A non-human primate model for investigating drug-induced risk of orthostatic hypotension and sympathetic dysfunction: Preclinical correlate to a clinical test

From the Cover: Evaluation of the Effects of Tanezumab, a Monoclonal Antibody Against Nerve Growth Factor, on the Sympathetic Nervous System in Adult Cynomolgus Monkeys (Macaca fascicularis): A Stereologic, Histomorphologic, and Cardiofunctional Assessment

“…8C and D ). The mean responses in tanezumab treated groups were typical, and similar to vehicle, as evidenced by a transient decrease in BP induced by the head-up tilt, which returned to pretilt (supine) levels within 20–30 s ( Figure 8C ) ( Bhatt et al , 2015 ). Isolated incidences of OH were observed during the 6-month treatment phase ( Table 4 ) and are detailed below.…”

“…In light of these morphologic changes and previously reported biochemical effects of anti-NGF ( Bjerre et al , 1975 ; Goedert et al , 1978 ), it was of interest to assess the function of the SNS in these animals. Radiotelemetry was used to assess ambulatory cardiovascular parameters and a validated nonclinical correlate of the clinical OH test was used to assess SNS function while undergoing a tilt challenge ( Bhatt et al , 2015 ). In these studies, one cohort of animals was treated the same way as in the morphology studies (approximately 5 times the clinical exposure) and another was dosed at a much higher level giving plasma exposure ∼900 times that achieved in the clinic.…”

“…The radiotelemetry device-fitted monkeys were also evaluated using a validated tilt paradigm to investigate the risk of OH ( Bhatt et al , 2015 ). Animals were acclimated to tilt chair procedures for a minimum of 3 months prior to baseline.…”

“…The tilt chair apparatus was designed to alternately position the conscious monkey between horizontal (supine in a seated position) and vertical (90° head-up) positions. The tilt procedure was conducted as previously described ( Bhatt et al , 2015 ). Briefly, the monkey was positioned horizontally (supine) for ∼10 min to achieve a stable hemodynamic baseline, followed by a 90° (head-up) vertical position for ∼3 min, then a horizontal position.…”