Pilot study on the influence of liver blood flow and cardiac output on the clearance of propofol in critically ill patients

Objective To investigate the effect of cardiac output and liver blood flow on propofol concentrations in critically ill patients in the intensive care unit. Methods Five medical/surgical critically ill patients were enrolled in this preliminary study. Liver blood flow was measured using sorbitol. The cardiac output was measured by bolus thermodilution. NONMEM ver. V was applied for propofol pharmacokinetic analysis. Results The clearance of propofol was positively influenced by the liver blood flow (P < 0.005), whereas no significant correlation between cardiac output and propofol clearance was found. A correlation between liver blood flow and cardiac output or cardiac index could not be assumed in this patient group. Conclusions Liver blood flow is a more predictive indicator than cardiac output for propofol clearance in critically ill patients when the techniques of hepatic sorbitol clearance and bolus thermodilution, respectively, are used. Further study is needed to determine the role played by liver blood flow and cardiac output on the pharmacokinetics of highly extracted drugs in order to reduce the observed high interindividual variabilities in response in critically ill patients

Critical Illness Is a Major Determinant of Midazolam Clearance in Children Aged 1 Month to 17 Years

Background: In children, a large variability in pharmacokinetics of midazolam, a cytochrome P450 3A4/5 (CYP3A4/5) enzyme substrate, has been described, which cannot be explained by age-related changes alone. In this study, these age-related changes are studied in relation to other covariates to explain the variability in the pharmacokinetics of midazolam in children. Methods: Population pharmacokinetic modeling was performed using a joint dataset of 3 studies conducted previously: study 1: pediatric intensive care patients requiring sedation in the intensive care unit; study 2: pediatric oncology patients undergoing an invasive procedure; study 3: otherwise healthy infants admitted for postoperative monitoring after elective major craniofacial surgery. Midazolam, 1-hydroxymidazolam, and 1-hydroxymidazolam glucuronide concentrations were considered to determi Results: Fifty-four children aged between 1 month and 17 years who received intravenous midazolam (bolus and/or continuous infusion) for sedation were included in this study. A reduction of 93% for CYP3A4/5 (midazolam to 1-hydroxymidazolam) and 86% for uridine diphosphate glucuronosyltransferase (1-hydroxymidazolam to 1-hydroxymidazolam glucuronide) mediated clearance was found in pediatric intensive care patients compared with the other 2 patient groups. We did not find a significant influence Conclusions: From infancy to adolescence, critical illness seems to be a major determinant of midazolam clearance, which may result from reduced CYP3A4/5 activity due to inflammation. This may have important implications for dosing of midazolam and other CYP3A drug substrates in critically ill children

Prediction of Propofol Clearance in Children from an Allometric Model Developed in Rats, Children and Adults versus a 0.75 Fixed-Exponent Allometric Model

Background and Objective: For propofol clearance, allometric scaling has been applied successfully for extrapolations between species (rats and humans) and within the human bodyweight range (children and adults) In this analysis, the human bodyweight range is explored to determine for which range an allometric model with a fixed or estimated exponent can be used to predict propofol clearance, without correction for in maturation Methods: The predictive value of the allometric equation, clearance (CL) is equal to 0.071 x bodyweight in kg(0.78), which was developed from rats, children and adults, and the predictive value of a fixed exponent allometric model derived from the basal metabolic rate. CL is equal to CL standardized to a 70 kg adult x (bodyweight in kg standardized to a 70 kg adult)(0.75), were evaluated across five independent patient groups Including (i) 25 (pre)term neonates with a postmenstrual age of 27-43 weeks, (n) 22 postoperative infants aged 4-18 months; (m) 12 toddlers aged 1-3 years, (iv) 14 adolescents aged 10-20 years, and (v) 26 critically ill adults sedated long term The median percentage error of the predictions was calculated using the equation %error= (CLallometric CLt)/CLt x 100, where CLallometric is the predicted propofol clearance from the allometric equations for each individual and CLt is the individual-predicted (post hoc) propofol clearance value derived from published population pharmacokinetic models. Results: In neonates, the allometric model developed from rats, children and adults, and the fixed-exponent allometric model, systematically overpredicted individual propofol clearance, with median percentage errors of 288% and 216%, respectively, whereas in infants, both models systematically underpredicted propofol clearance, with median percentage errors of 43% and 55%, respectively In toddlers, adolescents and adults, both models performed reasonably well, with median percentage errors of -12% and 32%, respectively, in toddlers, 16% and 14%, respectively, in adolescents, and 12% and 18%, respectively, in adults Conclusion: Both allometric models based on bodyweight alone may be of use to predict propofol clearance in individuals older than 2 years. Approaches that also incorporate maturation are required to predict clearance under the an of 2 years

A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span

To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. Data from seven previously published propofol studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different structures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model. Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different exponents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight

Morphine Glucuronidation and Elimination in Intensive Care Patients: A Comparison with Healthy Volunteers

BACKGROUND: Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations. METHODS: A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion. RESULTS: For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers. CONCLUSIONS: Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made

A Novel Maturation Function for Clearance of the Cytochrome P450 3A Substrate Midazolam from Preterm Neonates to Adults

Major changes in cytochrome P450 (CYP) 3A activity may be expected in the first few months of life with, later, relatively limited changes. In this analysis we studied the maturation of in vivo CYP3A-mediated clearance of midazolam, as model drug, from preterm neonates of 26 weeks gestational age (GA) to adults. Pharmacokinetic data after intravenous administration of midazolam were obtained from six previously reported studies. Subjects were premature neonates (n = 24; GA 26-33.5 weeks, postnatal age (PNA) 3-11 days, and n = 24; GA 26-37 weeks, PNA 0-1 days), 23 children after elective major craniofacial surgery (age 3-23 months), 18 pediatric intensive-care patients (age 2 days-17 years), 18 pediatric oncology patients (age 3-16 years), and 20 healthy male adults (age 20-31 years). Population pharmacokinetic modeling with systematic covariate analysis was performed by use of NONMEM v6.2. Across the entire lifespan from premature neonates to adults, bodyweight was a significant covariate for midazolam clearance. The effect of bodyweight was best described by use of an allometric equation with an exponent changing with bodyweight in an exponential manner from 0.84 for preterm neonates (0.77 kg) to 0.44 for adults (89 kg), showing that the most rapid maturation occurs during the youngest age range. An in-vivo maturation function for midazolam clearance from premature neonates to adults has been developed. This function can be used to derive evidence-based doses for children, and to simulate exposure to midazolam and possibly other CYP3A substrates across the pediatric age range in population pharmacokinetic models or physiologically based pharmacokinetic models