Neurology -- Correspondence for Sandrini et al., 59 (8) 1210-1217

Correspondence published:

Reply to Letter to the Editor: G Sandrini, M Farkkila and E Forster (22 January 2003)

Eletriptan vs sumatriptan: A double-blind, placebo-controlled, multiple migraine attack study: Dirk Deleu, Yolande Hanssens (22 January 2003)

Reply to Letter to the Editor 22 January 2003

G Sandrini
University Centre for Adaptive Disorders and Headache Pavia Italy,
M Farkkila and E Forster
Send Correspondence to journal:
Re: Reply to Letter to the Editor

gsandrin{at}unipv.it G Sandrini, et al.

Deleu and Hanssens appear to accept the superiority of eletriptan vs. sumatriptan 100 mg dose but question the superiority of eletriptan vs the 50 mg dose of sumatriptan. They acknowledge that the encapsulated sumatriptan used in our comparator study [1] met standard regulatory bioequivalence (BE) criteria but feel that this is “less relevant” than the unconventional (AUC0-2) BE criteria. Before addressing their concerns, we would like to note the following paradox: use of a 50% lower dose of sumatriptan (50 vs. 100 mg) in this study, as in most studies, resulted in no meaningful change in clinical efficacy, and yet significant changes in clinical efficacy are somehow supposed to be caused by possible minor alterations in bioavailability due to encapsulation.
The bioequivalence of encapsulated sumatriptan in this trial is based on a series of studies that are among the most extensive ever undertaken to validate blinding of a comparator drug in clinical trials. This evidence includes the following: (1) in vitro dissolution studies of the 50 mg and 100 mg doses that found dissolution met FDA standards for both formulations; (2) a gamma scintigraphy study [2] in which the encapsulated and non-encapsulated tablets were radioactively labeled to permit direct visualization of dissolution in vivo in humans; complete tablet disintegration occurred earlier (16 minutes) for the encapsulated formulation and later (18 minutes) for the non-encapsulated, and (3) BE studies conducted according to rigorous regulatory standards.
We would also like to emphasize the following points: (1) AUC 0-2 is not a standard criteria and GSK has never used early AUC0-2 BE criteria for sumatriptan, not even when they switched to the current commercial formulation; (2) differences in sumatriptan plasma levels (at any time- point) have never been correlated with clinically significant differences in headache response; oral sumatriptan has a relatively flat dose-response curve, and a 6-fold dose increase from 50 to 300 mg is associated with no change in headache response; (3) oral sumatriptan has highly variable absorption: in one study [3] subjects who took non-encapsulated sumatriptan on two separate occasions had a mean coefficient of variation of 26%; (4) headache response rates at 2 hours vary by as much as 20% across sumatriptan studies; and (5) the 50% headache response rate achieved on encapsulated sumatriptan in the current study was very similar to the response rates (50% and 54%) shown in 2 out of 3 the original NDA studies of 50 mg sumatriptan (see sumatriptan USPI).
Oral sumatriptan exhibits variability in absorption and response, and this variability exists regardless of whether the drug is encapsulated or not. The Fuseau study cited by Deleu and Hanssens examines the performance of a formulation that was totally different from the one used in the current study, so the results are not relevant to this clinical trial.
Therefore we maintain that the encapsulated formulation of sumatriptan has been demonstrated to be bioequivalent and thus, the significantly superior efficacy vs. sumatriptan demonstrated by the 40 mg and 80 mg doses of eletriptan in a series of recent head-to-head comparator trials is a genuine efficacy advantage. [1, 4, 5]
References
1.Sandrini G, Farkkila M, Burgess G, Forster E, Haughie S; Eletriptan Steering Committee. Eletriptan vs sumatriptan: a double-blind, placebo- controlled, multiple migraine attack study. Neurology 2002;59:1210-1217.
2.Sikes C, Muirhead N, Alderman J, Connor AL, Clark D, Wilding I. In vivo disintegration characteristics of encapsulated and unencapsulated sumatriptan: results of a scintigraphy study in humans. Headache Journal of Head and Face Pain 2002;42:399.
3.Rani PU, Naidu MUR et al. A bioequivalence study of two brands of sumatriptan tablets. Curr Ther Res 1996;27:1996.
4.Goadsby PJ, Ferrari MD, Olesen J, Stovner LJ, Senard JM, Jackson NC, Poole PH. Eletriptan in acute migraine: a double-blind, placebo- controlled comparison to sumatriptan. Neurology 2000;54:1560-1563.
5.Mathew NT, Schoenen J, Winner P, Muirhead N, Sikes CR. Comparative efficacy of eletriptan 40 mg vs sumatriptan 100 mg. Headache (in press)

Eletriptan vs sumatriptan: A double-blind, placebo-controlled, multiple migraine attack study 22 January 2003

Dirk Deleu
Sultan Qaboos University Sultanate of Oman,
Yolande Hanssens
Send Correspondence to journal:
Re: Eletriptan vs sumatriptan: A double-blind, placebo-controlled, multiple migraine attack study

dtodeleu{at}squ.edu.om Dirk Deleu, et al.

Sandrini et al. [1] reported the efficacy and safety data of a double -blind, placebo-controlled multiple migraine attack parallel-group comparison of two 5-HT1B/1D agonists, eletriptan and sumatriptan. Like in a previous study, a double-dummy design was used in which eletriptan (not encapsulated) was compared with encapsulated sumatriptan. [2] Irrespective of the dose of eletriptan, the percentage of patients with a headache response at 2 hours post-dosing - the most widely used efficacy measure in acute migraine, but not the primary clinical end-point in this trial - was at least 14% higher compared with the generally accepted standard, 50 mg sumatriptan.
The interpretation of the results is however flawed by the encapsulation of the comparator drug, sumatriptan. The authors claimed correctly that the bioequivalence of encapsulated 50 mg sumatriptan was comparable to that of its commercially available tablet. Unfortunately, their evidence is based on traditional pharmacokinetic measures of bioequivalence (AUC0-¡Þ and Cmax), which are known to be less relevant in migraine where drug absorption in the first two hours post-dosing is the main determinant of efficacy. [3] Moreover data from Fuseau et al. [4], referred to by the authors, clearly indicated that in patients experiencing a migraine attack, the AUC0-2 of encapsulated 50 mg sumatriptan was exactly 30% lower compared to its conventional formulation.
This probably explains why the best response achieved for encapsulated 50 mg sumatriptan in Sandrini et al.¡¯s study was 50% 2 hours post-dosing compared with a 66 to 68% patient response in other comparative trials using unencapsulated 50 mg sumatriptan. [5] Hence we believe that in Sandrini et al.¡¯s comparative trial, the encapsulation of the comparator drug most likely introduced a potential bias against sumatriptan. Therefore they can only infer from their study that eletriptan is superior to non-commercial encapsulated 50 mg sumatriptan.
References
1. Sandrini G, Farkkila M, Burgess G, Forster E, Haughie S; Eletriptan Steering Committee. Eletriptan vs sumatriptan: a double-blind, placebo-controlled, multiple migraine attack study. Neurology 2002;59:1210 -1217.
2. Goadsby PJ, Ferrari MD, Olesen J, et al. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Eletriptan Steering Committee. Neurology 2000;54:156-163.
3. US Department of health and Human Services, Center for Drug Evaluation and Research, Guidance for industry BA and BE studies for orally administered drug products ¨C general considerations. August 1999. Available at: http//www.fda.gov/cder/guidance. Accessed November 2002.
4. Fuseau E, Petricoul O, Sabin A, et al. Effect of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine. Clin Ther 2001;23:242-251.
5. Deleu D, Hanssens Y. Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol 2000;40:687-700.