Histamine H1-receptor antagonist activity assessed in conscious dogs

Wright, Annette; Raval, P.; Eden, R. J.; Owen, David A.

doi:10.1016/0160-5402(87)90004-0

Cited by 7 publications

(1 citation statement)

References 4 publications

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“…It is a potent Ikr channel blocker, causing QT prolongation as part of its pharmacology (Vaughan Williams 1970, Katoh et al 1990. Dog is widely used in drug discovery and development to evaluate pharmacokinetics, metabolism and toxicology (Wright et al 1987) and has also been used in the study of TDP (Gras and Llenas 1999).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic assessment of the effects of E4031, cisapride, terfenadine and terodiline on monophasic action potential duration in dog

et al. 2001

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1. Torsades de pointes (TDP) is a potentially fatal ventricular tachycardia associated with increases in QT interval and monophasic action potential duration (MAPD). TDP is a side-effect that has led to withdrawal of several drugs from the market (e.g. terfenadine and terodiline). 2. The potential of compounds to cause TDP was evaluated by monitoring their effects on MAPD in dog. Four compounds known to increase QT interval and cause TDP were investigated: terfenadine, terodiline, cisapride and E4031. On the basis that only free drug in the systemic circulation will elicit a pharmacological response target, free concentrations in plasma were selected to mimic the free drug exposures in man. Infusion regimens were designed that rapidly achieved and maintained target-free concentrations of these drugs in plasma and data on the relationship between free concentration and changes in MAPD were obtained for these compounds. 3. These data indicate that the free ED50 in plasma for terfenadine (1.9 nM), terodiline (76 nM), cisapride (11 nM) and E4031 (1.9 nM) closely correlate with the free concentration in man causing QT effects. For compounds that have shown TDP in the clinic (terfenadine, terodiline, cisapride) there is little differentiation between the dog ED50 and the efficacious free plasma concentrations in man (< 10-fold) reflecting their limited safety margins. These data underline the need to maximize the therapeutic ratio with respect to TDP in potential development candidates and the importance of using free drug concentrations in pharmacokinetic/pharmacodynamic studies.

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Section: Introductionmentioning

confidence: 99%