The Effects of Sex and Genotype on the Population Pharmacokinetics and Pharmacodynamics Modeling and Simulation of Low Dose Epinephrine and Cardiac Output

Abstract

OBJECTIVEMen and women differ in cardiac output. We hypothesize a sex by genotype interaction may exist during a low‐dose adrenaline infusion affecting the β2 adrenergic receptor.METHODSSubjects: Ten males (mean ± SD: age=27.8±6.6, height=178.5±8.0cm, weight=83.9 ±12.4kg, BMI=26.3±2.9kg/m^2, BSA=2.0±0.2) and fourteen females (mean ± SD: age=26.3±5.9, height=164.3±7.0cm, weight=60.8±6.2kg, BMI=22.5±2.1kg/m^2, BSA=1.7±0.1) were studied. Three males were homozygous for Arginine (Arg/Arg) and 7 males were homozygous for Glycine (Gly/Gly) at position 16. In the female cohort, eight females were Arg/Arg and six females were Gly/Gly, at position 16. Procedure: A 1‐hour epinephrine infusion dosed at 5ng/kg/min was administered. BP was measured via an arterial catheter and HR via EKG. Stroke volume and Cardiac output were estimated via Modelflow and TPR was calculated. Plasma samples were collected at time: 0, 30, 45, 60, and 70 minutes and catecholamines measured using HPLC with electrochemical detection. Population Pharmacokinetic‐Pharmacodynamic Analysis: Plasma epinephrine concentrations and cardiac output responses were analyzed using the Nonlinear Mixed Effects (NLME) Stochastic Approximation Expectation‐Maximization (SAEM) algorithm in MATLAB® SimbiologyTM (version 2015a, Mathworks, Natick, MA). The Visual Predictive Check was conducted using the R statistical software (version 3.2.2, The R Foundation for Statistical Computing, Vienna, Austria).RESULTSEpinephrine pharmacokinetics were well‐described using a one‐compartment model with an ‘effect compartment’ and elimination from the central compartment. The population mean estimates for the volume of distribution and elimination rate were 22.81 L (CV=27.52%) and 8.77 L/hour (13.00%), respectively. Cardiac Output was modeled using the Hill Stimulation Equation and resulted in mean population estimates of E0=4.94 L/min (13.56%) for baseline, Emax=34.86 L/min (38.61%), and EC50=2486.23 ng/L (CV=5.54%). Bodyweight (mean=70kg) and Sex:Genotypes were the main covariates for the model. A visual predictive check revealed adequate central tendency for the linked PK/PD model. Dosing (300ng/kg/hour for a 70kg individual) simulations resulted in a PK/PD profile stratified for the population mean and Sex:Genotype covariates. Plasma Concentration‐Response curves produced subpopulation (Male Arg/Arg, Male Gly/Gly, Female Arg/Arg, and Female Gly/Gly) differences.CONCLUSIONBased on the plasma concentration‐response curves, the interaction of sex and genotype influences the ability to increase cardiac output during an infusion of low‐dose epinephrine.Support or Funding InformationNIH T32 Clinical Pharmacology Fellowship Grant GM008685‐17.