Effect of decontamination on the pharmacokinetics and pharmacodynamics of venlafaxine in overdose
Venkata Pavan Kumar Vajjah1, Geoffrey K Isbister2,3, Stephen B Duffull1
1. School of Pharmacy, University of Otago, Dunedin, New Zealand; 2. Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, NSW, Australia; 3. Menzies School of Health Research, Charles Darwin University, Darwin, Australia
Background and Objectives: Venlafaxine is a serotonin-noradrenalin reuptake inhibitor. The drug appears to be more toxic in overdose than other newer antidepressants, being associated with increased risk of seizures . Patients ingesting an overdose of venlafaxine are treated with decontamination procedures. Single dose activated charcoal (SDAC), whole bowel irrigation (WBI) and a combination of both (SDAC/WBI) are the most commonly used decontamination procedures. The aims of the work were 1. To quantify the effects of decontamination procedures on the pharmacokinetics of venlafaxine in overdose; 2. To investigate the relationship between decontamination procedures and seizure events. 3. To determine the time at which 90% (T90) of patients would have had their first seizure in the presence and absence of decontamination.
Methods: The PK data included 339 concentration time points from 76 venlafaxine overdose occasions; 69 took a slow release formulation; the median dose in the PK study was 2625 (150-13,500mg). The PD data included 436 overdose occasions (including the PK data set). The median dose in the PD study was 1500 mg (75-13500 mg). Seizures occurred in 5% of patients. In both studies SDAC, WBI, and SDAC/WBI were administered to patients according to the treating clinician. Data were modelled using WinBUGS. Compartmental models were used to describe the PK of venlafaxine in overdose. Logistic regression and time to event analysis were used to investigate the PD data.
Results: A one-compartment model with first-order input and elimination provided an adequate description of the PK data. No evidence of nonlinearities in the PK profile were seen. SDAC increased clearance of venlafaxine by 35% and SDAC/WBI reduced the fraction absorbed by 29%, but the latter produced a greater reduction in maximum plasma concentration (Cmax) for a similar drop in area under curve (AUC). A linear logistic regression model without random effects described the PD data well. Simulation from the model showed that the probability of seizure was 0.05 (0.03-0.08) at 1000 mg, 0.19 (0.09-0.35) at 5000 mg and 0.75 (0.30-0.96) at 10000 mg. At a dose of 2100 mg the odds ratios in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25-0.89), 0.71 (0.35-1.22) and 0.25 (0.08-0.62). Modified Gompertz model provided the best description of the time to seizures. Simulations from the time to event model showed that the T90 values for first seizure was 26 h at and was not affected by dose or decontamination procedure.
Conclusion: SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. The results of logistic regression analysis concur with the results from pharmacokinetic study. Patients should be observed for 24 hours based on the dose and risk of seizure occurring.
. Whyte, I.M., Dawson, A.H. & Buckley, N.A. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 96, 369-374 (2003).