Clinical Pharmacokinetics

, Volume 47, Issue 2, pp 139–146 | Cite as

Relevance of Absorption Rate and Lag Time to the Onset of Action in Migraine

  • Hugo J. Maas
  • Marc A. H. Spruit
  • Meindert Danhof
  • Oscar E. Della Pasqua
Original Research Article


Objective: The objective of this analysis was to simulate the performance of oral triptan formulations with varying absorption characteristics and their impact on the onset and magnitude of the antimigraine effect using a Markov model for migraine attacks.

Analysis: Sumatriptan pharmacokinetic data were obtained from clinical pharmacology studies in which marketed solid formulations were administered. Based on a population pharmacokinetic model, mean concentration-time profiles were generated by varying the absorption rate constant and lag time. Subsequently, the simulated profiles were evaluated in a disease model of migraine to predict the onset and duration of the effect (the pain-free, pain-relief response).

Results: Based on a therapeutic dose of 50 mg of sumatriptan, a maximum gain in the pain-free response of 12% was achieved with an increased absorption rate. This gain in the response was reached approximately 0.5 hours after administration. A decrease only in the lag time with respect to the currently available formulations (i.e. 0.24 hours) resulted in a maximum gain of 5% in the pain-free response, which in contrast may not be interpreted as clinically relevant.

Conclusion: Model-based predictions suggest that increases in the absorption rate of the currently marketed oral formulation of sumatriptan result in a gain in the pain-free response that is both clinically and statistically relevant.



This manuscript is part of a PhD research fellowship programme sponsored by GlaxoSmithKline, UK. GlaxoSmithKline had no further role in the research rationale, collection, analysis and interpretation of the data in the final contents of the manuscript submitted for publication. The authors have no conflicts of interest that are directly relevant to the content of this study.


  1. 1.
    McCrory DC, Gray RN. Oral sumatriptan for acute migraine. Cochrane Database Syst Rev 2003; (3): CD002915PubMedGoogle Scholar
  2. 2.
    Dodick DW. Triptan nonresponder studies: implications for clinical practice. Headache 2005; 45(2): 156–62PubMedCrossRefGoogle Scholar
  3. 3.
    Walls C, Lewis A, Bullman J, et al. Pharmacokinetic profile of a new form of sumatriptan tablets in healthy volunteers. Curr Med Res Opin 2004; 20(6): 803–9PubMedCrossRefGoogle Scholar
  4. 4.
    Sheftell FD, Dahlof CG, Brandes JL, et al. Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets. Clin Ther 2005; 27(4): 407–17PubMedCrossRefGoogle Scholar
  5. 5.
    Ahrens SP, Farmer MV, Williams DL, et al. Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Rizatriptan Wafer Protocol 049 Study Group. Cephalalgia 1999; 19(5): 525–30PubMedCrossRefGoogle Scholar
  6. 6.
    Stockli HR, Sword A. Zolmitriptan as fast-melt tablet in the acute treatment of patients with migraine attacks: the ZORO study. Schweiz Rundsch Med Prax 2003; 92(9): 379–89Google Scholar
  7. 7.
    Olson NZ, Otero AM, Marrero I, et al. Onset of analgesia for liquigel ibuprofen 400 mg, acetaminophen 1000 mg, ketoprofen 25 mg, and placebo in the treatment of postoperative dental pain. J Clin Pharmacol 2001; 41(11): 1238–47PubMedCrossRefGoogle Scholar
  8. 8.
    Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol 2004; 55(1): 19–26PubMedCrossRefGoogle Scholar
  9. 9.
    Hu XH, Raskin NH, Cowan R, et al. Treatment of migraine with rizatriptan: when to take the medication. Headache 2002; 42(1): 16–20PubMedCrossRefGoogle Scholar
  10. 10.
    Loder E. Menstrual migraine: timing is everything. Neurology 2004; 63(2): 202–3PubMedCrossRefGoogle Scholar
  11. 11.
    Maas HJ, Danhof M, Della Pasqua OE. Prediction of headache response in migraine treatment. Cephalalgia 2006; 26(4): 416–22PubMedCrossRefGoogle Scholar
  12. 12.
    Troconiz IF, Wolters JM, Tillmann C, et al. Modelling the anti-migraine effects of BIBN 4096 BS: a new calcitonin gene-related peptide receptor antagonist. Clin Pharmacokinet 2006; 45(7): 715–28PubMedCrossRefGoogle Scholar
  13. 13.
    Cosson VF, Fuseau E. Mixed effect modeling of sumatriptan pharmacokinetics during drug development: II. From healthy subjects to phase 2 dose ranging in patients. J Pharmacokinet Biopharm 1999; 27(2): 149–71PubMedGoogle Scholar
  14. 14.
    Box GEP, Cox DR. An analysis of transformations. J R Stat Soc Series B-Stat Methodol 1964; 26(2): 211–52Google Scholar
  15. 15.
    Rabiner LR. A tutorial on hidden Markov models and selected applications in speech recognition. Proc IEEE 1989; 77(2): 257–86CrossRefGoogle Scholar
  16. 16.
    Maas HJ, Danhof M, Della Pasqua, et al. A model-based approach to treatment comparison in acute migraine. Br J Clin Pharmacol 2006; 62(5): 591–600PubMedCrossRefGoogle Scholar
  17. 17.
    Holford NH, Sheiner LB. Pharmacokinetic and pharmacodynamic modeling in vivo. CRC Crit Rev Bioeng 1981; 5(4): 273–322Google Scholar
  18. 18.
    Tfelt-Hansen P, Block G, Dahlof C, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000; 20(9): 765–86PubMedCrossRefGoogle Scholar
  19. 19.
    Bureau A, Hughes JP, Shiboski SC. An S-Plus implementation of hidden Markov models in continuous time. J Computat Graphical Stat 2000; 9(4): 621–32Google Scholar
  20. 20.
    Anisimov VV, Maas HJ, Danhof M, et al. Analysis of responses in migraine modelling using hidden Markov models. Stat Med 2007; 26(22): 4163–78PubMedCrossRefGoogle Scholar
  21. 21.
    Edmeads J. Defining response in migraine: which endpoints are important?. Eur Neurol 2005; 53 Suppl. 1: 22–8PubMedCrossRefGoogle Scholar
  22. 22.
    Lanteri-Minet M. What do patients want from their acute migraine therapy?. Eur Neurol 2005; 53 Suppl. 1: 3–9PubMedCrossRefGoogle Scholar
  23. 23.
    Mondell BE. A review of the effects of almotriptan and other triptans on clinical trial outcomes that are meaningful to patients with migraine. Clin Ther 2003; 25(2): 331–41PubMedCrossRefGoogle Scholar
  24. 24.
    Lipton RB, Hamelsky SW, Dayno JM. What do patients with migraine want from acute migraine treatment?. Headache 2002; 42 Suppl. 1: 3–9PubMedCrossRefGoogle Scholar
  25. 25.
    Davies GM, Santanello N, Lipton R. Determinants of patient satisfaction with migraine therapy. Cephalalgia 2000; 20(6): 554–60PubMedCrossRefGoogle Scholar
  26. 26.
    Moschiano F, D’Amico D, Allais G, et al. Early triptan intervention in migraine: an overview. Neurol Sci 2005; 26 Suppl. 2: s108–10PubMedCrossRefGoogle Scholar
  27. 27.
    Rapoport AM, Bigal ME, Tepper SJ, et al. Intranasal medications for the treatment of migraine and cluster headache. CNS Drugs 2004; 18(10): 671–85PubMedCrossRefGoogle Scholar
  28. 28.
    Duquesnoy C, Mamet JP, Sumner D, et al. Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration. Eur J Pharm Sci 1998; 6(2): 99–104PubMedCrossRefGoogle Scholar
  29. 29.
    Oldman AD, Smith LA, McQuay HJ, et al. Pharmacological treatments for acute migraine: quantitative systematic review. Pain 2002; 97(3): 247–57PubMedCrossRefGoogle Scholar
  30. 30.
    Volans GN. Migraine and drug absorption. Clin Pharmacokinet 1978; 3(4): 313–8PubMedCrossRefGoogle Scholar
  31. 31.
    Boyle R, Behan PO, Sutton JA. A correlation between severity of migraine and delayed gastric emptying measured by an epigastric impedance method. Br J Clin Pharmacol 1990; 30(3): 405–9PubMedCrossRefGoogle Scholar
  32. 32.
    Cutler NR, Hussey EK, Sramek JJ. Oral sumatriptan in pharmacokinetics in the migrainous state. Cephalalgia 1991; 11 Suppl. 11: 222–3Google Scholar
  33. 33.
    Hussey EK, Donn KH, Busch MA, et al. Pharmacokinetics of oral sumatriptan in migraine patients during an attack and while pain free [abstract no. PI-46]. Clin Pharmacol Ther 1991; 49: 46Google Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Hugo J. Maas
    • 1
  • Marc A. H. Spruit
    • 1
  • Meindert Danhof
    • 1
  • Oscar E. Della Pasqua
    • 1
    • 2
  1. 1.Leiden/Amsterdam Center for Drug ResearchLeiden UniversityLeidenThe Netherlands
  2. 2.Clinical Pharmacology & Discovery MedicineGlaxoSmithKlineGreenfordUK

Personalised recommendations