Abstract
This study was designed to assess the pharmacokinetics of almotriptan, a 5-HT1B/1D agonist, when administered in the presence and absence of propranolol. Healthy male (n = 10) and female (n = 2) volunteers received (i) 80 mg propranolol twice daily for 7 days and 12.5 mg almotriptan on day 7, and (ii) 12.5 mg almotriptan on day 7, according to a two-way crossover design. Plasma and urinary almotriptan concentrations were measured by high performance liquid chromatography (HPLC) methods. Treatment effects on pharmacokinetic parameters were assessed by analysis of variance (
Introduction
5-HT1B/1D receptor agonists have proven effective in the treatment of migraine. 5-HT1B/1D receptors are located on blood vessels in the main carotid arterial tree, and in pial and dural vessels, and agonists at these receptors cause vasoconstriction (1, 2). Almotriptan (Fig. 1) is a selective ligand for the 5-HT1B/1D receptors, with ≥35-fold lower affinity for other serotonin receptor subtypes (3). Almotriptan likewise has been shown in clinical trials to be effective in the treatment of acute migraine (4).
Structure of almotriptan.
The absolute oral bioavailability of almotriptan is 70% (5). The drug shows dose-linear pharmacokinetics (through a dosage of 200 mg) and a mean elimination half-life of 1.4–3.8 h (5, 6). Approximately 40–50% of the dose is recovered unchanged in the urine; renal elimination probably occurs via active tubular secretion (6). The balance of the dose is primarily metabolized, with < 5% excreted unchanged in the faeces. Monoamine oxidase, cytochrome P-450 (3A4 and 2D6 isozymes) and flavin monooxygenase (listed in order of decreasing degree of contribution) are responsible for almotriptan metabolism in humans (7). Five almotriptan metabolites have been observed in human liver microsomal preparations; these are devoid of pharmacological activity (8). The unbound fraction of almotriptan in plasma is > 60% (data on file, Almirall Prodesfarma S.A.).
Propranolol hydrochloride is a β-adrenergic blocking agent that is sometime used for prophylaxis of migraine headaches in adults (9). The mechanism of the antimigraine effect is not known. Propranolol is almost completely metabolized in the liver; metabolism appears to be mediated by CYP2D6 and CYP1A2 (10). Propranolol has been shown to inhibit the metabolic pathways of cytochrome P-450 of several drugs (11), and shares at least one elimination pathway with almotriptan (CYP2D6). In addition, propranolol can alter the clearance of other compounds by altering liver blood flow (12). Therefore, as almotriptan and propranolol may be given concurrently in a clinical setting, it is important to determine the potential for an interaction between the two drugs.
The primary objective of this study was to measure plasma and urine drug concentrations and assess the pharmacokinetics of almotriptan when administered in the presence and absence of propranolol. The secondary objectives of this study were to measure safety parameters including changes in pulse rate and blood pressure, clinical chemistry laboratories, and adverse events.
Subjects and methods
Subjects
Twelve healthy male and female subjects between the ages of 18 and 55 years were to be enrolled in this study. All females had a negative serum pregnancy test at screen, and testing was repeated before administration of experimental medication in each study period to assure that females were not pregnant. Females of childbearing potential were using a medically acceptable, non-hormonal method of birth control. Smokers of cigarettes were enrolled into the study if the amount they smoked was less than or equal to one pack per day. A complete physical examination, patient history, vital signs, ECG, and clinical laboratory tests were obtained at the time of selecting subjects for this study. Subjects with clinically abnormal results were excluded from participation. Subjects with a history of ethanol abuse were likewise excluded. Written, informed consent was obtained prior to any screening procedure. The study was conducted in accordance with the Declaration of Helsinki and subsequent amendments.
Study design
This study was a randomized, open label, two-way crossover study. Each subject received both of the following treatments with a minimum 1 week washout between periods: (i) one 80-mg propranolol immediate release tablet at approximately 8 a.m. and 8 p.m. on days 1–7 and one 12.5-mg almotriptan tablet (administered with 8 a.m. propranolol dose on day 7); (ii) one 12.5-mg almotriptan tablet at approximately 8 a.m. on day 7 (no treatment on days 1–6). All dose administrations were taken with 200 ml of tap water. Almotriptan was administered after an overnight fast (approximately 10 h), and subjects remained fasting until 4 h following the dose. Ethanol consumption was prohibited during the study period.
Clinical assessments
Subjects were asked daily for any symptoms or effects they may have noticed during the interval since the last query. Symptoms, worsening of pre-existing conditions, or any conditions or symptoms noted by the investigator were recorded. Spontaneous reports were also recorded.
Supine blood pressure, heart rate, aural temperature, and respiratory rate were recorded over 1 min (predose, 1, 2, 3, 4, 6, 8, 12 and 24 h after dosing on day 7). Twelve lead ECGs were done (screen, day 1 predose, and at hours 2 and 4, on day 7). QT intervals were determined by hand measurement in lead II and corrected for heart rate by Bazett's formula.
Clinical laboratory tests, including haematology (complete blood count with differential and platelet count), clinical chemistry, and urinalysis were conducted at screen and days −1 and 8 of each study period.
Almotriptan assays
Blood samples for the analysis of almotriptan were collected just before the almotriptan dose (hour 0) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 h after drug administration. Venous whole blood (7 ml) was collected into green-top tubes containing sodium heparin. The tubes were centrifuged at approximately 1000
Heparinized plasma samples were assayed for almotriptan concentrations using a validated LC/MS/MS assay (13). Calibration standard responses were linear over the curve range (0.50–200 ng/ml) using a weighted (1/concentration2) least squares linear regression based on peak area ratios. Correlation coefficients, which measure the goodness of fit, were ≥0.9997. The lower limit of quantification (LLOQ) for almotriptan was 0.5 ng/ml. Assay precision, expressed as the coefficient of variation (CV) of the estimated concentrations of QC standards, was 8.3%, 1.6%, and 1.9%, respectively, for the 1.5, 50, and 150 ng/ml QC pools. By including QC standards with concentrations > 15% from target concentrations, the mean accuracy for the low pool was 107.5%, with a corresponding CV of 8.2%.
Data analysis
Pharmacokinetic parameters were calculated by the Clinical Pharmacokinetics Analysis Package, Version 1.0 (14), using non-compartmental methods (15). The terminal rate constant (λz) was determined by linear regression of the terminal portion of the log concentration-time profile. The terminal half-life (t½) was calculated as 0.693/λz. Area under the plasma concentration-time curve (AUC0-∞) was determined by trapezoidal rule up to the last time at which a measurable concentration was observed and extrapolated to infinity. Oral clearance (CLPO) was calculated as dose/AUC0-∞. Volume of distribution (Vz/F) was calculated as CLPO/λz. Maximal concentrations (Cmax) and the time at which they occurred (tmax) were determined by inspection of the concentration–time profile.
Analysis of variance for a crossover study was used to assess treatment effects on almotriptan pharmacokinetics. In addition, 90% confidence interval analysis was used to assess equivalence of pharmacokinetic parameters between treatments. Blood pressure measures and QTc intervals were analysed for treatment effects by analysis of variance for a crossover study at each time point. All statistical analyses were performed by SAS (16).
Assuming a 15% coefficient of variation (CV) for area under the curve (AUC), the power to detect a 20% difference in this parameter between treatments is 83.9% at an α level of 0.05. The actual CV from the
Results
Clinical
Two women and 10 men participated in this trial. All subjects were of Caucasian origin, with the exception of one African-American male. The mean age was 29.4 ± 10 years and the mean weight was 77.9 ± 14.8 kg.
Eight of the 12 subjects in this study reported a number of adverse events of mild and moderate intensity. No serious adverse events were reported. The most common were headache, nausea, and dizziness. Of these, only nausea was reported more frequently during propranolol co-administration (three vs. zero reports).
No clinically significant abnormal laboratory measurements were observed. Oral temperature, pulse, and respiration did not differ significantly between treatments. Significant effects of treatment on blood pressure or pulse were not observed. No significant effects of treatment on change from baseline in QTc were apparent. Mean change from baseline data for blood pressure, pulse, and QTc are shown in Table 1.
Mean (±
Pharmacokinetics
Mean plasma concentrations of almotriptan are depicted in Fig. 2. Mean almotriptan concentrations after concomitant administration of almotriptan and propranolol and after almotriptan administration alone were virtually superimposable. Mean almotriptan pharmacokinetic parameters are summarized in Table 2. There were statistically significant differences between treatments in several pharmacokinetic parameters; however, they were < 7%. The results of 90% confidence interval analysis of log-transformed pharmacokinetic parameters are shown in Table 3. For all parameters, the confidence intervals were within the range of 80–125% of the reference treatment (almotriptan alone).
Mean plasma concentrations of almotriptan after the administration of 12.5 mg almotriptan in the presence (▪) and absence (□) of 80 mg propranolol administered twice daily to healthy male and female volunteers.
Results for 90% confidence interval analysis of log transformed plasma pharmacokinetic parameters for almotriptan following the 12.5-mg almotriptan given orally in the presence and absence of 80 mg propranolol twice daily
Mean (±
Discussion
Propranolol is often used in migraine prophylaxis (9, 17); therefore, it may be co-administered with almotriptan. Both compounds share a common metabolic pathway (CYP2D6), although the degree of metabolism of almotriptan via this route appears to be small (7). Therefore, we assessed the potential pharmacokinetic interaction between these compounds in healthy volunteers.
In this study, statistically significant effects on almotriptan AUC, clearance, and half-life were observed. In all of these cases, however, the differences between the means were small, and the 90% confidence intervals for the ratios of mean parameters for all log-transformed parameters were within the 80–125% range generally used to assess equivalence. Thus, propranolol had no effect on the pharmacokinetics of almotriptan.
Propranolol has previously been shown to have no effect on the pharmacokinetics of sumatriptan (18). In contrast, propranolol increased zolmitriptan AUC and Cmax by 37% and 56%, respectively, presumably through inhibition of cytochrome P-450 (19). Both of these studies were conducted using a 160-mg daily dose of propranolol, as we did in the present study. Propranolol, at a dose of 240 mg/day, increased plasma concentrations of rizatriptan by approximately 70% (20). Therefore, the present study should have identified an interaction between propranolol and almotriptan, if indeed one exists.
In addition to the lack of any pharmacokinetic interaction, no pharmacodynamic interaction was apparent. There were no clinically significant treatment effects on vital signs, and there were no prolongations in QTc intervals. Therefore, the results of this study suggest that concomitant administration of these agents in the management of migraine will be well tolerated.