Respiratory safety pharmacology: positive control drug responses in Sprague-Dawley rats, Beagle dogs and cynomolgus monkeys.
Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.
Authier
Simon
S
LAB Research, Inc., Laval, Quebec, Canada H7V 4B3. authier@labresearch.com
Legaspi
Margarita
M
Gauvin
Dominique
D
Troncy
Eric
E
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D006985:Hyperventilation / Q000139:chemically induced / Q000503:physiopathology; D007040:Hypoventilation / Q000139:chemically induced / Q000503:physiopathology; D008252:Macaca fascicularis; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000145:classification; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D000077208:Remifentanil; D012119:Respiration / Q000187:drug effects*; D012129:Respiratory Function Tests; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D013045:Species Specificity
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D004364:Pharmaceutical Preparations; D010880:Piperidines; D016210:Methacholine Chloride; D000077208:Remifentanil; D000420:Albuterol