A model-based approach to treatment comparison in acute migraine.
OBJECTIVE
Currently, direct comparisons between 5-HT(1B/d) receptor agonists are used to assess differences and similarities in antimigraine response. Such comparisons depend on the selected sampling time and do not allow evaluation of entire response profiles. A thorough evaluation of drug properties requires that the time course of the response be taken into account. In this investigation we show the advantages of a model-based approach to compare the efficacy of two triptans (sumatriptan vs. naratriptan).


METHODS
A Markov model was used to describe the course of a migraine attack over three clinically identified stages. Drug effects were modelled as concentration-dependent increases in transition rates and were parameterised as potency (EC(50)) and maximum effect (E(max)). Parameters were estimated using headache measurements from efficacy studies. Model estimates were then used to compare the pharmacodynamics of the two drugs in a time-independent manner.


RESULTS
Efficacy parameters could be derived, allowing for comparison between compounds. The potency ratio (EC50(suma)/EC50(nara)) for headache relief was 3.3 (0.9, 12). The ratio of maximum effects (Emax(suma)/Emax(nara)) for this endpoint was 0.74 (0.55, 0.97). To interpret these efficacy measures and explore their value for the development of antimigraine drugs, results were evaluated against the reported in vitro potency at 5-HT(1B) and 5-HT(1D) receptors.


CONCLUSIONS
Comparison of the effects of two or more drugs based on preset sampling times does not allow proper assessment of the antimigraine properties in vivo. Disease dynamics must be considered to evaluate treatment response adequately and optimise the dosing regimen in migraine.
Maas
Hugo J
HJ
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, the Netherlands.
Danhof
Meindert
M
Della Pasqua
Oscar
O
D004305:Dose-Response Relationship, Drug; D006801:Humans; D008390:Markov Chains; D008881:Migraine Disorders / Q000188:drug therapy*; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018170:Sumatriptan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014363:Tryptamines / Q000008:administration & dosage / Q000493:pharmacokinetics*
D010880:Piperidines; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D018170:Sumatriptan; C106783:naratriptan