Source: Marketing Authorisation Holder Revision Year: 2018 Publisher: Dafra Pharma GmbH, Mühlenberg 7, 4052 Basel, Switzerland Manufacturer: Bilim Pharmaceuticals, GOSB 41480 Gebze, Kocaeli, Turkey
Pharmacotherapeutic group: centrally acting myorelaxant
ATC code: M03BX05
Thiocolchicoside is a sulphur-containing, synthetic analogue of a natural colchicum glucoside which behaves pharmacologically as a muscle relaxant, both in humans and in animals. It eliminates, or substantially decreases, centrally originating muscle contracture: in spastic hypertonia, it reduces the muscle's passive resistance to stretching and decreases, or removes, the residual contracture. Its muscle-relaxing effect can also be observed on the visceral muscles: it has, in particular, been demonstrated on the uterus.
However, thiocolchicoside has no curariform effect, since it acts through the central nervous system rather than paralysing the muscle's motor plaque. The pharmacological mode of action of thiocolchicoside has been partially explained: research conducted in 2003 and 2007 has shown that its myorelaxant activity may be caused by an agonist action on the glycine receptors located primarily in the brain stem and the spinal cord. Thiocolchicoside does not, therefore, impair voluntary motility or cause paralysis, and thus is devoid of any respiratory risk.
Thiocolchicoside has no influence on the cardiovascular system.
Lastly, thiocolchicoside also acts as an antagonist of A-type GABA receptors (mainly located in the cerebral cortex), this pharmacological action being known to have convulsant or pro-convulsant properties.
Following oral administration, thiocolchicoside is undetectable in plasma. Only two metabolites are observed: the pharmacologically active metabolite SL18.0740 and the inactive metabolite SL59.0955. For these two metabolites, the maximum plasma concentrations occur 1 hour after thiocolchicoside administration.
After a single oral dose of 8 mg of thiocolchicoside, the Cmax and AUC for SL18.0740 are approximately 60 ng/ml and 130 ng.h/ml, respectively. For SL59.0955, these values are significantly lower: Cmax approximately 13 ng/ml and AUC from 15.5 ng.h/ml (AUC calculated up to 3h) to 39.7 ng.h/ml (AUC up to 24h).
After intramuscular (IM) administration, the maximum plasma concentration (Cmax) for thiocolchicoside occurs in 30 min and reaches values of 113 ng/ml after a 4 mg dose, and 175 ng/ml after an 8 mg dose. The corresponding AUC values (area under curve) are, respectively, 283 and 417 ng.h/ml.
The pharmacologically active metabolite SL18.0740 is also observed at lower concentrations with a Cmax at 11.7 ng/ml occurring 5 hours following administration of thiocolchicoside and an AUC of 83 ng.h/ml. There are no data regarding the inactive metabolite SL59.0955.
The apparent volume of distribution of thiocolchicoside is estimated to be approximately 42.7LI after an 8 mg intramuscular administration. There is no data regarding the two metabolites.
Following oral administration, thiocolchicoside is initially metabolised to aglycone 3-demethyl thiocolchicine or SL59.0955. This step occurs mainly through intestinal metabolism, which explains the absence of unmodified thiocolchicoside through this route of administration. SL59.0955 is then glucuro-conjugated into SL18.0740, which has a pharmacological activity equivalent to thiocolchicoside, and therefore contributes to the pharmacological activity following oral administration of thiocolchicoside. SL59.0955 is also demethylated into didemethyl-thiocolchicine.
Following oral administration of radio-labelled thiocolchicoside, total radioactivity is mainly excreted in the faeces (79%), while urine excretion only represents 20%. Unmodified thiocolchicoside is not excreted in the urine or faeces. SL18.0740 and SL59.0955 are found in the urine and faeces, while didemethyl-thiocolchicine is only found in the faeces.
Following oral administration of thiocolchicoside, the SL18.0740 metabolite is eliminated with an apparent t1/2 ranging from 3.2 to 7 hours, and the SL59.0955 metabolite with a t1/2 of approximately 0.8 hours.
The toxicology profile of thiocolchicoside has been evaluated in vitro, and in vivo following parenteral and oral administration.
Thiocolchicoside is well tolerated following repeated oral administration up to 6 months in rats and non-human primates at doses ≤2 mg/kg daily in rats and 2.5 mg/kg daily in non-human primates, and following repeated intramuscular administration for 4 weeks in primates at doses up to 0.5 mg/kg daily. At higher doses, following a single oral administration, thiocolchicoside causes vomiting in dogs, diarrhoea in rats, and seizures in rodents and non-rodents.
Following repeated administration, thiocolchicoside caused gastro-intestinal disorders (enteritis, vomiting) when administered orally, and vomiting when administered intramuscularly.
Thiocolchicoside itself does not induce gene mutation in bacteria (Ames test), in vitro chromosomal aberration (chromosomal aberration test on human lymphocytes), or in vivo chromosomal aberration (in vivo micronucleus assay in mouse bone marrow following intraperitoneal administration).
The main glucuro-conjugated metabolite SL18.0740 does not induce gene mutation in bacteria (Ames test); it does, however, cause in vitro chromosomal aberrations (in vitro micronucleus assay on human lymphocytes) and in vivo chromosomal aberrations (in vivo micronucleus assay in mouse bone marrow following oral administration). The micronuclei resulted mainly from chromosome loss (presence of centromere in the micronuclei revealed by centromere-specific FISH staining), suggesting aneugenic properties. The aneugenic effect of SL18.0740 was observed at concentrations (in the in vitro test) and plasma exposures (in the in vivo test) which were higher (over 10-fold, based on AUC) than those observed in human plasma at therapeutic doses.
The aglycone metabolite (3-demethyl-thiocolchicine, or SL59.0955), formed mainly following oral administration, does induce in vitro chromosomal aberrations (in vitro micronucleus assay on human lymphocytes) and in vivo chromosomal aberrations (in vivo micronucleus assay in rat bone marrow following oral administration). The micronuclei resulted mainly from chromosome loss (presence of centromere in the micronuclei revealed by centromere-specific FISH or CREST staining), suggesting aneugenic properties. The aneugenic effect of SL59.0955 was observed at concentrations (in the in vitro test) and exposures (in the in vivo test) close to those observed in human plasma at therapeutic doses of 8 mg administered twice daily per os. The aneugenic effect in dividing cells may result in aneuploid cells.
Aneuploidy is a modification in the number of chromosomes and a loss of heterozygosis, which has been recognised as a risk factor for teratogenesis, embryotoxicity/spontaneous abortion, and impaired male fertility when impacting germ cells, and as a potential risk factor for cancer when impacting somatic cells. As the presence of the aglycone metabolite (3-demethyl-thiocolchicine, or SL59.0955) following intramuscular administration has never been evaluated, its formation through this route of administration cannot be ruled out.
In rats, a daily oral dose of 12 mg/kg of thiocolchicoside caused major malformations and foetotoxicité (delayed growth, embryo death, alteration of the sex distribution ratio). The dose level with no toxic effect was 3 mg/kg daily. In rabbits, thiocolchicoside showed maternal toxicity starting from 24 mg/kg daily. In addition, minor abnormalities were observed (supernumerary ribs, delayed ossification). In a rat fertility toxicity study, no fertility impairment was observed at doses up to 12 mg/kg daily, i.e. at dose levels not inducing any clinical effect. Thiocolchicoside and its metabolites exert aneugenic activity at various dose levels, which is recognised as a risk factor for impairment of human fertility. The carcinogenic potential has not been evaluated.
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