A rapid, sensitive and selective high performance liquid chromatography-electrospray ionization-tandem mass spectrometry method (HPLC-ESI-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of lomerizine in human plasma. Protein precipitation process was used to extract lomerizine from human plasma. Plasma samples were separated by HPLC on an Agela Venusil XBP Phenyl column (100 mm × 2.1 mm, 5 μm) using a mobile phase consisting of methanol-2mM ammonium acetate-formic acid (70:30:0.1, v/v/v) and the flow rate was set at 0.35 mL/min. The total run time was 4.0 min and the elution of lomerizine was at 1.9 min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring (MRM) mode using the respective [M+H](+) ions m/z 469.2→181.0 for lomerizine and m/z 405.2→202.9 for the I.S. The calibration curve was linear over the range of 0.1-25 ng/mL (r(2)>0.99) with a limit of quantitation (LOQ) of 0.1 ng/mL. The intra- and inter-day precision (relative standard deviation, RSD) values were below 9.65% and the mean accuracy was from 99.00 to 103.00% at four quality control levels. Lomerizine was stable during stability studies, i.e., long term, auto-sampler and freeze/thaw cycles. The method was successfully applied for the evaluation of pharmacokinetics of lomerizine after single oral doses of 10 mg lomerizine to 18 healthy volunteers.

Although lomerizine is used as a first-line prophylactic drug for migraines in Japan, approximately 30% of patients fail to respond to this treatment. On the basis of medical records, we investigated the involvement of clinical factors in response to lomerizine used in patients with migraine as primary headache and established a scoring system for predicting clinical responses to prophylactic therapy. Ninety-four consistent responders and 33 inconsistent responders to lomerizine were enrolled in this study. Multivariate stepwise logistic regression analysis revealed that migraine plus tension-type headache as primary headache and frequency of headache attacks were significant factors that contributed independently to negative response [odds ratio, 3.817 (no vs. yes; 95% confidence interval (CI), 1.264-11.628) and 5.814 (>15 episode days/month vs. 0-14 episode days/month; 95% CI, 2.381-14.286), respectively]. The predictive index (PI) of clinical responses to lomerizine in patients with migraine was calculated using the regression coefficients of two factors as an integer, where the score for inconsistent responders (1.00±0.71) was significantly higher than that for consistent responders (0.37±0.53, p<0.001). Sensibility of the low-scoring group (PI=0) was 75.8%, and specificity of the high-scoring group (PI=2) was 97.9%. Groups scoring low, intermediated and high included 11.6%, 35.4% and 80.0% of inconsistent responders, respectively. The PI value obtained might represent an appropriate scoring system to predict responses in these patients.