Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin.
OBJECTIVE
This study was conducted to investigate any potential effect of the dipeptidyl peptidase-4 inhibitor linagliptin (which is being developed to improve glycemic control in patients with Type 2 diabetes) on the pharmacokinetics of simvastatin (a lipid-lowering, HMG-CoA reductase inhibitor).


METHODS
This open-label, multiple-dose study was conducted in 20 healthy male Caucasian subjects. Simvastatin (40 mg/day) was administered alone for 6 days, followed by co-administration with linagliptin (10 mg/ day) for 6 days, followed by simvastatin single administration for a further 8 days. Plasma concentrations of simvastatin and its active metabolite simvastatin beta-hydroxy acid were determined on Day 6 (before co-administration of linagliptin) and Days 12, 16 and 20 (after co-administration of linagliptin).


RESULTS
The geometric mean ratio (GMR) (90% confidence interval (CI)) following co-administration of linagliptin with simvastatin (Day 12) compared with administration of simvastatin alone (Day 6) for simvastatin AUC was 134.2% (119.4, 150.7) and for simvastatin acid AUC was 133.3% (118.1, 150.3). The GMR (90% CI) for simvastatin Cmax,ss was 110.0% (89.3, 135.6) and for simvastatin acid Cmax,ss was 120.7% (101.5, 143.6). 20 adverse events were reported by 11 subjects. Both simvastatin and linagliptin were well tolerated.


CONCLUSIONS
Linagliptin-mediated effects on simvastatin exposure are not considered to be clinically relevant in terms of patient tolerability or safety. Therefore, a dose adjustment of linagliptin is not necessary when these two agents are administered together and linagliptin co-administration is not expected to exert a clinically relevant effect on the pharmacokinetics of other CYP3A4 substrates.
Graefe-Mody
U
U
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Ingelheim, Germany. Ulrike.Graefe-Mody@boehringer-ingelheim.com
Huettner
S
S
Stähle
H
H
Ring
A
A
Dugi
K A
KA
D000328:Adult; D019540:Area Under Curve; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000009:adverse effects / Q000494:pharmacology*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology*; D019821:Simvastatin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D054873:Dipeptidyl-Peptidase IV Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011687:Purines; D011799:Quinazolines; C532833:simvastatin hydroxyacid; D000069476:Linagliptin; D019821:Simvastatin