Theory-based analysis of clinical efficacy of triptans using receptor occupancy

Abstract

Abstract Background Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. Methods To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ 1B and AUCФ 1D). Moreover, parameters expressing drug transfer and binding rates (A cp , A Ф 1B , A Ф 1D ) were calculated. Results Our calculations showed that Фmax 1B and Фmax 1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ 1B, AUCΦ 1D, and A cp  · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and A Φ 1B  · AUCΦ 1B or A Φ 1D  · AUCΦ 1D that was not affected by the drug and the form of administration. Conclusions These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.