Boram Ohk, Joomi Lee, Mi-Ri Gwon, Bo Kyung Kim, Hae Won Lee, Hyun-Ju Kim,Seungil Cho, Sook-Jin Seong, Woo Youl Kang, Hee-Doo You and Young-Ran Yoon
1Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Cell and Matrix Research Institute and Clinical Trial Center, Kyungpook National University Graduate School and Hospital, Daegu 41944, Republic of Korea
Objectives:
Migraine is a chronic, disabling neurological disorder with episodic clinical findings of headache, often associated with nausea and vomiting. Sumatriptan is a 5-hydroxytryptamine (5-HT1B/1D) receptor agonist, which is a one of the most commonly used triptans for treatment of migraine. Sumatriptan acts as a vasoconstrictor of detailed intracranial blood vessels and, also as an inhibitor of the pro-inflammatory neuropeptide release to relieve migraine headache. Epidemiological studies on migraine have consistently shown that migraine is far more common among women than men. In addition, the results that frequency, severity, and type of migraine with greater consequent disability were different between women and men are reported. But the mechanisms behind sex differences are still poorly understood. In this study we focused on the sex differences in the population pharmacokinetics of sumatriptan in healthy Koreans.
Methods:
This study was conducted in 38 healthy volunteers (male: 29, female: 9). All subjects were received 50 mg sumatriptan. Blood samples for pharmacokinetic profiles were collected at 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours after dosing. Plasma sumatriptan concentrations were analyzed using ultra-performance liquid chromatography mass spectrometry mass spectrometry (UPLC/MS/MS). A population PK analysis was conducted using NONMEM (Version 7.3, Icon Development Solution, Ellicott City, MD, USA). The dataset consisted of a total of 532 sumatriptan concentration measurements.
Results:
A one-compartment model with first-order elimination, and combined transit compartment model and first-order absorption with lag time was chosen to describe the PK of sumatriptan. Demographic variables and creatinine clearance, calculated with the Cockcroft-Gault equation, were screened as potential covariate for PK parameters. The screening process was performed using visual and numerical approaches. The covariate analysis showed that sex significantly (p < 0.01) influenced the clearance (male: 429 L/h, female: 330 L/h) of sumatriptan. For model evaluation, graphical diagnostics (basic goodness-of-fit plot and other accessory plots) were used for single run based diagnostics during model development. The robustness and the predictive performance were evaluated using bootstrapping and the visual predictive check(VPC). A bootstrap procedure was conducted with a total of 1,000 bootstrap-resampled datasets from the original dataset. The median and 90% confidence intervals (CIs, 5th and 95th percentiles) of parameters obtained from this step were compared with the final parameter estimates. Results from the VPC with 1,000 simulations were assessed by graphical comparison of the 90% prediction interval from the simulated data with an overlay of the raw data.
Conclusions:
In conclusion, a population PK model was successfully developed and reasonable parameters were obtained. The enhanced recognition to sex differences will help to understand migraine and may help guide the direction of future headache research.
Reference: PAGE 27 (2018) Abstr 8537 [www.page-meeting.org/?abstract=8537]
Poster: Drug/Disease Modelling - Other Topics