Professor Diener and Dr McHarg reply

Abstract

We appreciate the opportunity to respond to Dr Allen's letter and to address some of the thoughtful points he raises. First, regarding the therapeutic dose of eletriptan, as Dr Allen is aware, the actual mg dosage of a drug is different from its potency or efficacy, and is determined by a variety of factors, including bioavailability (which Dr Allen mentions) and degree of protein binding (which he neglects to mention). Only the free (non-protein bound) form of a triptan is physiologically active. In fact, the maximal molar concentration (Cmax) of the physiologically active non-protein bound fraction of the 80 mg dose of eletriptan is 58 nM. This is very similar to the molar Cmax of free rizatriptan achieved after a 10 mg dose (62 nM), and both are lower than the molar Cmax of free sumatripian achieved after a 100 mg dose (160 nM). As can be seen, it is not ‘odd’, nor is an unexpectedly ‘high dose of eletriptan required’ to produce a therapeutic effect. Nor is it necessary to resort to speculative theories about the central activity of triptans and P-glycoprotein pumps that must be ‘overcome’. In fact, there is no consistent evidence that sumatriptan significantly penetrates the blood-brain barrier, yet there is not inconsiderable evidence that suggests sumatriptan has efficacy in the treatment of migraine. Regarding the points made in the third paragraph of his letter, we agree that the results of pre-clinical models of vascular contractility must be extrapolated with great caution to the clinical setting. We also agree that clinical symptoms such as chest pain are usually not due to coronary ischaemia. We intended to make no claim of superiority over sumatriptan in terms of the coronary vasoconstrictive potential of eletriptan; we believe that the risk for clinically significant coronary vasoconstriction is low for all triptans. Regarding the issue of Tmax and delayed absorption during a migraine attack, we find ourselves using Dr Allen's own good advice from the previous paragraph: to pay attention to the clinical data and be cautious about extrapolating too literally from preclinical research. PK studies suggest that sumatriptan and rizatriptan both report minimal-to-no delay in Tmax during a migraine. Yet in two head-to-head trials against the 100 mg dose of sumatriptan, mean headache response at 1 hour for sumatriptan 100 mg vs eletriptan 40 mg vs eletriptan 80 mg was 23.2% vs 34.00% vs 38.8%, respectively. No head-to-head studies have been reported comparing eletriptan to rizatriptan, but if we examine therapeutic gain at 1 hour, based on pooled results across multiple studies.1-11 the therapeutic gain (over placebo) for the 10 mg dose of rizatriptan is 19%, compared with 21.8% far the 40 mg dose of eletriptan and 26.6% for the 80 mg dose. These results provide suggestive evidence that onset of headache relief is at least as fast, if not faster, on eletriptan. Finally, in the last paragraph of his letter, Dr Allen notes that in none of the studies presented in the review was eletriptan 80 mg statistically superior to 40 mg. In fact, in Figure 4 of the original article, which summarised the results of a cafergot comparator study, eletriptan 80 mg was statistically superior to the 40 mg dose (68% vs 54%; p=0.003). We should have noted that in the Figure.