Distribution: After oral administration of 14C-labeled racecadotril in healthy volunteers, racecadotril concentration was more than 200 fold higher in plasma than in blood cells and 3-fold higher in plasma than in total blood. Thus, the drug did not bind to blood cells to any significant extent. Radiocarbon distribution in other body tissues was moderate, as indicated by the mean apparent volume of distribution in plasma of 66.4 kg. Ninety percent of the active metabolite of racecadotril (thiorphan=(RS)-N-(1-oxo-2-(mercaptomethyl)-3- phenylpropyl) glycin), is bound to plasma proteins, mainly to albumin.

The duration and extent of the effect of racecadotril are dose dependent. Time to peak plasma enkephalinase inhibition is approximately 2 hours and corresponds to an inhibition of 90% with the dose of 1.5 mg/kg. The duration of plasma enkephalinase inhibition is approximately 8 hours.

Metabolism: The half-life of racecadotril, measured as plasma enkephalinase inhibition, is approximately 3 hours. Racecadotril is rapidly hydrolysed to thiorphan (RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycin, the active metabolite, which is in turn transformed into inactive metabolites identified as sulfoxyde of Smethylthiorphan, S-methyl thiorphan, 2-methanesulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which all were formed at greater than 10% of parent drug systemic exposure.

Additional minor metabolites were also detected and quantified in urine and faeces.

In vitro data indicate that racecadotril/thiorphan and the four major inactive metabolites do not inhibit the major CYP enzymes isoforms 3A4, 2D6, 2C9, 1A2 and 2C19 to an extent that would be clinically relevant. In vitro data indicate that racecadotril/thiorphan and the four major inactive metabolites do not induce the CYP enzymes isoforms (3A family, 2A6, 2B6, 2C9/2C19, 1A family, 2E1) and UGTs conjugating enzymes to an extent that would be clinically relevant.

In the paediatric population, pharmacokinetic results are similar to those of the adult population, reaching Cmax at 2 hours 30 min after administration. There is no accumulation after multiple dose administrated every 8 hours, for 7 days.

Excretion: Racecadotril is eliminated as active and inactive metabolites. Elimination is mainly via the renal route (81.4%), and to a much lesser extent via the faecal route (around 8%). The pulmonary route is not significant (less than 1% of the dose).

5.3 Preclinical safety data
Chronic 4-week toxicity studies in monkeys and dogs, relevant for the duration of treatment in human, do not point out any effect at doses up to 1250 mg/kg/day and 200 mg/kg, respectively corresponding to safety margins of 625 and 62 (vs human). Racecadotril was not immunotoxic in mice given racecadotril for up to 1 month. Longer exposure (1 year) in monkeys showed generalized infections and reduced antibody responses to vaccination at a 500 mg/kg/day dose and no infection/immune depression at 120 mg/kg/day. Similarly in the dog receiving 200 mg/kg/day for 26 weeks some infection/immune parameters were affected. The clinical relevance is unknown see section 4.8.

No mutagenic or clastogenic effect of racecadotril has been found in the standard in vitro and in vivo tests.

Carcinogenicity testing has not been performed with racecadotril as the drug is provided for short-term treatment.

Repro