European Journal of Clinical Pharmacology

, Volume 64, Issue 5, pp 489–495

Interindividual variability of oral sumatriptan pharmacokinetics and of clinical response in migraine patients

Authors

    • Division of Toxicology and Clinical Pharmacology, Headache CentreUniversity Centre for Adaptive Disorders and Headache, Section Modena II, University of Modena and Reggio Emilia
    • Division of Toxicology and Clinical Pharmacology, Headache CentreUniversity of Modena and Reggio Emilia
  • Diego Pinetti
    • Division of Toxicology and Clinical Pharmacology, Headache CentreUniversity Centre for Adaptive Disorders and Headache, Section Modena II, University of Modena and Reggio Emilia
  • Alfio Bertolini
    • Division of Toxicology and Clinical Pharmacology, Headache CentreUniversity Centre for Adaptive Disorders and Headache, Section Modena II, University of Modena and Reggio Emilia
  • Ciro Coccia
    • Division of Toxicology and Clinical Pharmacology, Headache CentreUniversity Centre for Adaptive Disorders and Headache, Section Modena II, University of Modena and Reggio Emilia
  • Emilio Sternieri
    • Division of Toxicology and Clinical Pharmacology, Headache CentreUniversity Centre for Adaptive Disorders and Headache, Section Modena II, University of Modena and Reggio Emilia
Pharmacokinetics and Disposition

DOI: 10.1007/s00228-007-0443-9

Cite this article as:
Ferrari, A., Pinetti, D., Bertolini, A. et al. Eur J Clin Pharmacol (2008) 64: 489. doi:10.1007/s00228-007-0443-9

Abstract

Background

The marketing of sumatriptan, a selective serotonin (5-HT) 1B/1D agonist, first of the class of triptans, has increased the therapeutic options for the treatment of migraine attacks. However, almost one third of patients in clinical trials fail to have headache relief after oral administration of sumatriptan.

Objective

To evaluate whether the interindividual differences in the clinical response following oral administration of sumatriptan are due to differences in its pharmacokinetics.

Methods

We compared the pharmacokinetics of sumatriptan after oral (100 mg) and subcutaneous (6 mg) administration in two age- and gender-matched groups: ten subjects (group A) with satisfactory response and ten (group B) with unsatisfactory response to oral sumatriptan. Patients were studied during headache-free intervals. Blood samples were taken serially from baseline to 360 min after oral administration and from baseline to 180 min after subcutaneous injection. Sumatriptan plasma concentrations were determined by high-performance liquid chromatography (HPLC) with an electrochemical detector.

Results

Following oral dosing, patients of group A absorbed sumatriptan significantly faster and achieved early plasma levels significantly higher than patients of group B. The systemic exposure to sumatriptan during the first 2 h, which are the most important for rapid onset of action and for antimigraine efficacy, was significantly greater in group A than in group B (P < 0.001, Student’s t test for independent data). On the other hand, after subcutaneous injection of sumatriptan, the profile of the curves was similar in all patients, and there were no differences in pharmacokinetics between group A and group B.

Conclusion

The slow rate and low extent of absorption of the drug during the first 2 h after dosing observed in patients of group B could explain their unsatisfactory response to oral sumatriptan.

Keywords

SumatriptanAbsorptionPharmacokineticsVariabilityResponse

Introduction

The marketing of sumatriptan, a selective agonist at 5-hydroxytryptamine (5-HT) 1B/1D receptor subtype and the first of the class of triptans, has meant an important innovation and has increased therapeutic options for the treatment of migraine attacks [1]. However, one third of patients in clinical trials fail to have headache relief after oral administration of sumatriptan [2]. Variability among individuals in response to triptans has been poorly explained [2]. Among the many factors that induce interindividual variability in response to drugs, important are disposition and, especially, metabolism, which influence concentrations at the site of action [3]. In the case of triptans, pharmacokinetics during early postdose interval (0–2 h) seems to be the most important for clinical response [4]. In particular, it has been suggested that the initial rate of absorption and the height of plasma levels reached may be closely related to headache relief [510]. These pharmacokinetic considerations are in line with triptan pharmacodynamics [11] and the neurobiology of migraine attacks [12, 13]. If the drug can reach its specific sites of action rapidly and in sufficient concentrations, central sensitisation and, therefore, the whole typical symptoms of migraine attacks could be prevented [12, 14]. This paradigm is also confirmed by the results of clinical research. All triptans have proved to be more effective if taken early [15]. Treating patients with triptans within 60 min after the onset of migraine effectively blocks the development of cutaneous allodynia, a manifestation of established central neural sensitisation. The presence of allodynia predicts, instead, a limited outcome of acute treatment [13, 16, 17].

Administration route and more effective delivery systems of triptans are therefore crucial to facilitate rapid onset of action and increase efficacy [18]. For this purpose, the original sumatriptan formulation was substituted on the market with the new, fast-disintegrating tablet [19].

Considering growing evidence and suggestions that early treatment and rapid absorption following oral dosing can improve efficacy, we hypothesised that there was a relationship between the pharmacokinetics and clinical response of sumatriptan following oral dosing. To explore the possibility of this relationship, we compared, outside migraine attack, the pharmacokinetic profiles of sumatriptan following oral and subcutaneous administration between patients who reported satisfactory response and those who reported unsatisfactory response to oral sumatriptan.

Methods

Subjects

We enrolled 20 subjects, all Caucasian, suffering from migraine without aura according to the International Classification of Headache Disorders (ICHD-II) criteria [20]. These subjects were recruited from the database of the Headache Centre of the University Hospital of Modena. We considered eligible for inclusion in the study patients with a history of at least five migraine attacks treated orally with 100 mg sumatriptan (fast-disintegrating tablet). We excluded subjects suffering from migraine with aura, those reporting that they did not tolerate sumatriptan, those presenting whatever contraindication to the use of the medication and those under prophylactic treatment.

The population (Table 1) was subdivided into two age- and gender-matched groups: ten subjects (group A) who referred a satisfactory response to oral sumatriptan (defined as improvement from moderate or severe to mild or no headache within 2 h in four out of five attacks); 10 subjects (group B) who referred unsatisfactory response (no response or improvement from moderate or severe to mild or no headache only beyond 2 h in four out of five attacks). Written informed consent was obtained from each subject following an exhaustive description of the study procedures and objectives. The study was approved by the Ethical Committee of Modena and conducted in compliance with the Declaration of Helsinki, latest version.
Table 1

Characteristics of patients with satisfactory (group A) or unsatisfactory (group B) response to oral sumatriptan

Characteristic

Group A (n = 10)

Group B (n = 10)

Females (%)

8 (80)

7 (70)

Males (%)

2 (20)

3 (30)

Age (years, mean ± SD)

48.2 ± 8.9

45 ± 5.4

Range

35–60

36–53

Weight (kg, mean ± SD)

61 ± 7.3

65.6 ± 13.3

Range

(57–75)

(50–85)

Age at migraine onset (years, mean ± SD)

24.9 ± 7.1

23.9 ± 6.0

Migraine attack frequency

  

  1–3 per month

7

6

  Weekly

3

4

Before every study session, all subjects underwent medical examination, and standard biochemical and haematological screenings were performed. At the time of the experimental sessions, patients did not present acute diseases as determined by histories and physical and laboratory evaluations. In particular, no patient had kidney or liver dysfunction or was taking drugs able to cause drug–drug interactions with sumatriptan [21].

Procedures

Patients were studied twice—after oral and after subcutaneous administration of sumatriptan—during headache-free intervals. A 1-week washout period was allowed between the administration of the two formulations. Experimental sessions were conducted at the in-patient ward (day hospital) of the Headache Centre. Under medical surveillance, sumatriptan was administered to each patient at 7 a.m. after overnight fasting. An intravenous cannula was inserted in one arm, and pulse, blood pressure and blood samples were taken at baseline and at 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min after oral administration of 100 mg [Imigran™ (sumatriptan succinate) fast-disintegrating 100-mg tablet, GlaxoSmithKline], at baseline and then at 5, 10, 15, 20, 25, 30, 60, 90, 120, and 180 min after subcutaneous injection of 6 mg [Imigran™ (sumatriptan succinate) injection 6 mg/0.5 mL, GlaxoSmithKline] into the deltoid region. Samples were immediately centrifuged and kept at −20°C until the time of assay. The administered drugs were provided by the internal pharmacy service of the University Hospital of Modena. Subjects were monitored throughout the treatment period for the occurrence of adverse events, which were defined as any untoward medical occurrence, regardless of its relationship to study medication.

Assay of sumatriptan

Sumatriptan concentrations were measured on serum by means of a slightly modified electrochemical detection high-pressure liquid chromatographic (HPLC/EC) method [22]. An HPLC Beckman System Gold (Beckman Coulter, Fullerton, CA, USA) was used consisting of a Solvent Module 118, an Analog Interface Module 406, and an electrochemical detector Coulochem II, with a Model 5010 analytical cell (ESA). Separation was performed using a Waters μBondapak (300 × 3.9 mm ID, 10 μm ps), with a Waters Symmetry Shield Sentry Guard RP18 precolumn (20 × 3.9 mm ID, 5 μm) (Waters Corp, Milford, MA).

Chromatographic separation was performed at 40°C using a Biorad column heater. A mobile phase consisting of 60% phosphate buffer (75 mM, pH 7.0) and 40% methanol was pumped isocratically at a flow rate of 0.8 ml/min, and electrochemical detection of sumatriptan was performed using the following settings: guard cell, 900 mV; analytical cell detector 1,600 mV; analytical cell detector 2,800 mV; a 2-s filter, and 50 μA sensitivity was set for both cells. Data acquisition and handling was carried out using a Beckman System Gold version 3.7 software (Beckman Coulter, Fullerton, CA).

A sumatriptan standard solution (100 μg/ml) was prepared in methanol and stored at −20°C, and a working solution (1 μg/ml) was obtained from the former by means of dilution with methanol and stored at 4°C. Calibration standards and quality control samples were prepared using human control serum. The desired quantity of sumatriptan was added to a 3-cc polypropylene tube, methanol was evaporated under a gentle stream of nitrogen at 37°C, and 1 ml of serum was added. Five-point calibration curve samples (3, 10, 30, 60, 90 ng/ml) were prepared and run prior to each assay.

Patients’ samples, calibration standards and quality control samples were prepared using solid-phase extraction. A 1 ml aliquot of serum sample was added to 1 ml of Tris buffer (50 mM, pH 7.0) and vortex mixed; the diluted sample was then applied to a Waters Oasis HLB solid-phase extraction column (1 ml, 30 mg) preconditioned with 1 ml of methanol and 0.5 ml of Tris buffer (50 mM, pH 9.0). The column was washed with 0.5 ml of 10% methanol in distilled water; the analyte was then eluted with phosphate buffer (75 mM, pH 7.0):methanol (50:50). An aliquot of the extract (100 μl) was injected on to the HPLC system. The efficiency of analyte extraction averaged 92.3 ± 4.5%. The assay was linear over the analytical calibration range of 3–90 ng/ml; inter- and intra-assay evaluation revealed the reproducibility and stability of the chromatographic method, relative standard deviation percentage being, respectively, 6.5% and 2.7% at 5 ng/ml and 4.6% and 2.4% at 50 ng/ml.

Data analysis and statistical evaluation

Individual plasma concentration-time profiles of sumatriptan after oral and subcutaneous injection were analysed by means of the P K Solutions 2.0. program (Non-Compartmental Pharmacokinetics Data Analysis, Summit Research Services, Montrose, CO, USA). This included calculation of elimination half-life (t1/2 min); absorption half-life (t1/2 ABS min); mean residence time calculated using \( {\text{AUC}}_{{0 \to \infty }} \) (MRT min); cumulative area under the plasma concentration time curve (AUC), only using observed data points \( {\left( {{{\text{AUC}}_{{0 \to t}} \,{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 \to t}} \,{\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}} \right)} \); total AUC computed by combining \( {\text{AUC}}_{{0 \to t}} \) with an extrapolated value \( {\left( {{{\text{AUC}}_{{0 \to \infty }} \,{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 \to \infty }} \,{\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}} \right)} \); apparent volume of distribution (Vd) based on \( {\text{AUC}}_{{0 \to \infty }} \), elimination rate, and fraction of dose absorbed, normalised by weight (Vd ml/kg); systemic clearance based on \( {\text{AUC}}_{{0 \to t}} \), and fraction of dose absorbed, normalised by weight (Cl ml/min/kg). Maximal plasma concentration (Cmax ng/ml) and the time needed to reach Cmax (Tmax min) were derived by data inspection. The absolute oral bioavailability (AVAIL %) was calculated and referred to the value of \( {\text{AUC}}_{{0 - \infty }} \) obtained after subcutaneous administration assuming that this value corresponded to 100% of bioavailability. In order to have further information during the absorption phase, the partial AUC from time 0 up to 2 h postdose \( {\left( {{{\text{AUC}}_{{0 \to 2}} \,{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 \to 2}} \,{\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}} \right)} \), and AUC0–2/AUC0-t (%) were also calculated. Moreover, the mean systemic rate of absorption during the loading phase (Cmax/Tmax ng/ml/min), according to Fox AW [10], and \( {{\text{AUC}}_{{0 - \infty }} } \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 - \infty }} } {T_{{\max }} \,{\left( {{{{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{ng}}} {{\text{min}}}}} \right. \kern-\nulldelimiterspace} {{\text{min}}}} \mathord{\left/ {\vphantom {{{{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{ng}}} {{\text{min}}}}} \right. \kern-\nulldelimiterspace} {{\text{min}}}} {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}} \right)}}}} \right. \kern-\nulldelimiterspace} {T_{{\max }} \,{\left( {{{{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{ng}}} {{\text{min}}}}} \right. \kern-\nulldelimiterspace} {{\text{min}}}} \mathord{\left/ {\vphantom {{{{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{ng}}} {{\text{min}}}}} \right. \kern-\nulldelimiterspace} {{\text{min}}}} {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}} \right)}} \) as indirect measures of rate of drug absorption according to Lacey et al. [23] were also estimated.

Statistical analysis

All data are expressed as mean ± standard deviation (SD). Student’s t test for independent data and chi-square test, when appropriate, were performed to assess statistical difference between the two groups. A level of P < 0.05 was considered significant [24].

Results

Following administration of an oral dose of 100 mg, plasma concentrations of sumatriptan (Fig. 1) showed large differences among patients, and one patient of group B had two peaks, the second higher than the first. Group A patients reporting a satisfactory response to the drug taken orally absorbed the drug more rapidly (in all subjects, maximal plasma concentrations were reached within 2 h) and achieved plasma levels significantly higher than (P < 0.05), more than double, group B patients after 30 min and up to 90 min. In group B patients who reported an unsatisfactory response, plasma concentration time curve shifted towards right. Plasma concentrations similar to those in group A were reached but more slowly, at least 3 h after oral administration. Furthermore, plasma levels of sumatriptan continued to be significantly higher than group A patients (P < 0.05) 360 min after dosing.
https://static-content.springer.com/image/art%3A10.1007%2Fs00228-007-0443-9/MediaObjects/228_2007_443_Fig1_HTML.gif
Fig. 1

Plasma concentrations [mean ± standard deviation (SD)] of sumatriptan after oral (100 mg) administration in patients with satisfactory (group A −▪− ) or unsatisfactory (group B - • - ) response to oral sumatriptan (statistical differences between mean levels: * P < 0.05, Student’s t test for independent data)

Notably (Table 2), the analysis of kinetic parameters showed significant differences in absorption rate and extent during the first 2 h between the two groups, whereas all other parameters were similar. In particular, absorption was slower in group B, as shown by the significantly higher values of Tmax (P < 0.001), and by the significantly lower values of parameters that express absorption rate (\( {{\text{AUC}}_{{0 \to 2}} } \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 \to 2}} } {{\text{AUC}}}}} \right. \kern-\nulldelimiterspace} {{\text{AUC}}}_{{0 \to t}} \), Cmax/Tmax, and \( {{\text{AUC}}_{{0 \to \infty }} } \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 \to \infty }} } {{\text{T}}_{{\max }} }}} \right. \kern-\nulldelimiterspace} {{\text{T}}_{{\max }} } \), P < 0.001). Moreover, systemic exposure to sumatriptan during the first 2 h (which are the most important for rapid onset of action and antimigraine efficacy) was significantly greater (P < 0.001) in group A than in group B, as shown by \( {\text{AUC}}_{{0 \to 2}} \) value in group A, which was double the value in group B (Student’s t test for independent data).
Table 2

Pharmacokinetic parameters after oral administration of sumatriptan (100 mg) in patients with satisfactory (group A) or unsatisfactory (group B) response to oral sumatriptan

Parameter

Group A (n = 10) mean ± SD

Group B (n = 10) mean ± SD

AVAIL0-t (%)

19.01 ± 8.41

14.63 ± 5.31

Tmax min

96.00 ± 25.10

246.00 ± 44.55 *

Cmax ng/ml

43.10 ± 12.68

47.10 ± 11.27

t1/2 min

71.70 ± 12.99

81.23 ± 20.31

t1/2 ABS min

49.47 ± 4.29

56.62 ± 11.34

MRT min

196.06 ± 19.84

261.34 ± 21.45 *

AUC0-t ng/min/ml

9091.26 ± 2468.78

8855.70 ± 2094.71

\( {\text{AUC}}_{{0 - \infty }} \,{{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}} \)

10312.00 ± 3075.75

11216.32 ± 2897.97

AUC0–2 ng/min/ml

3174.26 ± 1186.05

1530.92 ± 256.36 *

Vd ml/kg

1925.10 ± 1363.33

1949.58 ± 128.66

Cl ml/min/kg

19.69 ± 16.67

15.12 ± 8.59

Cmax/Tmax ng/ml/min

0.45 ± 0.12

0.19 ± 0.03 *

AUC0–2/AUC0-t %

34.90 ± 7.93

17.31 ± 4.86 *

\( {{\text{AUC}}_{{0 - \infty }} } \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 - \infty }} } {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} \mathord{\left/ {\vphantom {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}}} \right. \kern-\nulldelimiterspace} {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} \mathord{\left/ {\vphantom {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}} \)

107.41 ± 28.63

45.65 ± 6.25 *

AVAIL absolute oral bioavailability, Cmax, maximal plasma concentration, Tmax time to reach Cmax, t1/2 estimation half life, t1/2 ABS absorption half life, Vd volume of distribution, MRT mean residence time, AUC area under the plasma concentration time curve

Group A vs. group B: * P < 0.001 (Student’s t test for independent data)

On the other hand, after subcutaneous administration of 6 mg of sumatriptan, even if there were still interindividual variations in plasma concentrations, the time-course of the curves was similar in the two groups of patients. Sumatriptan was rapidly absorbed, the peak level was reached 5–15 min from administration in all subjects, and there were no significant differences in any of the kinetic parameters calculated between group A and group B (Table 3).
Table 3

Pharmacokinetic parameters after subcutaneous administration of sumatriptan (6 mg) in patients with satisfactory (group A) or unsatisfactory (group B) response to oral sumatriptan

Parameter

Group A (n = 10) mean ± SD

Group B (n = 10) mean ± SD

Tmax min

12.00 ± 5.70

10.80 ± 3.54

Cmax ng/ml

74.74 ± 26.39

75.86 ± 26.37

t1/2 min

50.79 ± 13.58

47.96 ± 8.94

t1/2 ABS min

3.22 ± 1.0

3.91 ± 2.86

MRT min

71.20 ± 18.70

60.90 ± 19.44

AUC0-t ng/min/ml

4084.60 ± 1738.65

3009.08 ± 842.42

\( {\text{AUC}}_{{0 - \infty }} \,{{\text{ng}}} \mathord{\left/ {\vphantom {{{\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}} \)

4358.48 ± 1683.41

3637.28 ± 841.43

Vd ml/kg

1853.20 ± 931.19

2059.10 ± 490.59

Cl ml/min/kg

25.91 ± 10.54

30.19 ± 8.10

Cmax/Tmax ng/ml/min

6.23 ± 0.11

7.02 ± 1.51

\( {{\text{AUC}}_{{0 - \infty }} } \mathord{\left/ {\vphantom {{{\text{AUC}}_{{0 - \infty }} } {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} \mathord{\left/ {\vphantom {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}}} \right. \kern-\nulldelimiterspace} {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} \mathord{\left/ {\vphantom {{{\text{T}}_{{{\text{max}}}} {\text{ng}}} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}}} \right. \kern-\nulldelimiterspace} {{\min } \mathord{\left/ {\vphantom {{\min } {{\text{ml}}}}} \right. \kern-\nulldelimiterspace} {{\text{ml}}}}} \)

363.20 ± 28.63

336.78 ± 30.10

Cmax, maximal plasma concentration, Tmax time to reach Cmax, t1/2 estimation half life, t1/2 ABS absorption half life, MRT mean residence time, AUC area under the concentration time curve, Vd volume of distribution

No serious adverse events were reported during any study session. The only reported adverse events were nausea in two subjects (one in group A and one in group B) after oral administration, and burning sensation at the injection site in one subject in group B. There were only minimal and transitory increases of arterial blood pressure values in five patients (three in group A and two in group B) after subcutaneous injection of sumatriptan. Heart rate remained unchanged in all patients.

Discussion

Our results (Fig. 1, Table 2) show that patients in group B, reporting an unsatisfactory response (defined as no response or improvement from moderate or severe to mild or no headache only beyond 2 h in four out of five attacks) to sumatriptan taken orally absorbed the drug slowly (Tmax 246.00 ± 44.55 min) and to a lower extent (AUC0–2 1530.92 ± 256.36 ng/min per ml) during the first 2 h postdosing. Patients in group A, reporting a satisfactory response (defined as improvement from moderate or severe to mild or no headache within 2 h in four out of five of attacks) to sumatriptan taken orally absorbed the medication more rapidly (Tmax 96.00 ± 25.10 min), and to a higher extent (AUC0–2 3174.26 ± 1186.05 ng/min per ml) in the first 2 h postdosing. The differences of rate and extent of absorption between the two groups were statistically significant (Student’s t test for independent data). On the whole, all kinetic parameters measured in our sample were consistent with published data. In particular, after 100 mg orally of sumatriptan in normal subjects, Tmax values range from 0.5 to 4.5 h [5, 79, 25].

Since absorption rate during the first 2 h postdosing is considered crucial both for onset of action and response rate [10, 19], slow and reduced early absorption after oral administration can explain the low efficacy of sumatriptan reported by patients in group B. A rapid and higher absorption in the same period can explain instead the good response reported by patients in group A. Wide intersubject variability in plasma concentrations of sumatriptan after oral administration has been reported in studies with traditional tablets [5, 8, 26]. A high variability has also been reported in healthy volunteers with the new fast-disintegrating formulation, especially in early exposure pharmacokinetic parameters [27]. Absorption therefore continues to be highly variable from one subject to another, even if fast-disintegrating tablets can offer more rapid relief from pain compared with traditional ones [19, 2729].

In a patient absorbing oral sumatriptan very slowly, the advantage of greater efficacy observed with early treatment of migraine attack might be thwarted [30]. Also for this reason, the better strategy to accelerate onset of action and enhance efficacy of migraine attack treatment is to change the route of administration instead of increasing the oral dosage of the drug [4, 10]. The kinetics of sumatriptan after subcutaneous administration has all the characteristics needed to facilitate fast relief from migraine attack [6, 31]. In our study, after a single subcutaneous administration of 6 mg, plasma sumatriptan concentration rose rapidly in both groups, reaching almost identical maximal average plasma concentrations (group A: 74.74 ± 26.39 ng/ml; group B: 75.86 ± 26.37 ng/ml) in the same Tmax (group A: 12.00 ± 5.70 min; group B: 10.80 ± 3.54 min). No kinetic parameter (Table 3) showed statistically significant differences between the two groups of patients regardless of the fact that they had a satisfactory or unsatisfactory response to the oral medication.

Pharmacokinetic differences between marketed triptans have been deeply analysed to assess their impact on treatment outcome [10, 32, 33]. Studying the kinetics of sumatriptan following subcutaneous administration, no differences were found between responders, nonresponders, patients with recurrence [34] and patients with adverse drug reactions [35]. These results, like the results in our study, confirm that intersubject variability in plasma concentrations after subcutaneous administration of sumatriptan is clinically nonsignificant [8, 26]. No response to subcutaneous administration of sumatriptan seems therefore to be independent of pharmacokinetic factors and to depend, rather, on the patient’s characteristics [34, 36]. The results of our study show that a poor response to oral drug could depend mostly on pharmacokinetic factors, in particular, on low and insufficient absorption during the first hours after administration. Probably, subcutaneous injection, with its high early concentration, provides an “overkill effect”. As results of clinical trials [3739] show, subcutaneous sumatriptan is the most effective form (headache relief at 2 h: about 80%; oral triptans: about 65%) and the most rapid (headache relief beginning: 10 min; oral triptans: 30 min) acute migraine treatment [40]. Moreover, it presents the highest intraindividual migraine response consistency (response in 3/3 attacks: up to 90% [31]; oral triptans 40–50% [38, 41]). These results seem to depend mainly on fast early increase in plasma levels, which is mirrored by a shorter Tmax after subcutaneous administration [42]. Onset of effect of sumatriptan formulations was found to correlate with the rate of sumatriptan absorption, and Tmax is a key variable in headache response [10]. Cmax is similar (72 ng/ml after 6 mg subcutaneous sumatriptan and 112 ng/ml after administration of 300 mg oral sumatriptan), but Tmax are different (10 min with subcutaneous dosing, and 180 min with oral dosing [8]). Despite this, therapeutic gain for headache relief is 51% after 1 h following subcutanous administration and only 40% after 2 h following oral administration [43]. Other favourable characteristics of sumatriptan after subcutaneous administration are that bioavailability is approximately 97% of that achieved with an intravenous injection [8]. Oral sumatriptan availability is low (approximately 15% of a dose), primarily because of presystemic hepatic metabolism and, to a lesser extent, incomplete absorption [8].

Our study has some limitations. The sample size was limited. We studied patients outside migraine attacks, and it was therefore impossible to relate plasma levels to pain score. However, it has been reported that plasma concentrations of sumatriptan are not directly related to the onset of action and clinical response [4] and that the rate and extent of absorption of this drug are not affected to a clinical extent by the gastric stasis that may accompany migraine headache [44]. The sample was selected retrospectively on the basis of data reported in medical records and of what patients directly reported. However, our sample reflects interindividual variability in absorption and response to the drug that, even if in different proportions, can be found in the population of patients who suffer from disabling migraines and are the target of triptan prescription.

Conflict of interest statement

None.

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© Springer-Verlag 2007