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.
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 (> or =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.
The nonlinear pharmacokinetic characteristics and the pharmacokinetic/pharmacodynamic relationship of linagliptin were independent of the mode of administration (intravenous or oral). Because of the nonlinear pharmacokinetics, the standard approach of comparing the AUC after oral administration with the AUC after intravenous administration was inappropriate to determine the absolute bioavailability of linagliptin. By a modelling approach, the absolute bioavailability of the 10 mg linagliptin tablet was estimated to be about 30%.
Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic dermatitis (AD) pathology. Four randomized clinical studies (Phase 1 and 2) investigated the safety, tolerability, efficacy, and pharmacokinetic profile of the anti-IL-17C monoclonal antibody MOR106 for up to 12 weeks (NCT03568071: n = 207 adults with moderate–severe AD; NCT03689829 Part 1: n = 32 healthy males; NCT03689829 Part 2: n = 44 adults with moderate–severe AD; and NCT03864627: n = 76 adults with moderate–severe AD). In these studies, MOR106 was either administered intravenously (i.v.) every 2 or 4 weeks at doses between 1–10 mg/kg, or subcutaneously (s.c.), either as a single dose or doses every 2 weeks at 320 mg. Overall, MOR106 was well-tolerated, and the safety profile was consistent with monoclonal antibodies approved for AD. Bioavailability following s.c. dosing was 55%, and steady-state drug levels were reached at 2–4 weeks. Ongoing studies were terminated following a futility analysis of the Phase 2 placebo-controlled dose-finding study (NCT03568071) due to a low probability for achieving the primary efficacy endpoint. Cumulatively, MOR106 demonstrated ineffectiveness for the treatment of AD, but its safety and pharmacokinetic characteristics warrant further drug development in other indications. Funding: sponsored by Galapagos NV; funded by Novartis AG.
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