Relpax (Eletriptan Hydrobromide) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

Eletriptan binds with high affinity to 5-HT_1B, 5-HT_1D and 5-HT_1F receptors, has modest affinity for 5-HT_1A, 5-HT_1E, 5-HT_2B and 5-HT₇ receptors, and little or no affinity for 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₄, 5-HT_5A and 5-HT₆ receptors. Eletriptan has no significant affinity or pharmacological activity at adrenergic alpha₁, alpha₂, or beta; dopaminergic D₁ or D₂; muscarinic; or opioid receptors.

Two theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT₁ receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT₁ receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

In the anesthetized dog, eletriptan has been shown to reduce carotid arterial blood flow, with only a small increase in arterial blood pressure at high doses. While the effect on blood flow was selective for the carotid arterial bed, decreases in coronary artery diameter were observed. Eletriptan has also been shown to inhibit trigeminal nerve activity in the rat.

Pharmacokinetics

Absorption

Eletriptan is well absorbed after oral administration with peak plasma levels occurring approximately 1.5 hours after dosing to healthy subjects. In patients with moderate to severe migraine the median T_max is 2.0 hours. The mean absolute bioavailability of eletriptan is approximately 50%. The oral pharmacokinetics are slightly more than dose-proportional over the clinical dose range. The AUC and C_max of eletriptan are increased by approximately 20 to 30% following oral administration with a high fat meal.

Distribution

The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%.

Metabolism

The N-demethylated metabolite of eletriptan is the only known active metabolite. This metabolite causes vasoconstriction similar to eletriptan in animal models. Though the half-life of the metabolite is estimated to be about 13 hours, the plasma concentration of the N-demethylated metabolite is 10–20% of parent drug and is unlikely to contribute significantly to the overall effect of the parent compound.

In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4 (see WARNINGS, DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY: Drug Interactions).

Elimination

The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CL_R) following oral administration is approximately 3.9 L/h. Non-renal clearance accounts for about 90% of the total clearance.

Special Populations

Age

The pharmacokinetics of eletriptan are generally unaffected by age.

Eletriptan has been given to only 50 patients over the age of 65. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults (see PRECAUTIONS).

There is a statistically significant increased half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age) (see PRECAUTIONS).

Gender

The pharmacokinetics of eletriptan are unaffected by gender.

Race

A comparison of pharmacokinetic studies run in western countries with those run in Japan has indicated an approximate 35% reduction in the exposure of eletriptan in Japanese male volunteers compared to western males. Population pharmacokinetic analysis of two clinical studies indicates no evidence of pharmacokinetic differences between Caucasians and non-Caucasian patients .

Menstrual Cycle

In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle.

Renal Impairment

There was no significant change in clearance observed in subjects with mild, moderate or severe renal impairment, though blood pressure elevations were observed in this population (see WARNINGS).

Hepatic Impairment

The effects of severe hepatic impairment on eletriptan metabolism have not been evaluated. Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The C_max was increased by 18% (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Drug Interactions

CYP3A4 inhibitors

In vitro studies have shown that eletriptan is metabolized by the CYP3A4 enzyme. A clinical study demonstrated about a 3-fold increase in C_max and about a 6-fold increase in the AUC of eletriptan when combined with ketoconazole. The half-life increased from 5 hours to 8 hours and the T_max increased from 2.8 hours to 5.4 hours. Another clinical study demonstrated about a 2-fold increase in C_max and about a 4-fold increase in AUC when erythromycin was co-administered with eletriptan. It has also been shown that co-administration of verapamil and eletriptan yields about a 2-fold increase in C_max and about a 3-fold increase in AUC of eletriptan, and that co-administration of fluconazole and eletriptan yields about a 1.4-fold increase in C_max and about a 2-fold increase in AUC of eletriptan.

Eletriptan should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. Eletriptan should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the CONTRAINDICATIONS, WARNINGS or PRECAUTIONS sections of their labeling (see WARNINGS and DOSAGE AND ADMINISTRATION).

Propranolol

The C_max and AUC of eletriptan were increased by 10 and 33%, respectively, in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol (see PRECAUTIONS).

The effect of eletriptan on other drugs

The effect of eletriptan on enzymes other than cytochrome P-450 has not been investigated. In vitro human liver microsome studies suggest that eletriptan has little potential to inhibit CYP1A2, 2C9, 2E1 and 3A4 at concentrations up to 100µM. While eletriptan has an effect on CYP2D6 at high concentration, this effect should not interfere with metabolism of other drugs when eletriptan is used at recommended doses. There is no in vitro or in vivo evidence that clinical doses of eletriptan will induce drug metabolizing enzymes. Therefore, eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes.

CLINICAL STUDIES

The efficacy of RELPAX in the acute treatment of migraines was evaluated in eight randomized, double-blind placebo-controlled studies. All eight studies used 40 mg. Seven studies evaluated an 80 mg dose and two studies included a 20 mg dose.

In all eight studies, randomized patients treated their headaches as outpatients. Seven studies enrolled adults and one study enrolled adolescents (age 11 to 17). Patients treated in the seven adult studies were predominantly female (85%) and Caucasian (94%) with a mean age of 40 years (range 18 to 78). In all studies, patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia and phonophobia were also assessed.

Maintenance of response was assessed for up to 24 hours post dose. In the adult studies, a second dose of RELPAX Tablets or other medication was allowed 2 to 24 hours after the initial treatment for both persistent and recurrent headaches. The incidence and time to use of these additional treatments were also recorded.

In the seven adult studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving RELPAX Tablets at all doses compared to those who received placebo. The two-hour response rates from these controlled clinical studies are summarized in Table 1.

Table 1: Percentage of Patients with Headache Response (Mild or No Headache) 2 Hours Following Treatment

	Placebo	RELPAX 20 mg	RELPAX 40 mg	RELPAX 80 mg
NA - Not Applicable
Study 1	23.8% (n=126)	54.3% 1 (n=129)	65.0% (n=117)	77.1% (n=118)
Study 2	19.0% (n=232)	NA	61.6% (n=430)	64.6% (n=446)
Study 3	21.7% (n=276)	47.3% (n=273)	61.9% (n=281)	58.6% (n=290)
Study 4	39.5% (n=86)	NA	62.3% (n=175)	70.0% (n=170)
Study 5	20.6% (n=102)	NA	53.9% (n=206)	67.9% (n=209)
Study 6	31.3% (n=80)	NA	63.9% (n=169)	66.9% (n=160)
Study 7	29.5% (n=122)	NA	57.5% (n=492)	NA

Comparisons of the performance of different drugs based upon results obtained in different clinical trials are never reliable. Because studies are generally conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

The estimated probability of achieving an initial headache response within 2 hours following treatment is depicted in Figure 1.

^*Figure 1 shows the Kaplan-Meier plot of probability over time of obtaining headache response (no or mild pain) following treatment with eletriptan. The plot is based on 7 placebo-controlled, outpatient trials in adults providing evidence of efficacy (Studies 1 through 7). Patients not achieving headache response or taking additional treatment prior to 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of RELPAX as compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of taking a second dose or other medications for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

^*This Kaplan-Meier plot is based on data obtained in 7 placebo-controlled trials in adults (Studies 1 through 7). Patients were instructed to take a second dose of study medication as follows: a) in the event of no response at 2 hours (studies 2 and 4–7) or at 4 hours (study 3); b) in the event of headache recurrence within 24 hours (studies 2–7). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. It should be noted that the protocols did not allow remedication within 2 hours post dose.

The efficacy of RELPAX was unaffected by the duration of attack; gender or age of the patient; relationship to menses; or concomitant use of estrogen replacement therapy/oral contraceptives or frequently used migraine prophylactic drugs.

In a single study in adolescents (n=274), there were no statistically significant differences between treatment groups. The headache response rate at 2 hours was 57% for both RELPAX 40 mg Tablets and placebo.