title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers.
abstract: 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.
authors.affiliation: Department of Clinical Research, Boehringer Ingelheim Pharma GmbH & Company KG, Biberach, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hüttner
authors.forename: E U
authors.initials: EU
authors.lastname: Graefe-Mody
authors.forename: B
authors.initials: B
authors.lastname: Withopf
authors.forename: A
authors.initials: A
authors.lastname: Ring
authors.forename: K A
authors.initials: KA
authors.lastname: Dugi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D006207:Half-Life; D006801:Humans; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin