Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients

Wildt, Saskia N. de; Hoog, Matthijs de; Vinks, Alexander A.; Giesen, Eva; Anker, J. N. van den

doi:10.1097/01.ccm.0000084806.15352.da

Cited by 122 publications

(76 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This approach provides for the preservation of data structure so that each individual condition contributes to the population description. The model estimate of clearance of midazolam was 18.5 l/h at 36.5°C, which was consistent with previous studies (Bolon et al, 2003;de Wildt et al, 2003;Shimizu et al, 2007). The relationship between core body temperature and the midazolam systemic clearance was described using the function, CL (liters per hour) ϭ 18.5 ϫ (TEM/36.5) 4.24 , which provided the basis for predicting the temperature relationship with clearance of midazolam.…”

Section: Pharmacokinetic Variables For Four Treatments From Noncomparsupporting

confidence: 65%

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

Hostler

Zhou

Tortorici

et al. 2010

Drug Metabolism and Disposition

View full text Add to dashboard Cite

ABSTRACT:The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4°C saline infusions and 4°C saline ؉ magnesium) and two normothermia groups (37°C saline infusions and 37°C saline ؉ magnesium). The lowest temperatures achieved in the 4°C saline ؉ magnesium and 4°C saline infusions were 35.4 ؎ 0.4 and 35.8 ؎ 0.3°C, respectively. A significant decrease in the formation clearance of the major metabolite 1-hydroxymidazolam was observed during the 4°C saline ؉ magnesium compared with that in the 37°C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5°C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted.

show abstract

Section: Pharmacokinetic Variables For Four Treatments From Noncomparsupporting

confidence: 65%

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

Hostler

Zhou

Tortorici

et al. 2010

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…We measured only midazolam, not its active metabolite, 1 0 -hydroxymidazolam. However, the plasma concentration of 1 0 -hydroxymidazolam is approximately 20% [21], and the affinity of 1 0 -hydroxymidazolam to the benzodiazepine receptor is approximately 60% of that of midazolam [22]. Of importance, approximately 90% of 1 0 -hydroxymidazolam is conjugated to form 1 0 -hydroxymidazolam glucuronide [21], which is only of clinical relevance in renal failure where accumulation occurs [22], suggesting that it has only a small effect on the EEG.…”

Section: Discussionmentioning

confidence: 95%

Electroencephalographic response following midazolam-induced general anesthesia: relationship to plasma and effect-site midazolam concentrations

et al. 2010

View full text Add to dashboard Cite

show abstract

“…In order to minimize drug dependence and unnecessarily long hospital admissions while maintaining adequate control of pain and anxiety or excitement, a growing number of pharmacokinetic and pharmacodynamic studies are performed in patients of diff erent age groups, varying from neonates to adolescents (Peeters et al, 2006;Bouwmeester et al, 2004;Peters et al, 2006;Simons and Anand, 2006;de Wildt et al, 2003). These studies require the quantifi cation of drugs and their metabolites in a limited sample volume.…”

Section: Introductionmentioning

confidence: 99%

Quantification of midazolam, morphine and metabolites in plasma using 96‐well solid‐phase extraction and ultra‐performance liquid chromatography–tandem mass spectrometry

Ahsman

Nagel

Mathôt

2010

Biomedical Chromatography

View full text Add to dashboard Cite

Currently, pharmacokinetic-pharmacodynamic studies of sedatives and analgesics are performed in neonates and children to find suitable dose regimens. As a result, sensitive assays using only small volumes of blood are necessary to determine drug and metabolite concentrations. We developed an ultra-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of midazolam, 1-hydroxymidazolam, hydroxymidazolamglucuronide, morphine, morphine-3-glucuronide and morphine-6-glucuronide in 100 microL of plasma. Cleanup consisted of 96 wells micro-solid phase extraction, before reversed-phase chromatographic separation (ultra-performance liquid chromatography) and selective detection using electrospray ionization tandem mass spectrometry. Separate solid-phase extraction methods were necessary to quantify morphine, midazolam and their metabolites because of each group's physicochemical properties. Standard curves were linear over a large dynamic range with adequate limits of quantitation. Intra- and interrun accuracy and precision were within 85-115% (of nominal concentration using a fresh calibration curve) and 15% (coefficient of variation, CV) respectively. Recoveries were >80% for all analytes, with interbatch CVs (as a measure of matrix effects) of less than 15% over six batches of plasma. Stability in plasma and extracts was sufficient, allowing large autosampler loads. Runtime was 3.00 min per sample for each method. The combination of 96-well micro-SPE and UPLC-MS/MS allows reliable quantification of morphine, midazolam and their major metabolites in 100 microL of plasma.

show abstract

Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients

Cited by 122 publications

References 30 publications

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

Electroencephalographic response following midazolam-induced general anesthesia: relationship to plasma and effect-site midazolam concentrations

Quantification of midazolam, morphine and metabolites in plasma using 96‐well solid‐phase extraction and ultra‐performance liquid chromatography–tandem mass spectrometry

Contact Info

Product

Resources

About