Pharmacotherapeutic Group: Other antidiarrhoeals. ATC Code: A07XA04.
Racecadotril is a prodrug that needs to be hydrolysed to its active metabolite thiorphan, which is an inhibitor of enkephalinase, a cell membrane peptidase enzyme located in various tissues, notably the epithelium of the small intestine.
This enzyme contributes both to the hydrolysis of exogenous peptides and to the breakdown of endogenous peptides eg, enkephalins.
Racecadotril protects enkephalins from enzymatic degradation, thereby prolonging the action at enkephalinergic synapses in the small intestine and reducing hypersecretion.
Racecadotril is a pure intestinal antisecretory active substance. It decreases the intestinal hypersecretion of water and electrolytes induced by the cholera toxin or inflammation, and does not have effects on basal secretory activity. Racecadotril exerts rapid antidiarrhoeal action, without modifying the duration of intestinal transit.
In 2 clinical studies in children, racecadotril reduced by 40% and 46%, respectively, the stool weights in the first 48 hrs. A significant reduction in the duration of the diarrhoea and the need for rehydration was also observed.
An individual patient data meta-analysis (9 randomised clinical trials racecadotril versus placebo, in addition to oral rehydration solution) collected individual patient data from 1384 boys and girls suffering from acute diarrhoea of miscellaneous severity and treated as in- or out-patients. The median age was 12 months (interquartile range: 6-39 months).
A total of 714 patients were <1 year and 670 patients were >1 year old. Mean weight ranged from 7.4-12.2 kg across studies. The overall median diarrhoea duration after inclusion was 2.81 days for placebo and 1.75 days for racecadotril.
The proportion of recovered patients was higher in racecadotril groups compared with placebo [Hazard Ratio (HR): 2.04; 95%CI: 1.85-2.32; p<0.001; Cox proportional hazards regression]. Results were very similar for infants (<1 year) (HR: 2.01; 95%CI: 1.71-2.36; p<0.001) and toddlers (>1 year) (HR: 2.16; 95%CI: 1.83-2.57; p<0.001).
For inpatient studies (n=637 patients), the ratio of mean stool output racecadotril/placebo was 0.59 (95%CI: 0.51-0.74); p<0.001).
For outpatient studies (n=695 patients), the ratio of the mean number of diarrhoeic stools racecadotril/placebo was 0.63 (95%CI: 0.47-0.85; p<0.001).
Racecadotril does not produce abdominal distension. During its clinical development, racecadotril produced secondary constipation at a rate comparable to placebo.
When administered via the oral route, its activity is exclusively peripheral, with no effects on the central nervous system.
A randomized crossover study demonstrated that racecadotril 100-mg capsule at therapeutic dose (1 capsule) or at supratherapeutic dose (4 capsules) did not induce QT/QTc prolongation in 56 healthy volunteers (at the opposite of moxifloxacin, used as a positive control).
Pharmacokinetics: Absorption: Following oral administration, racecadotril is rapidly absorbed.
Distribution: After oral administration of 14C-labeled racecadotril in healthy volunteers, racecadotril concentration was >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 olume 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) glycine), 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 hrs and corresponds to an inhibition of 90% with the dose of 1.5 mg/kg. The duration of plasma enkephalinase inhibition is approximately 8 hrs.
Metabolism: The half-life of racecadotril, measured as plasma enkephalinase inhibition, is approximately 3 hrs. Racecadotril is rapidly hydrolysed to thiorphan (RS)-N-(1-oxo-2- (mercaptomethyl)-3-phenylpropyl) glycine, the active metabolite, which is in turn transformed into inactive metabolites identified as sulfoxyde of S-methylthiorphan, S-methyl thiorphan, 2-methanesulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which all were formed at >10% of parent drug systemic exposure.
Additional minor metabolites were also detected and quantified in urine and faeces.
Repeated administration of racecadotril does not cause any accumulation in the body.
In vitro data indicate that racecadotril/thiorphan and the 4 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 4 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.
Racecadotril does not modify protein-binding of active substances strongly bound to proteins eg, tolbutamide, warfarin, niflumic acid, digoxin or phenytoin.
In patients with liver failure (cirrhosis, Child-Pugh Grade B), the kinetic profile of the active metabolites of racecadotril showed similar time to maximum plasma concentration (Tmax) and half-life, and lesser maximum plasma concentration (Cmax) -65% and area under the concentration-time curve (AUC) -29% as compared to healthy subjects.
In patients with severe renal failure [creatinine clearance (CrCl) 11-39 mL/min], the kinetic profile of the active metabolite of racecadotril showed smaller Cmax (-49%) and greater AUC (+16%), and half-life as compared to healthy volunteers (CrCl >70 mL/min).
In the paediatric population, pharmacokinetic results are similar to those of the adult population, reaching Cmax at 2 hrs 30 min after administration. There is no accumulation after multiple dose administrated every 8 hrs, 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 (<1% of the dose).
Toxicology: 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 (versus 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 Adverse Effects.
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.
Reproductive and developmental toxicity (fertility and early embryonic development, prenatal and postnatal development including maternal function, embryo-foetal development studies) have not revealed any special effects of racecadotril.
A toxicity study in juvenile rats has not revealed any significant effects of racecadotril up to a dose of 160 mg/kg daily which is 35 times higher than the usual paediatric regimen (ie, 4.5 mg/kg daily). Despite the immature renal function in children <1 year, higher exposure levels are not expected in these individuals.
Other preclinical effects (eg, severe, most likely aplastic anaemia, increased diuresis, ketonuria, diarrhoea) were observed only at exposures considered sufficiently in excess of maximum human exposure.
The clinical relevance is unknown.
Other safety pharmacology studies did not evidence any deleterious effects of racecadotril on the central nervous system, the cardiovascular and the respiratory functions.
In animals, racecadotril reinforced the effects of butylhyoscine upon bowel transit and on the anticonvulsive effects of phenytoin.