Rizatriptan

Rizatriptan binds selectively with high affinity to human 5-HT_1B and 5-HT_1D receptors and has little or no effect or pharmacological activity at 5-HT₂, 5-HT₃; adrenergic alpha₁, alpha₂ or beta; D₁, D₂, dopaminergic, histaminic H₁; muscarinic; or benzodiazepine receptors.

The therapeutic activity of rizatriptan in treating migraine headache may be attributed to its agonist effects at 5-HT_1B and 5-HT_1D receptors on the extracerebral intracranial blood vessels that are thought to become dilated during an attack and on the trigeminal sensory nerves that innervate them. Activation of these 5-HT_1B and 5-HT_1D receptors may result in constriction of pain producing intracranial blood vessels and inhibition of neuropeptide release that leads to decreased inflammation in sensitive tissues and reduced central trigeminal pain signal transmission.

Absorption

Rizatriptan is rapidly and completely absorbed following oral administration. The mean oral bioavailability of the tablet is approximately 40-45%, and mean peak plasma concentrations (C_max) are reached in approximately 1-1.5 hours (T_max). Administration of an oral tablet dose with a high-fat breakfast had no effect on the extent of rizatriptan absorption, but absorption was delayed for approximately one hour.

Effect of Food

The effect of food on the absorption of rizatriptan from the oral lyophilisate has not been studied. For the rizatriptan tablets, T_max is delayed by approximately 1 hour when the tablets are administered in the fed state. A further delay in the absorption of rizatriptan may occur when the oral lyophilisate is administered after meals.

Distribution

Rizatriptan is minimally bound (14%) to plasma proteins. The volume of distribution is approximately 140 litres in male subjects, and 110 litres in female subjects.

Biotransformation

The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not pharmacologically active. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT_1B/1D receptors, is formed to a minor degree, but does not contribute significantly to the pharmacodynamic activity of rizatriptan. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites include the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite. None of these minor metabolites is pharmacologically active. Following oral administration of ¹⁴C-labelled rizatriptan, rizatriptan accounts for about 17% of circulating plasma radioactivity.

Elimination

Following intravenous administration, AUC in men increases proportionally and in women near-proportionally with the dose over a dose range of 10-60 1g/kg. Following oral administration, AUC increases near-proportionally with the dose over a dose range of 2.5-10 mg. The plasma half-life of rizatriptan in males and females averages 2-3 hours. The plasma clearance of rizatriptan averages about 1,000-1,500 mL/min in males and about 900-1,100 mL/min in females; about 20-30% of this is renal clearance. Following an oral dose of ¹⁴C-labelled rizatriptan, about 80% of the radioactivity is excreted in urine, and about 10% of the dose is excreted in faeces. This shows that the metabolites are excreted primarily via the kidneys.

Consistent with its first pass metabolism, approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite. No more than 1% is excreted in urine as the active N-monodesmethyl metabolite.

If rizatriptan is administered according to the maximum dosage regimen, no drug accumulation in the plasma occurs from day to day.

Characteristics in Patients

Patients with a migraine attack

A migraine attack does not affect the pharmacokinetics of rizatriptan.

Gender

The AUC of rizatriptan (10 mg orally) was about 25% lower in males as compared to females, C_max was 11% lower, and T_max occurred at approximately the same time. This apparent pharmacokinetic difference was of no clinical significance.

Elderly

The plasma concentrations of rizatriptan observed in elderly subjects (age range 65 to 77 years) were similar to those observed in young adults.

Paediatric population

A pharmacokinetics study of rizatriptan (as the oral lyophilisates formulation) was conducted in paediatric migraineurs 6 to 17 years of age. The mean exposures following a single dose administration of 5 mg rizatriptan oral lyophilisates to paediatric patients weighing 20-39 kg or 10 mg rizatriptan oral lyophilisates to paediatric patients weighing ≥40 kg were respectively 15% lower and 17% higher compared to the exposure observed following single dose administration of 10 mg rizatriptan oral lyophilisates to adults. The clinical relevance of these differences is unclear.

Hepatic impairment (Child-Pugh’s score 5-6)

Following oral administration in patients with hepatic impairment caused by mild alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar to those seen in young male and female subjects. A significant increase in AUC (50%) and C_max (25%) was observed in patients with moderate hepatic impairment (Child-Pugh’s score 7). Pharmacokinetics were not studied in patients with Child-Pugh’s score >7 (severe hepatic impairment).

Renal impairment

In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m²), the AUC of rizatriptan was not significantly different from that in healthy subjects. In haemodialysis patients (creatinine clearance <10 mL/min/1.73 m²), the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function. The maximal plasma concentration of rizatriptan in patients with all degrees of renal impairment was similar to that in healthy subjects.

Preclinical data indicate no risk for humans based on conventional studies of repeat dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity, safety pharmacology, and pharmacokinetics and metabolism.