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.
In Europe an abundance of humus taxonomies exists starting with early approaches in the late 19th century. Frequently used in an international context, they do not cover all site conditions in the ...European area. Although having basic concepts and general lines, the European (and North American, Canadian) classification systems differ in important parameters used for the description and classification of humus forms. These discrepancies result in incongruities, so they require adjustments when exchanging partially compatible soil data, even between nearby countries. In 2003, 26 European specialists in humus forms met in Trento (Italy) and decided to formulate rules of classification based on morphogenetic descriptions and diagnostic horizons, adapted to European ecological conditions. Taking into account old and new European and North American systems of humus forms classification, six main references (Anmoor, Mull, Moder, Mor, Amphi and Tangel) were defined, each of them further divided into more detailed categories. This inventory assigned a strong discriminatory power to the action of soil animals. Both semiterrestrial (anoxic) and terrestrial (aerated) topsoils were classified. Descriptors of diagnostic horizons were conceived in accordance with recent international soil classifications. Assigning an ‘ecological value’ to each main humus form along a gradient from biologically active forms, degrading and incorporating all organic remains, to those characterized by the accumulation of poorly transformed organic matter, this European system of classification avoids a strong hierarchical structure and allows a flexible approach open to additional ecological contributions and renditions.
► European specialists conceive principles of a new classification of humus forms. ► Only morphological characters with evident functional effects were considered. ► Ten basic humus forms were circumscribed, available in a wide array of ecosystems. ► Environmental factors determine the structure of the classification tree.
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.
Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake ...are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four‐way crossover study. Each subject received an onion supplement or quercetin‐4′‐O‐glucoside (both equivalent to 100 mg quercetin), as well as quercetin‐3‐O‐rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12‐channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailabilityand pharmacokinetic parameters between the onion supplement and quercetin‐4′‐O‐glucoside. Peak plasma concentrations were 2.3 ± 1.5 μg•mL−1 and 2.1 ± 1.6 μg•mL−1 (mean ± SDJ and were reached after 0.7 ± 0.2 hours and 0.7 ± 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were—despite the higher dose—only 0.6 ± 0.7 μg•mL−1 and 0.3 ± 0.3 μg•mL−1, respectively. Peak concentrations were reached 4.3 ± 1.8 hours after administration of buckwheat tea and 7.0 ± 2.9 hours after ingestion of rutin. The terminal elimination half‐life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin‐4′‐O‐glucoside and quercetin‐3‐O‐rutinoside. The significance of specific carriers on the absorption of quercetin glycosides, as well as specific intestinal b‐glucosidases, needs to be further evaluated.
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.
This study focuses on the biological and morphological development of humus profiles in forested Italian Alpine soils as a function of
climate
. Humus form description, systematic investigation of ...microannelid communities and polyphasic biochemical fingerprinting of soil microbial communities (denaturing gradient gel electrophoresis (DGGE) and phospholipid fatty acid analysis (PLFA)) were performed to compare sites differing in mean annual temperature due to different altitude and exposure. Although the soil biota showed complex responses, several differences in soil biological properties seem to be due to thermal differences. Although soil acidity also determines biological properties, it is not a state factor but rather influenced by them. The thickness of the organic layer and the acidification of the subjacent mineral horizon increased under cooler conditions (north-exposure; higher altitude), whereas the thickness of the A horizon inversely decreased. Species richness of microannelid assemblages was higher under warmer conditions (south-exposure; lower altitude) and the vertical distribution of microannelids shifted along the gradient to lower temperatures from predominant occurrence in the mineral soil to exclusive occurrence in the organic layer. Microbial biomass (total PLFA) was higher at the cooler sites; the prevalence of Gram-negative bacteria could be ascribed to their better adaptation to lower temperature, pH and nutrient contents. The δ
13
C signatures of the PLFA markers suggested a lower decomposition rate at the cooler sites, resulting in a lower respiratory loss and an accumulation of weakly decomposed organic material. DGGE data supported the PLFA results. Both parameters reflected the expected thermal sequence. This multidisciplinary case study provided indications of an association of
climate
, mesofauna and microbiota using the humus form as an overall link. More data are however needed and further investigations are encouraged.
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.
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