A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data

Abstract

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. The final combined dataset consisted of 266 plasma drug concentrations in 45 subjects with a median (interquartile range) postnatal age of 40.1 (11.0-120.4) days and weight of 3.9 (3.1-5.1) kg. Since the median sampling time after the first dose was short (study: 95 h; literature: 72 h) relative to the terminal half-life estimated in adult PopPK studies, values of the deep compartment volume and flow were fixed to literature values. A 3-compartment model best described the data and was validated by visual predictive checks and non-parametric bootstrap analysis. The final model included body weight as a covariate on all volumes and on both inter-compartmental and elimination clearances. The empiric Bayesian estimates for clearance (CL), volume of distribution at steady state, and terminal half-life were 0.25 (90% CL 0.14-0.36) L/kg/h, 93 (68-174) L/kg, and 266 (197-477) h, respectively. These studies will provide useful information for future PopPK studies of amiodarone in infants and children that could improve dosage regimens.

Evaluation of Different Formulations and Routes for the Delivery of the Ionizing Radiation Mitigator GS-Nitroxide (JP4-039)

“…The results of the present study demonstrate highly effective mitigation against total-body irradiation using JP4-039 delivered IM in captisol (35,36), cyclodextrin (37,39), or Miglyol-812-N (25) with Miglyol-812-N being the easiest to prepare.…”

“…There are multiple FDA-approved drugs containing Captisol. Some examples include Kyprolis (33), IV administration of Vfend-Lyophilized powder (34), and Nexterone (Amiodarone) (35). Each ml of Nexterone Figure 16.…”

“…The comparison between each treated group and the radiation only group was performed with the stratified log-rank test. Bonferroni correction method was used to adjust the p-values (Table I) (35). A Phase II study has been performed using Captisol as a formulation for delivery of melphalan (36) in the BEAM regimen to prepare lymphoma patients for autologous stem cell transplantation.…”

Acute Fulminant Hepatic Failure and Renal Failure Induced by Oral Amiodarone: A Case Report and Literature Review

“…Amiodarone is slowly and widely distributed and is highly lipophilic. It has a remarkable volume of distribution and is metabolized by the liver via cytochrome P4502C8 (CYP2C8) and cytochrome P450 3A4 (CYP3A4) [2]. Enteral administration takes between two and 21 days to fully achieve the antiarrhythmic effect.…”

“…Enteral administration takes between two and 21 days to fully achieve the antiarrhythmic effect. Interestingly, a single oral dose of oral amiodarone has a mean half-life elimination of 58 days [2]. With this being said, amiodarone is associated with a high incidence of adverse events and patients must be monitored closely for any complications.…”