Pharmacology: Mechanism of action: Linagliptin Inhibits dipeptidyl peptidase-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in increased concentrations of active incretin hormones, stimulating the release of insulin and decreasing levels of glucagon in the circulation.
Pharmacodynamics: Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
Pharmacokinetics: Absorption: The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant.
Linagliptin may be administered with or without food.
Distribution: The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma.
Plasma binding is not altered in patients with renal or hepatic impairment.
Metabolism: Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin.
Excretion: Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.