Zolmitriptan

【 Drug name 】

Name in English: zolmitriptan

Chinese phonetic alphabet: zuomiquputan

【 Traits 】This product is a white like crystalline powder and odorless.This product is freely soluble in methanol, dissolved in ethanol, slightly soluble in chloroform or acetone, and very slightly soluble in water; Soluble in 0.1 mol / L hydrochloric acid solution.

【 Specifications 】1kg / bag

【 Indications 】For the acute treatment of migraine with or without aura symptoms in adults.

【 Pharmacology and toxicology 】pharmacological action

Zolmitriptan is a selective 5 - HTiB / ID receptor agonist. Causes intracranial vasoconstriction and inhibits the release of proinflammatory neuropeptides by agonizing 5 - HTiB / ID receptors on intracranial blood vessels (including arteriovenous anastomoses) and sympathetic nerves in the trigeminal system.

Toxicological studies

Genotoxicity:

Ames test, 2 of 5 S. typhi isolates showed mutagenic effects in the presence of metabolic activators. In vitro mammalian cell mutation test (CHO / HGPRT) was negative. In vivo and in vitro human lymphocyte assays, with or without the presence of metabolic activators, zolmitriptan demonstrated a clastogenic effect on chromosome fission; This effect was not seen in the mouse in vivo micronucleus assay. It has also not been shown to be genotoxic in nonprogrammed DNA synthesis assays.

Reproductive toxicity:

Male and female rats were given zolmitriptan from before mating until implantation at doses up to 400 mg / kg / day (the exposure at this dose is approximately 3000 times the human maximum recommended dose of 10 mg / day) and showed no impairment of fertility.

In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryonic death and abnormal litters. Oral administration of zolmitriptan at 100, 400 and 1200 mg / kg / day to pregnant mice during organogenesis (maternal plasma exposures approximately 280, 1100 and 5000 times the human daily maximum recommended dose of 10 mg, respectively) resulted in dose related increases in embryonic mortality that were statistically significant at high doses. High doses produce maternal toxicity manifested by reduced maternal weight growth during pregnancy. In a similar trial in rabbits, embryonic mortality was increased at maternal toxic doses of 10 and 30 mg / kg / day (maternal plasma exposure equivalent to 11 and 42 times the maximum daily recommended dose of 10 mg exposure that a person receives). At a dose of 30 mg / kg / day, an increased incidence of malformations (sternal fusion, rib anomalies) and variants (major vascular variants, irregular ossification patterns of the ribs) in the litters was observed. 3 mg / kg / day for a no effect dose (equivalent to the human exposure at the 10 mg dose). The administration of zolmitriptan during pregnancy, labor, and lactation in female rats revealed an increased incidence of hydronephrosis in the offspring at a maternal toxic dose of 400 mg / kg / day (1100 times the human exposure).

One hour after zolmitriptan administration in lactating rats, drug levels in milk were comparable to maternal plasma levels, and 4 h was four times the plasma levels.

Carcinogenicity:

The carcinogenicity study of zolmitriptan administered by gavage at a dose of 400 mg / kg / D was performed on both large and small mice. Administration periods were 92 and 85 weeks in female and male mice, respectively, and the exposure (plasma AUC of protozoa) at the highest dose was approximately 800 times that at a single dose of 10 mg (maximum daily recommended dose) in humans, resulting in no effect of zolmitriptan on tumor incidence. For the rat assays, rats in the control, low dose, and medium dose groups were dosed for 104-105 weeks, and the high dose group was sacrificed after 101 weeks (males) and 86 weeks (females) due to excessive mortality, resulting in the development of thyroid follicular cell hyperplasia and an increased incidence of thyroid follicular cell adenoma in male rats only in the 400 mg / kg / day (approximately 3000 fold the exposure after a human dose of 10 mg) group.

【 Pharmacokinetics 】

Zolmitriptan is absorbed rapidly after oral administration, reaching 75% of the peak plasma concentration within 1 h, and the plasma concentration is subsequently maintained for 4-6 H. The mean absolute bioavailability of the parent compound was approximately 40%. There is an active metabolite, the N-demethyl metabolite, which is also a 5htid agonist. Results from animal tests suggest that its potency is 2-6 times that of zolmitriptan. After administration of a single dose of zolmitriptan to healthy adults, the area under the curve and peak plasma concentration of zolmitriptan and its active metabolites were both positively dose proportional in the 2.5-50 mg dose range. Zolmitriptan absorption was not affected by food.

Zolmitriptan is mainly biotransformed by the liver, and the metabolites are then excreted in the urine. The three main metabolites were: indoleacetic acid (the major metabolite in plasma and urine), N-oxide, and N-demethyl metabolites. The N-demethyl metabolite was active, and the other metabolites were inactive. The plasma concentration of the N-demethyl metabolite was approximately half that of the parent drug; Therefore, it is expected to contribute to the therapeutic effects of the present drug. More than 60% of an oral single dose is excreted in the urine (mainly indoleacetic acid metabolite) and the other approximately 30% is excreted in the feces as the parent compound in its original form. The renal clearance of this product is greater than the glomerular filtration rate, suggesting the presence of tubular secretion.

Plasma protein was poorly bound (approximately 25%) and had an average clearance half-life of 2.5-3 HR, and similar half lives were observed for their metabolites, suggesting that their clearance is limited by turnover rate. Patients with moderate to severe renal impairment compared with healthy subjects showed reduced renal clearance of zolmitriptan and its metabolites (7 - to 8-fold), despite only modest increases in the area under the curve for the parent compound and its active metabolite (16% and 35%, respectively) and increased half-life. Zolmitriptan did not produce accumulation after multiple administrations.

【 Approval No.】NMPN H20050071