Pharmacokinetic profile of alniditan nasal spray during and outside migraine attacks

Abstract

Aims

To compare the pharmacokinetic profile of intranasal alniditan during and outside migraine attacks, and to investigate the relationship between initial rise of alniditan plasma concentration, and headache improvement.

Methods

Twenty-seven migraine patients (age: 18–65 years) were randomized to receive alniditan 2 mg or 4 mg, and investigated both during and outside a migraine attack. Maximal plasma concentrations (C_max), time to C_max (t_max), and the area under the curve over 2 h (AUC(0,2 h)), were calculated from the individual plasma concentration-time profile, obtained from 10 blood samples in each patient, during each of the two administrations.

Results

Alniditan was rapidly absorbed into the systemic circulation (t_max = 11min). All investigated pharmacokinetic parameters (C_max, t_max, AUC(0,2 h)) were similar during and outside migraine attacks, both in the 2 mg (n = 13) and the 4 mg group (n = 14). In the 4 mg group, during attacks, mean plasma alniditan concentration at 5 min after administration (C_{t = 5}) in responders (21±16 ng ml⁻¹; n = 10) was significantly higher than the C_{t = 5} in nonresponders (3±3 ng ml⁻¹; P = 0.01; n = 4). However, the C_max and AUC(0,2 h) in responders (33±18 ng ml⁻¹ and 12±6 ng ml⁻¹ h) were also significantly higher than the C_max and AUC(0,2 h) in nonresponders (13±9 ng ml⁻¹; P = 0.048 and 5±3 ng ml⁻¹ h; P = 0.03).

Conclusions

Absorption of alniditan nasal spray was not affected by migraine attacks, although 95% confidence intervals were wide. Early rise of plasma concentrations and the amount of drug in the circulation were related to headache improvement in the higher dose group.

Introduction

During attacks most migraine patients suffer from gastrointestinal symptoms such as nausea, vomiting and diarrhoea [1]. In addition, gastric stasis delays and impairs the gastro-intestinal absorption of drugs [2], making oral treatment of migraine sometimes unsatisfactory [3, 4]. Subcutaneously administrated antimigraine drugs are an alternative, but dislike of injections or an inability to self-administer makes subcutaneous treatment unacceptable to some patients. Absorption of drugs via the nasal mucosa circumvents the gastro-intestinal problems associated with migraine attacks and avoids first-pass metabolism by the liver. Intranasally administrated sumatriptan [5–8] showed similar clinical efficacy to that of orally administrated sumatriptan [9–11]. The absence of superiority of the nasal route could be caused by lack of nasal absorption either because most of the drug is swallowed or because of a possible influence of migraine attacks on the nasal mucosa resulting in decreased absorption.

The magnitude of headache relief of 5-HT_1B/1D receptor agonists appears to be related to the initial rise of plasma levels of the drugs [8, 12, 13], rather than to the total amount of drug in the circulation [14]. Rate of absorption (initial rise of plasma levels) can be measured by the concentration of drugs 5 min after administration. We hypothesized that patients without headache relief have lower plasma concentration of 5-HT_1B/1D receptor agonists at 5 min after administration compared with patients with headache relief.

Alniditan is a novel, selective nonindole 5-HT_1B/1D receptor agonist [15], with antimigraine action [16]. The compound has a high aqueous solubility and can be administrated intranasally as an aqueous solution. The average nasal bioavailibility in healthy volunteers is 35–40% and the half-life is 8–12 h. Addition of the natural bioadhesive excipient chitosan to the formulation prolongs the contact time of alniditan with the nasal mucosa by means of decreasing the mucociliary clearance. This reduces the rate and extent of swallowing of the drug, and thus facilitates absorption of alniditan through the nasal mucosa.

In this trial we have used alniditan nasal spray as a model to study the effect of migraine attacks on the absorption of drugs thought the nasal mucosa. We compared the pharmacokinetic profile of intranasal alniditan during and outside migraine attacks, and we investigated the relationship between the initial rise of plasma concentrations and headache relief to determine whether an early rise of plasma levels predicts efficacy.

Methods

Patients

A total of 27 migraine patients [17] between 18 and 65 years of age were recruited from the migraine patient database of the neurology outpatient clinic of Leiden University Medical Centre. Patients were eligible for inclusion if they had at least a 6 month history of moderate or severe migraine attacks. Patients were excluded if they had a history of ischaemic heart disease, hypertension (baseline diastolic blood pressure >95 mmHg), other serious disorders (neurologic, hepatic, renal, gastrointestinal, pulmonary, metabolic, endocrine or psychiatric), abuse of alcohol and/or drugs, or had moderate or severe hay fever or other diseases which obstructed the nose. On the study days, patients were excluded if they had a headache-free interval of less than 24 h, had taken ergotamine containing medication within the previous 24 h or any other analgesics within the previous 8 h, or were pregnant or breast feeding. The study was conducted in accordance with the declaration of Helsinki and the principles of Good Clinical Practice. Approval was obtained from the local ethics committee and informed consent was obtained from each patient before the study.

Study design and treatment

The study was carried out between September 1995 and January 1996 at Leiden University Medical Centre, The Netherlands. The study was double-blind and randomized for the dose of alniditan (2 mg or 4 mg). It consisted of two trial sessions, one during and one outside a migraine attack. On the day of the migraine attack, patients phoned the investigators, who went as soon as possible to the patients’ homes. On arrival their medical history, a physical and neurological examination, and 12-lead electrocardiogram (ECG) were recorded and routine blood laboratory tests were taken. Thereafter, an intravenous cannula for blood sample collection was inserted into a lower arm vein. All patients received a 0.1 ml insufflation of alniditan (20 mg ml⁻¹ or 40 mg ml⁻¹) in one nostril in accordance with the predetermined randomization list. During 2 h, 10 blood samples for measurement of plasma alniditan concentration were taken and headache severity, functional disability, associated symptoms (nausea, vomiting, photo-and phonophobia) and tolerability were assessed. Patients could use escape medication, except ergot derivatives from 2 h following initial study medication. After the investigators departure, the patients continued to record their migraine symptoms on diary cards for up to 24 h after dosing. In the second trial session, 1–6 weeks after the first, patients received the same intranasal dose of alniditan for evaluation of the pharmacokinetics, tolerability and safety outside a migraine attack.

Pharmacokinetic assessments

Ten blood samples (5 ml each) for alniditan assay were taken at predose and 5, 10, 15, 20, 30, 40, 60, 90 and 120 min postdose, in both sessions during and outside a migraine attack. Plasma was separated by centrifugation within 4 h after collection and stored at −70° C. Concentrations of alniditan were determined per patient at the Janssen Research Foundation by a radioimmunoassay following extraction of plasma samples at alkaline pH using Extrelut® prepacked extraction columns. The lower limit of quantification of the assay was 0.10 ng ml⁻¹. The intra-assay (interassay) coefficients of variation of the radioimmunoassay, as determined concomitantly with assays for this trial, were 4.8% (7.6%) at 0.15 ng ml⁻¹, 8.4% (7.5%) at 2.0 ng ml⁻¹ and 3.9% (1.1%) at 20 ng ml⁻¹. From individual plasmaconcentration-time profiles, the maximum plasma concentration (C_max) and the time to C_max (t_max) were observed. The area under curve was estimated over 2 h (AUC(0,2 h)) using linear trapezoidal integration.

Other assessments

The primary efficacy measure was headache response as defined as an improvement from moderate or severe headache to mild or no headache at 2 h. Migraine symptoms, i.e. headache severity, nausea, photophobia, phonophobia and functional disability were recorded before treatment and at 15, 30, 60, 90 and 120 min post dose. Four parameters describing nasal tolerability (nasal irritation, runny nose, throat irritation, watering eyes) were rated by means of a 4-point scale (0 = none, 1 = mild but still acceptable, 2 = moderate and disturbing, 3 = severe and not acceptable).

Statistical analysis

Non-compartimental pharmacokinetic data analysis was used to evaluate the alniditan concentration-time data, and results were summarized by descriptive statistics (mean±s.d.). Trial sessions during and outside migraine attacks were compared by anova (C_max, AUC(0,2 h)) or Wilcoxon matched-pair signed rank test (t_max). Differences in pharmacokinetic parameters were compared by Mann–Whitney rank tests for patients who were classified as responders and nonresponders at 2 h.

Results

Patients

Twenty-seven patients were treated during a migraine attack with 2 mg (n = 13) or 4 mg (n = 14). Twenty-six patients were treated outside a migraine attack, one patient withdrew consent for personal reasons and dropped out before trial completion. The demographic and clinical characteristics of all 27 patients are shown in Table 1.

Table 1.

Demographic and clinical characteristics of study population (n = 27).

Pharmacokinetics

In general, alniditan was rapidly absorbed into the systemic circulation after intranasal administration, and peak concentrations were reached within 5–15 min. Mean plasma concentration curves of alniditan during and outside migraine attacks were very similar for both groups (2 mg and 4 mg) (Figure 1). Statistical analysis revealed no significant differences for C_max, t_max, nor for AUC (0,2 h) during compared with outside a migraine attack (Table 2).

Figure 1.

Mean plasma alniditan concentrations following 2 mg intranasal doses during (▵) and outside (○) migraine attacks; and 4 mg intranasal doses during (▴) and outside (•) migraine attacks.

Table 2.

Pharmacokinetic parameters (mean±s.d.) of alniditan during and outside migraine attacks.

Twenty patients experienced a headache response (improvement from moderate or severe to mild or no headache) at 2 h (responders). There were no differences in time to response (30 min) nor in percentage of responders (≈75%), between the 2 mg group and the 4 mg group. Differences in body mass and pharmacokinetic parameters for both the 2 mg and 4 mg group are shown in Table 3. The initial rate of plasma level rise, measured by the concentrations of alniditan at 5 min after administration, in the 4 mg group was significantly higher in responders (n = 10) compared with nonresponders (n = 4) (difference in C_{t = 5}: 17.7 ng ml⁻¹; 95%CI: 5.1, 30.3 ng ml⁻¹; P = 0.013) (Figure 2; upper panel). The same differences were noted in maximal concentration of alniditan (difference in C_max: 20.1 ng ml⁻¹; 95%CI: 3.7, 36.5 ng ml⁻¹; P = 0.048) (Figure 2; lower panel) and AUC(0,2 h) (difference in AUC(0,2 h): 6.8 ng ml⁻¹ h; 95%CI: 1.6, 12.1 ng ml⁻¹ h; P = 0.034). Neither of the three pharmacokinetic parameters (C_{t = 5}, C_max or AUC(0,2 h)) showed significant differences in the 2 mg group (difference in C_{t = 5}: 0 ng ml⁻¹; 95%CI: −7.5, 7.4 ng ml⁻¹ and difference in C_max: 4.3 ng ml⁻¹; 95%CI: −1.3, 9.8 ng ml⁻¹ and differences in AUC(0,2 h): 1.6 ng ml⁻¹ h; 95%CI: −0.7, 4.0 ng ml⁻¹ h) (Figure 2).

Table 3.

Mean (±s.d.) for body mass and pharmacokinetic parameters in responders and nonresponders, both in the 2 mg and the 4 mg group.

Figure 2.

Individual values and mean±s.d. of C_{t = 5} (upper panel) and C_max (lower panel) of responders (•) and nonresponders (▵) after 2 mg or 4 mg intranasally administrated alniditan.

Tolerability and safety

Intranasally administrated alniditan was generally well tolerated. Shortly after drug administration, patients in both groups reported some nose and throat irritation as well as taste disturbance. Adverse events were not dose related and occurred both during and outside a migraine attack. There were no serious adverse events.

Discussion

We compared pharmacokinetic profiles of intranasal alniditan during with those outside migraine attacks. Alniditan was rapidly absorbed into the systemic circulation. Peak plasma concentrations were reached within 5–15 min and no secondary peaks were seen, suggesting that all the alniditan was absorbed through the nasal mucosa. The kinetics of alniditan in this dose range appears linear, based on the C_max and AUC values. No differences in pharmacokinetic profile of intranasal alniditan were found during and outside attacks. This absence of differences might be caused by a lack of power of the study to detect differences had they been present. The 95% confidence intervals indicate that the findings cannot exclude a 3 min (30%) difference in the main index of speed of absorption (t_max). Likewise differences of 50% in the C_max or AUC(0,2 h) could not be excluded with confidence. Therefore, the lack of significant differences in the pharmacokinetics of alniditan nasal spray during compared with outside migraine attacks could have been due to type II error. Although the possible differences do not seem clinically relevant, these considerations must temper the conclusion that absorption through nasal mucosa is not affected by migraine attacks.

The t_max of alniditan nasal sprays (mean 11 min) is very short compared with sumatriptan (90 min) [18] and dihydroergotamine (54 min) [19] nasal spray. The pharmacokinetics of sumatriptan following different routes of administration have been studied in healthy controls [20]. The bioavailibility and absorption rate were the same for intranasal and oral sumatriptan (15.8%vs 14.3%; mean t_max = 1.5 h for both). This findings suggest that for this drug the mucociliary clearance is so rapid that a major part of the drug is swallowed and orally absorbed. The alniditan nasal spray was combined with chitosan, which prolonged the contact-time of alniditan with the nasal mucosa by decreasing the mucociliary clearance. This might be the reason why this nasal spray was so rapidly absorbed.

We hypothesized that the magnitude of headache relief is predicted by the initial rise in plasma levels as measured by C_{t = 5} [21, 22]. In the highest dose group there appears to be such a relationship between initial rise in plasma levels and response. Responders had a significantly higher C_{t = 5} than had nonresponders, these results are compatible with our hypothesis. However, we also found a relationship between the total amount of drug in the circulation, reflected by C_max and AUC(0,2 h), and headache response. In this study we could not differentiate between the importance of speed of absorption or total amount of drug for headache improvement.

The relationship between plasma alniditan concentrations and response was not found in the 2 mg group. The lack of difference can be explained by the fact that the concentration difference in the 2 mg group is smaller. Since, small differences are more difficult to detect, a larger sample size should have been used, to detect with confidence the same effect as in the 4 mg group.

In conclusion, absorption of alniditan nasal spray is not affected by migraine attacks. The kinetics of alniditan in this dose range appears linear. Early rise of plasma concentrations and the total amount of drug in the circulation are related with, and are possible predictors, of headache improvement in the highest dose group.