Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?

Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of ‘true’ paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated ‘true’ paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on ‘true’ CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age

Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

Introduction: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. Methods: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106–193.1 kg] and body mass index [BMI] of 45.1 kg/m2 [40–55.2 kg/m2]) and eight non-obese patients (with a TBW of 69.4 kg [53.4–91.7] and BMI of 21.8 kg/m2 [19.4–27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. Results: In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC0–8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0–8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001). Conclusion: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment

Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults

Background The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. Methods Data from 19 obese adolescents [102.7 kg (62–149.5 kg)] and 20 morbidly obese adults [144 kg (112–186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW − WTfor age and length) was evaluated. Results The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called ‘excess weight’ model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed. Discussion We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents

Towards rational dosing algorithms for vancomycin in neonates and infants based on population pharmacokinetic modeling

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De status van de link: een uitgemaakte zaak? [article]

For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month