Clinic Diabetes


Linagliptin and metformin hydrochloride

  • TRAJENTAMET are film-coated tablets for oral administration:
    -TRAJENTAMET 2.5 mg/500 mg contains 2.5 mg linagliptin and 500 mg metformin hydrochloride
    -TRAJENTAMET 2.5 mg/850 mg contains 2.5 mg linagliptin and 850 mg metformin hydrochloride
    -TRAJENTAMET 2.5 mg/1000 mg contains 2.5 mg linagliptin and 1000 mg metformin hydrochloride.

  • Bioequivalence studies in healthy subjects demonstrated that the TRAJENTAMET (linagliptin/metformin hydrochloride) combination tablets are bioequivalent to co-administration of linagliptin and metformin hydrochloride as individual tablets following a single dose.
  • Administration of TRAJENTAMET 2.5 mg/1000 mg with food resulted in no change in overall exposure of linagliptin. With metformin there was no change in AUC, however mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time to peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely to be clinically significant.
  • Linagliptin -The pharmacokinetics of linagliptin has been extensively characterized in healthy subjects and individuals with type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteers, linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours post dose.
  • Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life (terminal half-life for linagliptin more than 100 hours), that is mostly related to the saturable, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of 5 mg linagliptin are reached by the third dose.
  • Plasma AUC of linagliptin increased approximately 33% following 5 mg doses at steady state compared to the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively).
  • Plasma AUC of linagliptin increased in a less than dose-proportional manner. The pharmacokinetics of linagliptin were generally similar in healthy subjects and in individuals with type 2 diabetes.

  • The absolute bioavailability of linagliptin is approximately 30%. Because co-administration of a high fat meal with linagliptin had no clinically relevant effect on the pharmacokinetics, linagliptin may be administered with or without food.

  • As a result of tissue binding, the mean apparent volume of distribution at steady state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1110 litres, 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 the peak plasma concentration in humans at 5 mg/day, approximately 10% of linagliptin is unbound.

  • Following a [14C] linagliptin oral 10 mg dose, approximately 5% of the radioactivity was excreted in urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with a relative exposure of 13.3% of linagliptin at steady state was detected and was found to be pharmacologically inactive and thus does not contribute to the plasma DPP-4 inhibitory activity of linagliptin.

  • Absorption: After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
    After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption is non-linear.
    At the recommended metformin hydrochloride doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/mL. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 5 microgram/mL, even at maximum doses.
    Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35-minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
  • Distribution: Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 L.
  • Metabolism: Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.
  • Excretion: Renal clearance of metformin hydrochloride is > 400 mL/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
    When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin hydrochloride in plasma.

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