Abstract:
OBJECTIVES:To compare the relative tolerability of 5-HT1B/1D agonists and to investigate the relationships (if any) among systemic exposure, lipophilicity, and clinical tolerability for 5-HT1B/1D agonists. METHODS:Post hoc correlations were sought among the following variables: absolute dose (= administered dose x oral bioavailability), Cmax, LogDpH7.4 (LogD), frequencies of all, neurological and dizziness/somnolence/drowsiness adverse events, adjusted for corresponding placebo-associated frequencies. RESULTS:For effective doses of all drugs with available data, absolute dose-response relationships exist for adverse event frequencies. The overall rank order of the frequency of adverse events was as follows: naratriptan < sumatriptan = rizatriptan < zolmitriptan. With the exception of eletriptan, 5-HT1B/1D agonists exhibit correlations between absolute dose, Cmax (R = 0.97), and LogD (R = 0. 71). For neurological and dizziness/somnolence/drowsiness adverse event frequencies, the overall rank order was sumatriptan < naratriptan < rizatriptan < zolmitriptan. Neither LogD nor absolute dose size predicted adverse event frequencies. CONCLUSIONS:Triptans may be distinguished in terms of their tolerability. Effectiveness, absolute dose size, and lipophilicity are related for the 5-HT1B/1D agonists considered here, except eletriptan. Adverse event frequencies cannot be predicted from in vitro measures of lipophilicity, in vivo estimates of absolute bioavailability, dose size, or any combination of these variables. Since these drugs are all agonists at 5-HT1B/1D receptors in the low nanomolar range, but differ in their tolerability profiles, adverse effects are not likely to be mediated through 5-HT1B/1D receptors. Drugs of this class must be studied individually and on a reasonably large scale in clinical development programs.
journal_name
Headachejournal_title
Headacheauthors
Fox AWkeywords:
subject
Has Abstractpub_date
2000-07-01 00:00:00pages
521-7issue
7eissn
0017-8748issn
1526-4610pii
hed083journal_volume
40pub_type
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