Christopher R. Lines

Lack of Efficacy of the Substance P (Neurokinin1 Receptor) Antagonist Aprepitant in the Treatment of Major Depressive Disorder

BACKGROUNDnAn early clinical trial suggested that the substance P (neurokinin(1) receptor) antagonist, aprepitant, might provide a unique mechanism of antidepressant activity. Phase III trials were conducted to confirm these findings.nnnMETHODSnFive 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depressive Disorder were performed. Aprepitant 160 mg and placebo were included in all trials. Aprepitant 80 mg and paroxetine 20 mg (active comparator) were included in three trials. Approximately 150 patients were enrolled per treatment group in each trial. The primary end point was the mean change-from-baseline of the first 17 items of the Hamilton Rating Scale for Depression (HAM-D(17)) score at 8 weeks. A positron emission tomography (PET) study was also performed in normal subjects to determine the relationship between neurokinin(1) receptor occupancy and aprepitant plasma concentrations in dosing regimens relevant to the trials.nnnRESULTSnNo statistically significant differences from placebo on the HAM-D(17) were observed at week 8 for either dose of aprepitant in any of the trials, whereas paroxetine 20 mg was significantly (p <or= .05) more effective than placebo at week 8 in each of the three trials in which it was included. Results from the PET study indicated that the aprepitant dosing regimens provided continuously high levels of neurokinin(1) receptor blockade over 8 weeks.nnnCONCLUSIONSnBecause the methodology employed confirmed the antidepressant efficacy of paroxetine, the absence of an effect for aprepitant indicates that it was not an effective treatment for depression. The concept of neurokinin(1) receptor antagonism as an antidepressant mechanism was not supported.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

Aprepitant is a neurokinin1 receptor antagonist that enhances prevention of chemotherapy‐induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5‐hydroxytryptamine3 (5‐HT3) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study.

Effect of Rizatriptan and Other Triptans on the Nausea Symptom of Migraine: A Post Hoc Analysis

Objective.—To compare the effects of oral rizatriptan, sumatriptan, naratriptan, and zolmitriptan on the relief and emergence of nausea during a migraine attack.

Rizatriptan in the Treatment of Migraine

Rizatriptan is a selective 5-hydroxytriptamine1B/1D receptor agonist that was launched in 1998 for the acute treatment of migraine in adults. Based on data from 6 large clinical trials in patients > or =18 years of age in whom migraine was diagnosed according to International Headache Society criteria, the marketed 10-mg and 5-mg oral doses of rizatriptan are effective in relieving headache pain and associated migraine symptoms. The 10-mg dose is more effective than the 5-mg dose. At 2 hours after dosing, up to 77% of patients taking rizatriptan 10 mg had pain relief compared with 37% of those taking placebo, up to 44% were completely pain free compared with 7% of those taking placebo, and up to 77% were free of nausea compared with 58% of those taking placebo (P < 0.05 for all 3 comparisons). Both doses of rizatriptan are generally well tolerated. In placebo-controlled studies involving treatment of a single migraine attack, the most common side effects (incidence > or =2%) occurred in <10% of patients, typically were transitory (2 to 3 hours), and were mild or moderate. Rizatriptan is an effective and well-tolerated acute treatment for migraine.

Next-day residual effects of gaboxadol and flurazepam administered at bedtime: a randomized double-blind study in healthy elderly subjects.

To evaluate the next‐day residual effects of the novel hypnotic, gaboxadol, following bedtime dosing in healthy elderly subjects.

Restoring Migraine Sufferers’ Ability to Function Normally: A Comparison of Rizatriptan and Other Triptans in Randomized Trials

Background: Many migraine patients are unable to function normally during a migraine attack. Assessments of treatment efficacy have tended to focus on migraine symptoms, rather than looking at functional impact. This study compared the efficacy of different oral triptans for restoring normal function in migraine sufferers. Methods: Retrospective subgroup analysis of data from five randomized, placebo-controlled, double-blind clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (772 attacks), 50 mg (2,227 attacks), and 25 mg (1,182 attacks), naratriptan 2.5 mg (413 attacks), and zolmitriptan 2.5 mg (578 attacks) for the acute treatment of a moderate or severe migraine attack. Functional disability was evaluated by patients on a 4-grade scale (‘normal’, ‘mild impairment’, ‘severe impairment’, ‘requires bedrest’) at baseline and at 0.5, 1, 1.5, 2, 3 and 4 h after dosing. This analysis looked at the percentage of patients who had normal functional ability at 2 h, the last time point before escape medications were allowed, in the subgroup of patients who had some level of disability at baseline. Results: Most patients in each trial and treatment group had some level of disability at baseline (range = 94–100%). At 2 h, more patients on rizatriptan 10 mg were able to function normally compared with sumatriptan 100 mg (39 vs. 32%, odds ratio = 1.4, p = 0.021), sumatriptan 50 mg (47 vs. 42%, odds ratio = 1.2, p = 0.033), sumatriptan 25 mg (48 vs. 36%, odds ratio = 1.7, p < 0.001), naratriptan 2.5 mg (39 vs. 22%, odds ratio = 2.5, p < 0.001), and zolmitriptan 2.5 mg (45 vs. 36%, odds ratio = 1.6, p = 0.008). Conclusion: In direct head-to-head comparative clinical trials, oral rizatriptan 10 mg enabled more migraine sufferers to function normally at 2 h after dosing than oral sumatriptan, naratriptan, and zolmitriptan.

Sum of Pain Intensity Differences (SPID) in migraine trials. A comment based on four rizatriptan trials

Sum of Pain Intensity Difference (SPID) is an outcome measure that summarizes treatment response over a clinically relevant period. SPID is widely reported in clinical trials of analgesics but has been little used in migraine trials. We compared SPID over 2 h with the standard migraine outcome measures of pain-free at 2 h and headache relief at 2 h using data from four published clinical trials of rizatriptan in migraine patients. In assessing treatment response (rizatriptan and sumatriptan versus placebo, rizatriptan versus sumatriptan, within-treatment dose effects), SPID usually yielded similar results to the more easily understood pain-free measure.

Rizatriptan: Pharmacological Differences from Sumatriptan and Clinical Results

SUMMARY Rizatriptan and sumatriptan are selective 5-HT1B/1D receptor agonists for the acute treatment of migraine. For oral formulations, the time to maximum plasma concentration is reached earlier with rizatriptan than with sumatriptan (1u2009h versus 2–2.5u2009h) and rizatriptan has greater bioavailability than sumatriptan (45% versus 15%). These pharmacological advantages appear to translate into a faster onset of action and a better overall response for oral rizatriptan versus oral sumatriptan. The two drugs have been directly compared in randomized, double-blind, placebo-controlled clinical trials of patients with moderate or severe migraine attacks. Rizatriptan 10u2009mg was generally superior to sumatriptan on a measure of time-to-pain-relief within 2u2009h, where pain relief was defined as a reduction of pain to mild or none (odds ratio for rizatriptan versus sumatriptan 100u2009mgu2009=u20091.21; odds ratios for rizatriptan 10u2009mg versus sumatriptan 50u2009mgu2009=u20091.14 and 1.10 in two studies). Rizatriptan 10u2009mg was also superior to sumatriptan on the International Headache Society recommended endpoint of the percentage of patients pain free at 2u2009h (40% for rizatriptan 10u2009mg, 33% for sumatriptan 100u2009mg, and 35% for sumatriptan 50u2009mg). Further advantages for rizatriptan were seen on stringent outcome measures of the percentage of patients who were completely free of all symptoms at 2u2009h, patient satisfaction with medication at 2u2009h, and 24-h sustained pain-free response. 5-HT1B/1D receptor agonists are contraindicated in patients with coronary artery disease because of their potential to cause vasoconstriction. In clinical trials which excluded such patients, rizatriptan and sumatriptan were both well-tolerated. The most common side-effects on both drugs occurred in <10% of patients and consisted of dizziness, drowsiness, and asthenia/fatigue. The adverse events were usually mild or moderate in severity and short-lasting.