Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

Seyedeh Sana Khezrnia; Bita Shahrami; Mohammad Reza Rouini; Atabak Najafi; Hamid Reza Sharifnia; Sima Sadrai; Arezoo Ahmadi; Aarefeh  Jafarzadeh Kohneloo; Farhad Najmeddin; Mojtaba Mojtahedzadeh

doi:10.18502/acta.v60i1.8323

Seyedeh Sana Khezrnia Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
Bita Shahrami Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Mohammad Reza Rouini Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Atabak Najafi Department of Anesthesiology and Intensive Care, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Hamid Reza Sharifnia Department of Anesthesiology and Intensive Care, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Sima Sadrai Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Arezoo Ahmadi Department of Anesthesiology and Intensive Care, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Aarefeh Jafarzadeh Kohneloo Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
Farhad Najmeddin Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Mojtaba Mojtahedzadeh Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran

DOI: https://doi.org/10.18502/acta.v60i1.8323

Keywords: Phenobarbital; Pharmacokinetics; Brain injury; Critical illness; Therapeutic drug monitoring

Abstract

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t_1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: V_d: 0.81±0.15 L/kg; t_1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and V_dwere significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.