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, cardiovascula r, and metabolic effects of high-dose verapamil continuous intravenous infu sion 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 di sease and without cardiovascular, renal, or hepatic dysfunctions. Interventions: After a loading dose (0.15 mg/kg followed by 12 hrs of conti nuous intravenous infusion at 0.20 mg/kg/hr), the infusion rate of verapami l was increased every 24 hrs (0.25, 0.30, 0.35, and 0.40 mg/kg/kr). The hig hest 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 system ic clearance of verapamil and nor verapamil (active metabolite) for each in fusion rate were calculated. Mean arterial pressure (MAP), central venous p ressure (CVP), heart rate (HR), PR, QT and QTc intervals, and left ventricu lar ejection fraction (LVEF) were measured, as well as daily body weight, b lood glucose and potassium. C-ss of verapamil and nor-verapamil increased more than proportionally to t he 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 betw een MAP, HR, CVP, and verapamil plasma concentrations was significant (r(2) = .25, .14, and .35, respectively; p<.0001), LVEF did not change. Six pati ents (11 courses) developed junctional rhythm, Three patients (six courses) showed a PR interval increase (p <.05), Patients with junctional rhythm ha d higher Css of verapamil (p<.009). Overall, QT and QTc intervals increased (p<.01). A linear relationship was observed between verapamil plasma conce ntrations 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 ver apamil, 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 chan ges.