Pilot Evaluation of Telemetered Cardiac Hemodynamics in the Setting of Fully‐Implanted Programmable Drug Delivery in Rats: A New Tool for Cardiovascular Drug Discovery?

Abstract

IntroductionThe mechanistic understanding of pharmacokinetics–pharmacodynamics (PK/PD) relationships is a key component of modern cardiovascular drug discovery. However, given that both PK properties and/or experimental techniques (such as anesthesia) can alter auto‐regulatory/autonomic control in vivo (thus masking true PD responses), tools permitting the determination of translationally‐relevant PK/PD relationships for cardio‐active agents are limited. This pilot study established the feasibility of combining implantable programable infusion pumps and telemetered cardiac hemodynamic monitoring for the assessment PK‐independent PD responses in untethered conscious rats.MethodsHealthy Sprague‐Dawley rats (n = 7) were chronically instrumented with both a digital telemetered micro‐manometer catheter (HD‐S21, Data Sciences International) in the LV, and with a fully‐implanted programmable/refillable infusion pump in a femoral vein (iPRECIO® SMP‐200). The pumps were programmed, a priori, to perform (after a 21‐day recovery period) a two‐arm drug delivery protocol, consisting (each arm) of a 72h active period (ON, @12.5μL/hr) followed by a 96h washout (OFF period, on patency mode @1μL/hr); prior to each active period the pumps were loaded with either vehicle (CTRL) or a novel pure negative inotrope (MYK‐581), while normal saline was loaded prior to OFF periods. Left‐ventricular pressures (LVP) and derived functional indices were evaluated continuously (via telemetry) before/during active periods, while cardiac function/geometry were assessed (via echocardiography) prior to the end of the active period.ResultsFully implanted conscious rats had normal cardiac hemodynamics (HR: 339 ± 8 bpm, LVPmax: 119±3 mmHg) and cardiac function (EF: 76 ± 2%, FS: 47± 1%, and dLVP/dtmax: 9275 ± 369 mmHg/s), showing normal circadian oscillations. Similar observations were made during vehicle administration (e.g., EF: 77 ± 1%, and dLVP/dtmax: 9585 ± 891 mmHg/s), while marked reductions in both echocardiographic (EF: 45 ± 8.7%, FS: 24 ± 6%, P < 0.05 vs. VEH) and LVP‐derived (dLVP/dtmax: −21 ± 6%, or 7313 ± 819 mmHg/s, P < 0.05 vs. VEH) functional indices were observed during the MYK‐treatment period.ConclusionsTaken together, these data demonstrate that telemetered hemodynamics and fully‐implanted programmable/refillable infusion pump technologies can be successfully integrated in vivo in order to generate translationally‐relevant PK‐independent pharmacodynamics data in untethered conscious rats.Support or Funding InformationThese studies were supported by MyoKardia