Pharmacokinetics / Pharmacodynamics of Intravenous Bolus Nicardipine in Adults Undergoing Cardiovascular Surgery
Divya Menon (1), John T. Mondick (1), Bhuvana Jayaraman (1), Albert T. Cheung (2), Jeffrey S. Barrett (1)
(1) Laboratory for Applied PK/PD, Division of Clinical Pharmacology and Therapeutics, The Children’s Hospital of Philadelphia, PA. (2) Department of Anesthesia, University of Pennsylvania, Philadelphia, PA.
Background: Nicardipine is a dihydropyridine calcium channel antagonist with selectivity for the coronary and peripheral vasculature, and minimal negative inotropic effects. The antihypertensive effect of nicardipine is characterized by a rapid onset of action and a short duration of effect, making it suitable for use in perioperative conditions. IV bolus administration of nicardipine in anesthetized patients has been shown to result in an acute decrease in arterial blood pressure without reflex tachycardia. Previous studies have concluded that nicardipine obeys linear pharmacokinetics.
Purpose: The objectives of this investigation were the following: (1) Construct a population pharmacokinetic / pharmacodynamic (PK/PD) model to describe the effect of an intravenous bolus nicardipine dose on the mean arterial blood pressure in anesthetized patients undergoing cardiovascular surgery. (2) Identify covariates that are predictors of variability. (3) Utilize the population PK/PD model to plan a multiple dose trial from which drug labeling can be defined.
Methods: A population PK/PD model was constructed from data collected from 40 anesthetized patients undergoing cardiovascular surgery, randomized to receive 0.25, 0.5, 1 or 2 mg of nicardipine. Nicardipine was administered directly into the right atrial port of the pulmonary artery catheter. PK samples were collected at predose, 2, 5, 7, 10, 20, 30, 90, 120, 180 and 240 min. Systolic and diastolic blood pressure was measured predose and every 15 seconds for up to 240s after nicardipine administration and every 60 s thereafter for up to 30 minutes. The data was analyzed using nonlinear mixed effects modeling with NONMEM. The predictive performance of the final model was evaluated by the predictive check method.
Results: The pharmacokinetics of nicardipine following IV bolus administration was well described by a two compartment model. The effects of nicardipine on mean arterial pressure were modeled using a slow receptor-binding model. The population mean (%CV) PK parameter estimates for CL, V1, Q and V2 were 23.6 (27.2) L/h, 0.22 (30.8) L, 10.3 (30.7) L/h and 3.08 (23.1) L. A graded increase in clearance was observed with increasing doses.
Conclusions: Contrary to the results reported following administration of an infusion, an effect mediated increase in the clearance of nicardipine was observed. We are exploring design elements in the planned multiple dose trial to aid us in discriminating equally plausible models. All possible models and approaches are discussed.
Cheung et al, Anesth Analg 1999, 89:1116-23