Clinical Pharmacokinetics of Intranasal Sumatriptan

Abstract

A substantial proportion of migraine patients have gastric stasis and suffer severe nausea and/or vomiting during their migraine attack. This may lead to erratic absorption from the gastrointestinal tract and make oral treatment unsatisfactory. For such patients, an intranasal formulation may be advantageous. Sumatriptan is a potent serotonin 5HT(1B/1D) agonist widely used in the treatment of migraine; the effectiveness of the intranasal formulation (20mg) has been well established in several clinical studies. This article reviews the pharmacokinetics of intranasal sumatriptan and includes comparisons with oral and subcutaneous administration. After intranasal administration, sumatriptan is directly and rapidly absorbed, with 60% of the maximum plasma concentration (C(max)) occurring at 30 minutes after administration of a single 20mg dose. Following intranasal administration, approximately 10% more sumatriptan is absorbed probably via the nasal mucosa when compared with oral administration. Mean C(max) after a 20mg intranasal dose is approximately 13.1 to 14.4 ng/mL, with median time to C(max) approximately 1 to 1.75 hours. When given as a single dose, intranasal sumatriptan displays dose proportionality in its extent of absorption and C(max) over the dose range 5 to 10mg, but not between 5 and 20mg for C(max). The elimination phase half-life is approximately 2 hours, consistent with administration by other routes. Sumatriptan is metabolised by monoamine oxidase (MAO; predominantly the A isozyme, MAO-A) to an inactive metabolite. Coadministration with a MAO-A inhibitor, moclobemide, leads to a significant increase in sumatriptan plasma concentrations and is contraindicated. Single-dose pharmacokinetics in paediatric and adolescent patients following intranasal sumatriptan were studied to determine the effect of changes in nasal morphology during growth, and of body size, on pharmacokinetic parameters. The pharmacokinetic profile observed in adults was maintained in the adolescent population; generally, factors such as age, bodyweight or height did not significantly affect the pharmacokinetics. In children below 12 years, C(max) is comparable to that seen in adolescents and adults, but total exposure (area under the concentration-time curve from zero to infinity) was lower in children compared with older patients, especially in younger children treated with 5mg. Clinical experience suggests that intranasal sumatriptan has some advantages over the tablet (more rapid onset of effect and use in patients with gastrointestinal complaints) or subcutaneous (noninvasive and fewer adverse events) formulations.

Unanticipated Acyloxymethylation of Sumatriptan Indole Nitrogen Atom and its Implications in Prodrug Design

“…(1) adequately describes the degradation kinetics of compound 4a. The kinetically determined pK a value is 9.26, which is close to, but lower than that for ionisation of the dimethylamino group in sumatriptan (pK a 9.63 [25]), and thus is also consistent with incorporation of the acyloxymethyl moiety at the indole nitrogen atom.…”

Preliminary brain-targeting studies on intranasal mucoadhesive microemulsions of sumatriptan

“…Reports in the literature revealed that following intranasal administration, preferential nose-to-brain transport bypassing the BBB occurred due to the unique connection between the nose and the CNS. 11,12,32 The SME (intranasal) shows significantly higher brain/ blood ratio at 0.5 hour compared with SSS and SMP (intranasal) and showed rapid nose-to-brain transport of ST from microemulsion. SME and SMME show 2-fold higher C max and 8-fold higher AUC compared with SMP.…”

“…A substantial proportion of migraine patients not only suffer from gastric stasis but also have severe nausea and vomiting, which results in erratic absorption of ST from the gastrointestinal tract. 5 ST is rapidly but incompletely absorbed following oral administration and undergoes first-pass metabolism, resulting in a low absolute bioavailability of 14% in humans. 6 Moreover, the transport of ST across the blood-brain barrier (BBB) is very poor, although evidence of detection of some drug in cerebrospinal fluid (CSF) following high IV dose has been cited in the literature.…”

Tablets and Other Solid Dosage Forms for Systemic Oral Mucosal Drug Delivery

“…Nasal administration is given at 10 or 20 mg, whereas subcutaneous formulation requires 6 mg every 24 h. The mean bioavailability is 96 % with subcutaneous administration and decreases to approximately 14 and 25 % with oral and nasal administration [27,28]. The lower bioavailability in the oral and nasal route is due to the incomplete absorption followed with high first-pass metabolism.…”