Non-linear pharmacokinetics of high-dose intravenous verapamil

Abstract

Aims: In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil.

Methods: We studied nine patients [seven males, two females; median age 46 years (range, 31-57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg-1 followed by 12 h continuous i.v. infusion at 0.20 mg kg-1 h-1), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg-1 h-1). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n = 4) or 60 to 108 h (n = 5). Blood samples and urine collections were taken every 12 h. Verapamil and nor-verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL = ko/Css) and renal clearance (CLr) of verapamil and nor-verapamil. The Css vs rate relationship was fitted to a Michaelis-Menten equation: Css = ko. (K(m)+Css)/(V.Vm).

Results: CL was dose-dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL +/- s.d. were 0.51 +/- 0.31, 0.38 +/- 0.16, 0.32 +/- 0.18, and 0.27 +/- 0.11 l h-1 kg-1, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg-1 h-1; P = 0.0001). Css increased more than proportionally to the dose rate and the Css vs rate relationship was best defined by a Michaelis-Menten equation (K(m) = 730 micrograms l-1; V.Vm = 0.55 mg kg-1 h-1), (r = 0.994; P = 0.006). CLr of verapamil and nor-verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose.

Conclusions: These findings suggest a non-linear, capacity-limited metabolic clearance of high-dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500-2500 ng ml-1) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses.