Tianeptine

Tianeptine is an antidepressant.

In animals, tianeptine has the following properties:

• Tianeptine increases the spontaneous activity of pyramidal cells in the hippocampus and accelerates their recovery after functional inhibition.
• Tianeptine increases the rate of serotonin re-uptake by neurones in the cortex and hippocampus and moderately increases dopamine levels in limbic areas.
• Tianeptine has no in vitro affinity for monoaminergic receptors and does not inhibit the uptake of 5-HT, NA or DA. Tianeptine might modulate the synaptic glutamatergic neurotransmission

The precise contribution of each effect to the antidepressant activity is unknown.

Absorption

Gastrointestinal absorption is rapid and complete with negligible influence of food.

Distribution

Distribution is rapid, and is associated with a high level of protein binding (approximately 94%), primarily to albumin.

Biotransformation

The molecule is extensively metabolised in the liver by the processes of beta-oxidation not through the CYP450 pathway. Its major metabolite is the active pentanoic acid (MC5) less potent than tianeptine.

Elimination

Elimination of tianeptine is characterized by a short terminal half-life of 3 hours with most metabolites recovered in urine.

Elderly, very old and frail patients

In elderly patients, the concentrations of tianeptine were increased by 30% and that of MC5 were approximately doubled after single and repeated administrations compared to younger ones.

In very old (87 ± 5 years) and frail (45 ± 9 kg) patients, a significant increase in C_max and AUC of tianeptine and MC5 after single administration was observed.

Patients with severe renal impairment (CLCR <19 ml/min)

Tianeptine pharmacokinetics is unchanged but the MC5 AUC is approximately doubled following single and repeated administrations.

Patients with severe hepatic cirrhosis (Class C, Child Pugh’s Scale)

AUC of both tianeptine and MC5, following a 12.5mg dose intake, increase as compared to the adult depressed patients.

In milder conditions of cirrhosis, such as for chronic alcoholics, effects on pharmacokinetic parameters are negligible.

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenicity. In a conventional fertility study, an increase in pre-implantation losses was observed at the maternotoxic dose of 45 mg/kg/day (about 12 times the human dose based on BSA). Tianeptine was not teratogenic in rats and rabbits.

In a peri- and postnatal study, dysgalactia in the dams and increased post-implantation and post-natal losses were observed in rats at a maternotoxic dose of 45 mg/kg/day (about 12 times the human dose based on BSA).