SUMMARYRufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V d /F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of −13.7% in female children comedicated with vigabatrin to a maximum of −46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from plac...

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Naratriptan is a novel, potent agonist at the 5HT1B/1D receptor. A total of 335 migraine patients were treated in this randomized, double-blind, placebo-controlled, dose-ranging, in-clinic study, to evaluate the efficacy, safety and tolerability of five doses of subcutaneous (sc) naratriptan (0.5, 1, 2.5, 5 or 10 mg) in comparison with sc sumatriptan (6 mg) and placebo in the acute treatment of a moderate/severe migraine attack. Headache relief [reduction of headache severity from moderate or severe (grade 2/3) to mild or none (grade 1/0)] at 1 and 2 h after each dose, was reported by a statistically significantly higher proportion of patients for all doses of sc naratriptan and sc sumatriptan (6 mg) than for placebo. The percentages of patients with headache relief at 2 h post-dose were: naratriptan (0.5 mg) 65%, (1 mg) 75%, (2.5 mg) 83%, (5 mg) 94% and (10 mg) 91%; sumatriptan (6 mg) 89%; placebo 41%, (P < 0.005). The earliest report of a statistically significant difference compared with placebo for the times assessed was with sc naratriptan (10 mg) at 10 min post-dose (P = 0.023). The percentages of patients reporting adverse events were dose-related; sc naratriptan (0.5 mg) 33%, (1 mg) 29%, (2.5 mg) 43%, (5 mg) 59% and (10 mg) 71%; sc sumatriptan 53%; placebo 22%. There were no clinically significant changes in electrocardiogram (ECG), vital signs or laboratory parameters. Systemic exposure increased proportionally to the dose, the absorption of sc naratriptan was rapid (tmax = 10 min) and the half-life was 5 h. In conclusion, sc naratriptan was an effective and well-tolerated acute treatment for migraine. Copyright 1998 Lippincott Williams & Wilkins

We describe a variation on an approach to simultaneous modeling of pharmacokinetics (PK) and pharmacodynamics (PD). Both approaches model the often-observed time lag between plasma drug concentration (Cp) and drug effect (E) in non-steady-state experiments by postulating an E site whose concentration (Ce) is kinetically linked to Cp by a first-order process. With the linking model, the time lag can be removed from the data and the underlying concentration-response (Ce-E) relationship can be estimated. The original method requires the analyst to postulate a particular parametric form for the Ce-E model, whereas ours does not. It estimates the rate constant of the linking model as the value that causes the hysteresis curve (Ce vs E points connected in time order) to collapse to a single curve that represents the (empirical) Ce-E relationship. The method is presented as an algorithm and is tested by means of simulation and a real-world example. The results suggest that the method can faithfully estimate the Ce-E curve for a variety of PD models and degrees of experimental error when its basic assumption of time-invariant PD holds.

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.