.0 to –68.1 mg × h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA1c from baseline compared with placebo, despite the relatively low baseline HbA1c (7.2%) and small sample size ( P < 0.01 for both groups). The greatest reduction in HbA1c (–0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linagliptin was well tolerated with no reported serious adverse events or symptoms suggestive of hypoglycemia. Overall, fewer adverse events were reported by patients after linagliptin than after placebo (11 of 55 20% vs 6 of 17 35%). Conclusions Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA1c as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted.
ABSTRACT
Objective: Linagliptin (BI 1356) is a novel, orally available inhibitor of dipeptidyl peptidase-4 (DPP-4). Linagliptin improves glycaemic control in type 2 diabetic patients by increasing ...the half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). Linagliptin is expected to be used as monotherapy or in combination with other antihyperglycaemic agents. This study was conducted to investigate potential pharmacokinetic or pharmacodynamic interactions between linagliptin and metformin.
Methods: This randomised, monocentric, open-label, two-way crossover design study was conducted in 16 healthy male subjects. Linagliptin (10 mg/day) and metformin (850 mg three times daily) were each administered alone and concomitantly. The steady-state pharmacokinetics of linagliptin and metformin and the inhibition of DPP-4 activity were determined at the end of each dosing period.
Results: Co-administration of linagliptin had no apparent effect on metformin exposure (metformin AUCτ,ss; geometric mean ratio GMR co-administration:individual administration was 1.01; 90% confidence interval CI was 0.89-1.14). Effects on maximum concentration (Cmax,ss) were small (GMR: 0.89; 90% CI: 0.78-1.00). Co-administration of metformin did not significantly affect Cmax,ss of linagliptin (GMR: 1.03; 90% CI: 0.86-1.24), but increased AUCτ,ss by 20% (GMR: 1.20; 90% CI: 1.07-1.34). Metformin alone had no effect on DPP-4 activity, and the inhibition of DPP-4 caused by linagliptin was not affected by concomitant administration of metformin. Tolerability was good whether linagliptin and metformin were administered alone or concomitantly. No serious adverse events occurred and the frequency of adverse events was low; 7 events in 6 subjects. The most frequent events were related to the gastrointestinal tract, as expected with metformin. Importantly, no subjects experienced signs or symptoms relating to episodes of hypoglycaemia.
Conclusion: In this small, multiple dose study carried out in healthy subjects, co-administration of linagliptin with metformin did not have a clinically relevant effect on the pharmacokinetics or pharmacodynamics of either agent. This study suggests linagliptin and metformin can safely be administered concomitantly in type 2 diabetes patients without dose adjustment; larger, longer-term clinical trials in diabetic patients are underway.
Abstract Background: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese ...populations, linagliptin showed potential as a once-daily oral antidiabetic drug. Objective: This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans. Methods: This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests. Results: Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean SD age, 24.5 3.6 years; mean weight, 61.2 6.2 kg; mean height, 171.5 5.3 cm) and multiple-dose groups (mean age, 25.4 3.7 years; mean weight, 61.6 5.2 kg; mean height, 170.9 4.9 cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and Cmax ) increased in a manner that was less than dose proportional. Tmax ranged from 1.50 to 6.00 hours, and elimination t½ ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent Vd (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t½ ranged from ∼10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (∼1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was ≥80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study. Conclusions: In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted.
