2013
   Glasgow, Scotland

Stochastic Simulations Assist to Select the Intravenous Digoxin Dosing Protocol in Elderly Patients in Acute Atrial Fibrillation

Ramon-Lopez Amelia (1), Más-Serrano Patricio (1,2), Mas-Fuster Maria Isabel (1), Carlos Pastor-Cerdán (2), Nalda-Molina Ricardo (1).

(1) Department of Engineering, Pharmacy and Pharmaceutics Division, University of Miguel Hernandez, San Juan de Alicante, Spain. (2) Clinical Pharmacokinetics Unit, Pharmacy Department, Hospital General Universitario de Alicante, Alicante, Spain)

Objective: To select the optimal intravenous (IV) loading dose schedule for digoxin in patients under acute atrial fibrillation (AAF), by using stochastic simulations of a previously published population pharmacokinetic model [1].

Methods: Five different IV dosing protocols of digoxin in AAF described in the literature [1,2,3,4] have been evaluated in terms of efficacy and toxicity. In three of them, either creatinine clearance or weight was included in the protocol to select the IV dosing schedule. The other two protocols did not include any covariate to select the IV dosing, relying it on the physician criteria. To evaluate these protocols, 1000 patients were simulated using NONMEM 7.2, based on a previously published population pharmacokinetic model [1]. To generate the input dataset, the covariates of 100 elderly patients with AAF, obtained from a dataset of the University Hospital of Alicante were resampled 1000 times. The criteria for toxicity and inefficacy of treatment were digoxin plasma concentrations at 8 hours after the last dose > 2 ng/mL and < 0.8 ng/mL, respectively.

Results: The simulations showed significant differences in the outcomes of the different protocols. The best protocol had 81% of the simulated patients within the proposed therapeutic range (0.8-2 ng/mL). The other protocols had lower percentages of 52%, 65%, 70% and 80%. Once the best protocol was selected,  a simplification of this protocol was proposed with the objective of starting the maintenance dose at the usual time in hospital wards (08 00 am) and achieve the maximum percentage of patients within the therapeutic range. To do so, the last dose included in the protocol was either given or not, depending on the time of the initiation of the therapy.

Conclusion: Although IV digoxin is a drug widely used in AAF, there is not a gold standard for the IV loading dose schedule. Stochastic simulations are useful to evaluate the different protocols described in the literature and assess the impact of patients' covariates as well as the time of the initiation of the therapy.

References:
[1] Hornestam B et al. Intravenously administered digoxin in patients with acute atrial fibrillation: a population pharmacokinetic/pharmacodynamic analysis based on the Digitalis in Acute Atrial Fibrillation trial. Eur J Clin Pharmacol (2003)
[2] Pujal-Herranz M et al. Intoxicaciones digitálicas agudas en pacientes de edad avanzada y propuesta de un nomograma de digitalización. Farmacia Hospitalaria (2007).
[3] Blanco-Echevarría A et al. Manual de Diagnóstico y Terapéutica Médica
[4] Anderson P et al. Handbook of Clinical Drug Data, 10th edition