Evaluation of the sensitivity of a new fully implantable telemetry device and the importance of simultaneously measuring cardiac output and left ventricular pressure.
BACKGROUND
The absence of drug-induced changes in heart rate (HR), aortic pressure (AOP) and ECG, the minimum endpoints suggested in ICH S7A, does not necessarily indicate the absence of cardiovascular (CV) pharmacodynamic activity. This potential pitfall can be avoided by prospectively incorporating "follow-up" endpoints in initial evaluations made possible by the advent of new telemetry implants capable of also measuring changes in cardiac output (CO) and left ventricular pressure (LVP). The purpose of this study was (1) to evaluate the sensitivity of a new, fully implantable telemetry device, and (2) to highlight the importance of the device to simultaneously measure cardiac output and left ventricular pressure in order to adequately evaluate the full potential for a drug to impact global cardiovascular function.


METHODS
4 dogs were instrumented with Konigsberg Instruments, Inc. (KI) TU7/T27H series fully implantable telemetry device and recovered for >8weeks. Sotalol (8mg/kg), milrinone (0.2mg/kg), hydralazine (0.2mg/kg) and control were administered 1week apart. Data were collected for 1h pre- and 24h post-treatment and time-averaged to fully characterize the a priori pharmacodynamic effects of interest for each drug. This included PR and QTci (sotalol); HR, AOP and LVP (milrinone); HR, AOP, CO and systemic vascular resistance (SVR) (hydralazine).


RESULTS
Expected changes in CV parameters were observed following all drugs with the following detection sensitivities: PR and QTci of 4ms and 3ms, respectively (sotalol); AOP and LVP dP/dt+max of 5mmHg and 232mmHg/s, respectively (milrinone); HR, CO and SVR of 11bpm, 0.302l/min and 5mmHg∗min/l, respectively (hydralazine).


CONCLUSIONS
KI TU7/T27H implant detects drug-induced CV changes with statistical significance using a standard, four-subject design. The ability of the TU7/T27H to also measure CO and LVP allowed for full characterization of the CV impact of hydralazine and milrinone, which could have been misinterpreted/missed altogether if these drugs were novel and the endpoints evaluated were prospectively limited to the minimum suggested in ICH S7A.
Baxter Healthcare Corporation, 25212 W. Illinois Route 120, Round Lake, IL 60050, United States. Electronic address: jeff_mckee@baxter.com.
Jeffrey
J
McKee
Baxter Healthcare Corporation, 25212 W. Illinois Route 120, Round Lake, IL 60050, United States.
Justin
J
Daller
Baxter Healthcare Corporation, 25212 W. Illinois Route 120, Round Lake, IL 60050, United States.
Bernhard
B
Baumgartner
RMISS, 56 Beverly Drive, Lakeville, PA 18438, United States.
Steve
S
Pettinger
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects*; D004285:Dogs; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects*; D006830:Hydralazine / Q000494:pharmacology; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology; D013686:Telemetry / Q000295:instrumentation / Q000379:methods*; D017725:Ventricular Pressure / Q000187:drug effects*
D006830:Hydralazine; D013015:Sotalol; D020105:Milrinone
Blood flow; Cardiac output; Hydralazine; ICH S7A; Implants; Methods; Milrinone; Safety pharmacology; Sotalol; Telemetry