Key result
Co-administration of linagliptin with simvastatin resulted in a geometric mean ratio for simvastatin AUC of 134.2% (90% CI 119.4-150.7) compared to simvastatin alone, lacking clinical relevance.
Why the study?
Does co-administration of linagliptin alter the steady-state pharmacokinetics of simvastatin in healthy male subjects?
Does co-administration of linagliptin alter the steady-state pharmacokinetics of simvastatin in healthy male subjects?
Linagliptin co-administration mildly increases simvastatin exposure, but this effect is not clinically relevant and does not require dose adjustment.
Answers are grounded in this paper and cite their sources.
No dose adjustment needed for simvastatin with linagliptin; extends pharmacokinetic data but leaves clinical relevance open in broader populations.
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.
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Graefe‐Mody et al. (2010) studied Healthy (n=20). Linagliptin vs. Simvastatin alone was evaluated on Simvastatin AUC (GMR 134.2%, 95% CI 119.4-150.7). Co-administration of linagliptin with simvastatin resulted in a geometric mean ratio for simvastatin AUC of 134.2% (90% CI 119.4-150.7) compared to simvastatin alone, lacking clinical relevance.
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