Novel methods for the assessment of safety pharmacology and toxicology parameters in anesthetized and ventilated dogs receiving inhaled drugs

K Bujold; J Pfeiffer; J Fink; R Malcolmson; S Authier; J Tepper

doi:10.1016/j.vascn.2019.04.004

Novel methods for the assessment of safety pharmacology and toxicology parameters in anesthetized and ventilated dogs receiving inhaled drugs

J Pharmacol Toxicol Methods. 2019 Sep-Oct:99:106578. doi: 10.1016/j.vascn.2019.04.004. Epub 2019 May 9.

Authors

K Bujold¹, J Pfeiffer², J Fink³, R Malcolmson³, S Authier¹, J Tepper⁴

Affiliations

¹ Citoxlab North America, 445 Boul. Armand-Frappier, Laval (Quebec), H7V 4B3, Canada.
² Scientific Research Partners, 1077 Pearl Ave. Moss Beach, CA 94038, United States.
³ Aerogen Pharma, 1660 S Amphlett Blvd. Suite 360 San Mateo, CA 94402, United States.
⁴ 197 Glasgow Lane, San Carlos, CA 94070, United States. Electronic address: teppertox@gmail.com.

PMID: 31078712
DOI: 10.1016/j.vascn.2019.04.004

Abstract

Introduction: For nonclinical drug development, it is optimal if safety pharmacology and toxicology studies are performed in a model that reasonably represents the patient the drug is intended to treat. To simulate prolonged inhalation therapy in ventilated patients, GLP inhalation toxicology methods, including safety pharmacology endpoints, in anesthetized, intubated and mechanically ventilated dogs were developed. This model required establishment of a canine intensive care unit (ICU) capable of providing prolonged anesthesia (propofol infusion and morphine titration) and partial parenteral nutrition (dextrose, amino acids and lipids) while safety parameters were monitored.

Method: Telemetry was used to continuously monitor heart rate, ECG and blood pressure. Blood gas parameters were periodically measured while oxygen saturation and core temperature were reported continuously. Glucose was measured hourly while other standard clinical pathology (hematology, coagulation, clinical chemistry) samples were evaluated approximately every 12 h. Aerosols were administered continuously over 48 h by inhalation using a mesh nebulizer (Aerogen Solo) fed by a syringe pump into a humidified circuit of a critical care ventilator (LTV® 1000) ending in an endotracheal tube placed in the trachea. Animals were ventilated with pressure control ventilation targeting a respiratory minute volume of 2.0-3.5 l per minute (LPM). Peak inspiratory pressure (PIP) was maintained between 10 and 17 cm H₂O and inspiratory time was set to 1 s with an inspiratory:expiratory (I:E) ratio of 1:2. Ventilator parameters and anesthesia were adjusted to maintain normal PaCO₂ levels and adequate sedation, respectively. Novel methods were developed to determine dose and particle size in vitro as on-line measurements were not feasible during in vivo aerosol delivery.

Results and discussion: Acceptable baseline measurements were established for all parameters over the 48-h evaluation period, qualifying the method as appropriate for assessment of GLP safety pharmacology and toxicology studies.

Keywords: Anesthetized; Blood pressure; Dog; Electrocardiogram; Inhalation; Partial parenteral nutrition; Pulmonary function, clinical pathology, histopathology; Ventilated.