Thiopental and esomeprazole in critically ill patients: Drug interaction.
Amélie Marsot (1), Françoise Goirand (2), Nadine Milési (3), Monique Dumas (2), Audrey Boulamery (1), Nicolas Simon (1)
(1) Service de Pharmacologie Médicale et Clinique APHM, Aix Marseille Université, Marseille, France; (2) Laboratoire de Pharmacologie-Toxicologie, CHU Dijon, France, (3) Service de Réanimation Chirurgicale, CHU Dijon, France.
Objectives: Thiopental is a thiobarbiturate given for induction of anesthesia or in case of brain injuries to reduce intracranial pressure and to manage cerebral ischemia. Esomeprazole is a proton pump inhibitor used to reduce stress ulcers, erosions of the stomach and upper gastrointestinal bleeding that are complications in critically ill patients. Previously a two-compartment model was described in critically ill patients [1] but esomeprazole wasn’t yet marketed. A new model is proposed describing the influence of concomitant administration of esomeprazole on the volume of distribution of thiopental.
Methods: 59 critically ill patients (weight: 16.9-114kg) aged 5 to 78 years, admitted in critical care unit for treatment of intracranial hypertension, induced by traumatic (58%), vascular (27%) or other origin (15%) acute brain diseases, were studied. High dose thiopental was administered by continuous infusion. Total mean dose of 295 +/- 181.3 mg/kg was given in 96 +/- 72 hours. Blood thiopental concentrations were determined by a liquid chromatography method. Pharmacokinetic analysis was performed by using a non linear mixed-effect population model (NonMEM software).
Results: A one-compartment open model with first-order elimination including two covariates: body weight on clearance and volume of distribution, and administration of esomeprazole on volume of distribution were used. The population typical mean (percent relative standard error (%RSE)) values for total clearance (CL), central volume of distribution (Vd) in patients with and without administration of esomeprazole were 5.4 L/h (8.5%), 261.0 L (6.6%) and 132.6 L (10.9%), respectively. The interindividual variabilities (%RSE) of CL and Vd were 50.3 % (21.5%) and 24.9% (34.1%), respectively. The residual variability (%RSE) was 7.12 mg (16.7%).
Conclusions: The pharmacokinetic parameters of thiopental in critically ill patients were estimated. These results are comparable to those presented by Russo in patients without administration of esomeprazole. Concomitant administration of thiopental and esomeprazole causes an increase in the volume of distribution of thiopental. A dose adjustment should be made to achieve the target concentrations in patients receiving esomeprazole. Esomeprazole has been reported as an inhibitor of P-glycoprotein which may suggest other potential drug interactions. Further studies on concomitant administration of esomeprazole should be conducted. .
References:
[1] H Russo et al. Clinical Pharmacology and Therapeutics 1997;62:15-20.