Blood concentrations are better predictors of chioroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships

Abstract

Introduction: Chloroquine causes rare but life-threatening toxicity. The prognostic value of plasma chloroquine concentrations in acute poisonings remains poorly investigated. We investigated the hypothesis that blood chloroquine concentrations better predicted chloroquine poisoning severity than plasma concentrations.

Methods: A prospective study of consecutive chloroquine poisonings admitted to an intensive care unit from 2003 to 2007 was performed with simultaneous measurements of blood and plasma chloroquine (chloroquine and desethylchloroquine) concentrations. A population pharmacokinetic-pharmacodynamic model described epinephrine infusion rate, our surrogate marker of cardiovascular toxicity, as function of blood or plasma chloroquine concentrations.

Results: Forty-four patients [29F/15M, 33 years (25-41), median (25-75th percentile), 34% with cardiac arrest] were included. Management included mechanical ventilation (80%), 8.4% sodium bicarbonate (66%), epinephrine [73%, maximal rate: 2.8 mg/h (0.8-5.0)], and extracorporeal life support (16%). Seven patients died. Blood [6.7 mg/L (4.0-13.0)] and plasma [1.5 mg/L (1.2-2.9)] chloroquine concentrations were weakly, although significantly correlated (r = 0.66, p < 0.0001, Spearman test). Admission chloroquine concentrations correlated with the reported ingested dose (r = 0.70 for blood vs. 0.48 for plasma), QRS duration (r = 0.82 vs. 0.64), lactate concentrations (r = 0.63 vs. 0.47), and epinephrine infusion rates (r = 0.70 vs. 0.62). Chloroquine concentrations differed significantly between patients with and without cardiac arrest (p = 0.0002 for blood vs. 0.02 for plasma). A one-compartment pharmacokinetic (PK) model adequately described blood chloroquine concentrations. An effect compartment linked to the blood compartment adequately described plasma chloroquine concentrations. Using a sigmoidal E(max) pharmacodynamic (PD) model, epinephrine infusion rate was better predicted with blood than plasma concentrations (p < 0.01), suggesting that time-course of blood concentrations is a better prognostic value than plasma concentrations.

Conclusion: Immediate and serial measurements of blood chloroquine concentrations are better than plasma for predicting cardiovascular severity of chloroquine poisonings.