Population pharmacokinetics of intravenous midazolam in critically ill patients supported with extracorporeal membrane oxygenation therapy
Heungjo Kim (1, 2), Byung Hak Jin (3), Hongjae Lee (1, 2), Jin Wi (4, 5), Min Jung Chang (1, 2, 6)
(1) Department of pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea, (2) Department of Pharmaceutical Medicine and Regulatory, Yonsei University, Incheon, Republic of Korea, (3) Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea, (4) Division of Cardiology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea, (5) Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea, (6) Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon, Republic of Korea
Objectives: Extracorporeal membrane oxygenation (ECMO), allows the life-supporting treatment for patients who have severe cardiac or respiratory failure, and the instrument has been widely used over the past years [1-5]. Two types of ECMO devices are mainly used in the clinical settings, among which veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can support both pulmonary and cardiac function [6]. Patients who provided the aid of VA-ECMO needs sedation to prevent the kinking of the cannula and formation of air embolus due to spontaneous breathing during the early stage of treatment [7].
Midazolam is a benzodiazepine-based sedative and is used primarily in patients with VA-ECMO due to its short elimination and water solubility [8]. Midazolam is metabolized in the liver to an active metabolite; 1-hydroxymidazolam (1-OH midazolam), and an inactive form; 4-hydroxymidazolam.
ECMO and pathophysiological changes caused by critical illness significantly affect the pharmacokinetics (PK) of midazolam. However, there are few studies reported regarding the effects of extracorporeal membrane on midazolam PK.
To ensure its safety and efficacy for using in ICU, the optimized dosing regimen should be recommended. Therefore, we aimed to develop a population PK model of midazolam in ECMO patients.
Methods: We collected blood samples and patients’ demographics from 20 critically ill patients (15 males, 5 females) undergoing VA-ECMO in one tertiary level hospital. Blood samples were collected for 96 h during infusion and 72 h after cessation of midazolam. A population PK model was presented using MonolixSuite2023R1 (Lixoft, Antony, France). One- and two-compartments were tested as a potential structural model for midazolam and 1-OH midazolam. Based on the structural model selected, covariate screening was performed for all collected covariates (ECMO, body mass index, weight, gender, serum creatinine, albumin, aspartate aminotransferase; AST, alanine aminotransferase; ALT). With the inclusion of selected covariates, the final model for midazolam and 1-OH midazolam were evaluated by goodness-of-fit (GOF) plots, visual predictive check (VPC), and bootstrap.
Results: In total, for each of midazolam and 1-OH midazolam, 170 concentrations of 20 patients were collected. A two-compartment model best explained the PK of both midazolam and its active metabolite. Patients receiving ECMO tended to increase the central volume of distribution of metabolite (V1m). Higher ALT affected to decrease the intrinsic clearance of metabolite formation (CLMF). And the weight was converted into a log-transform, and as the value increased, central volume of distribution of parent drug (V1) also increased. The final population PK models of midazolam were best described by the following equations:
V1 = 23.17×(weight/69.44)^2.49
V1m = 1.67×(1+ECMO)^1.29
CLMF = 2.79×(ALT/117.65)^(-2.12)
Goodness‐of‐fit (GOF) plots demonstrated that the final model was described adequately.
Conclusions: This is the first study on a population PK model of midazolam in ECMO patients. Our results suggest that close monitoring of liver function, particularly ALT levels, is important for patients with ECMO. In addition, since the central volume of distribution of the parent drug (V1) is affected by the patient's weight, a higher dose of midazolam may be required as the weight increases to provide effective analgesia and sedation and promote recovery.
(This work was supported by a grant (No. 2020R1F1A107054913) from the National Research Foundation (NRF) of Korea, funded by the Korean government (Ministry of Science, ICT & Future Planning.)
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