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

BACKGROUND: Triptans, serotonin 5-HT(1B/1D) receptor agonists, exert their action by targeting serotonin 5-HT(1B/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-HT(1B/1D) receptor occupancy (Φ(1B) and Φ(1D)). 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 (AUC(cp)) and the areas under the time curves for Ф(1B) and Ф(1D) (AUC(Ф)(1B) and AUC(Ф)(1D)). Moreover, parameters expressing drug transfer and binding rates (A( cp ), A( Ф )( 1B ), A( Ф )( 1D )) were calculated. RESULTS: Our calculations showed that Ф(max)(1B) and Ф(max)(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 AUC(cp), AUC(Φ)(1B), AUC(Φ)(1D), and A( cp ) · AUC(cp) differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and A( Φ )( 1B ) · AUC(Φ)(1B) or A( Φ )( 1D ) · AUC(Φ)(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.