Pharmacokinetic and pharmacodynamic effects of high-dose continuous intravenous verapamil infusion: Clinical experience in the intensive care unit

Objective: Our study aimed at evaluating the pharmacokinetic, cardiovascular, and metabolic effects of high-dose verapamil continuous intravenous infusion in cancer patients, Design: Prospective clinical and pharmacokinetic study, Setting: Intensive care unit of a Cancer Research Institute. Patients: Nine patients (age range 31 to 57 yrs) with progressive cancer disease and without cardiovascular, renal, or hepatic dysfunctions. Interventions: After a loading dose (0.15 mg/kg followed by 12 hrs of continuous intravenous infusion at 0.20 mg/kg/hr), the infusion rate of verapamil was increased every 24 hrs (0.25, 0.30, 0.35, and 0.40 mg/kg/kr). The highest rate was maintained for 48 hrs, Doxorubicin was given from the 60th to the 108th hr, Hydrochlorothiazide (25 mg/day) and potassium (36 mmol/day) were given orally. Altogether, 17 courses were completed, Measurements and Main Results: Steady state concentration (C-ss) and systemic clearance of verapamil and nor verapamil (active metabolite) for each infusion rate were calculated. Mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), PR, QT and QTc intervals, and left ventricular ejection fraction (LVEF) were measured, as well as daily body weight, blood glucose and potassium. C-ss of verapamil and nor-verapamil increased more than proportionally to the infusion rate (p <.001), Systemic clearance of verapamil decreased over the range of the infusion rate (p <.005), MAP and HR decreased at the 12th hr(p<.001) and then plateaued, CVP increased (p<.01), The relationship between MAP, HR, CVP, and verapamil plasma concentrations was significant (r(2) = .25, .14, and .35, respectively; p<.0001), LVEF did not change. Six patients (11 courses) developed junctional rhythm, Three patients (six courses) showed a PR interval increase (p <.05), Patients with junctional rhythm had higher Css of verapamil (p<.009). Overall, QT and QTc intervals increased (p<.01). A linear relationship was observed between verapamil plasma concentrations and QT intervals (r(2) = .09, p<.01), Cardiovascular side effects did not determine treatment withdrawal in any patient, Body weight, blood glucose, and potassium did not show significant changes, Conclusions: Our data suggest a capacity-limited clearance of high-dose verapamil, In the absence of heart disease, following a step by step increase of the dosage, the high plasma verapamil concentrations (617 to 2970 ng/mL) produce frequent but well tolerated hemodynamic and electrocardiogram changes.