Size does matter : drug glucuronidation in children

The maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was developed for morphine, which was used as a paradigm compound. In this model, the maturation of morphine glucuronidation is described by a bodyweight-based exponential relationship with an exponent of 1.44. The model-derived dosing algorithm was evaluated prospectively in a clinical trial and it was shown that this dosing algorithm may reduce overdosing of neonates and exposure to ineffective doses in older infants. Additionally, it was found that the bodyweight-based exponential relationship that describes the maturation of morphine glucuronidation can be directly applied to the maturation of zidovudine, which is also a UGT2B7 substrate. This expedites the development of paediatric pharmacokinetic models and evidence-based paediatric drug dosing algorithms. Based on a study using physiologically-based pharmacokinetic modeling it was concluded that the equation for maturation of morphine glucuronidation could be applicable to all small molecular drugs and to paediatric patient populations with normal hepatic function. Finally, a framework was developed to properly validate paediatric pharmacokinetic population models and the validation of paediatric pharmacokinetic models for morphine in literature were investigated.TI PharmaUBL - phd migration 201

The Predictive Value of Glomerular Filtration Rate-Based Scaling of Pediatric Clearance and Doses for Drugs Eliminated by Glomerular Filtration with Varying Protein-Binding Properties

Introduction: For drugs eliminated by glomerular filtration (GF), clearance (CL) is determined by GF rate (GFR) and the unbound fraction of the drug. When predicting CL of GF-eliminated drugs in children, instead of physiologically based pharmacokinetic (PBPK) methods that consider changes in both GFR and protein binding, empiric bodyweight-based methods are often used. In this article, we explore the predictive value of scaling using a GFR function, and compare the results with linear and allometric scaling methods for drugs with different protein-binding properties. Methods: First, different GFR maturation functions were compared to identify the GFR function that would yield the most accurate GFR predictions across the pediatric age range compared with published pediatric inulin/mannitol CL values. Subsequently, the accuracy of pediatric CL scaling using this GFR maturation function was assessed and compared with PBPK CL predictions for hypothetical drugs binding, to varying extents, to serum albumin or α-acid glycoprotein across the pediatric age range. Additionally, empiric bodyweight-based methods were assessed. Results: The published GFR maturation functions yielded comparable maturation profiles, with the function reported by Salem et al. leading to the most accurate predictions. On the basis of this function, GFR-based scaling yields reasonably accurate (percentage prediction error ≤ 50%) pediatric CL values for all drugs, except for some drugs highly bound to AGP in neonates. Overall, this method was more accurate than linear or 0.75 allometric bodyweight-based scaling. Conclusion: When scaling CL and dose by GFR function, maturational changes in plasma protein concentrations impact GF minimally, making this method a superior alternative to empiric bodyweight-based scaling

The predictive value of glomerular filtration rate-based scaling of pediatric clearance and doses for drugs eliminated by glomerular filtration with varying protein-binding properties

Introduction For drugs eliminated by glomerular filtration (GF), clearance (CL) is determined by GF rate (GFR) and the unbound fraction of the drug. When predicting CL of GF-eliminated drugs in children, instead of physiologically based pharmacokinetic (PBPK) methods that consider changes in both GFR and protein binding, empiric bodyweight-based methods are often used. In this article, we explore the predictive value of scaling using a GFR function, and compare the results with linear and allometric scaling methods for drugs with different protein-binding properties. Methods First, different GFR maturation functions were compared to identify the GFR function that would yield the most accurate GFR predictions across the pediatric age range compared with published pediatric inulin/mannitol CL values. Subsequently, the accuracy of pediatric CL scaling using this GFR maturation function was assessed and compared with PBPK CL predictions for hypothetical drugs binding, to varying extents, to serum albumin or alpha-acid glycoprotein across the pediatric age range. Additionally, empiric bodyweight-based methods were assessed. Results The published GFR maturation functions yielded comparable maturation profiles, with the function reported by Salem et al. leading to the most accurate predictions. On the basis of this function, GFR-based scaling yields reasonably accurate (percentage prediction error <= 50%) pediatric CL values for all drugs, except for some drugs highly bound to AGP in neonates. Overall, this method was more accurate than linear or 0.75 allometric bodyweight-based scaling. Conclusion When scaling CL and dose by GFR function, maturational changes in plasma protein concentrations impact GF minimally, making this method a superior alternative to empiric bodyweight-based scaling.Pharmacolog

Vancomycin clearance in obese adults is not predictive of clearance in obese adolescents

Contradictory pharmacokinetic (PK) results have been observed between obese adults and obese adolescents, with absolute clearance (CL) reported to be either unaltered, lower, or higher in obese adolescents compared to obese adults. This study investigates the PK of vancomycin in adolescents and adults who are overweight or obese. Data from 125 overweight and obese adolescents (aged 10-18 years, weight 28.3-188 kg) and 81 overweight and obese adults (aged 29-88 years, weight 66.7-143 kg) were analysed using population PK modelling. In addition to age, sex, renal function estimates, and regular weight descriptors, we evaluated standard weight (WTstandard, defined as weight for length, age, and sex in adolescents and weight for length in adults) and excess weight (WTexcess, defined as total body weight (TBW) minus WTstandard) as covariates in order to distinguish between weight resulting from length versus weight resulting from obesity. Analyzing adolescents and adults together, vancomycin CL was found to increase with TBW and decrease with increasing age (p standard in adolescents and adults, albeit with different functions, with adolescents having a higher CL per WTstandard than adults. Moreover, in this separate model, adolescent males had 21% higher CL than adolescent females of the same WTstandard, while in adults, CL decreased with increasing age (p Pharmacolog

The influence of drug properties and ontogeny of transporters on pediatric renal clearance through glomerular filtration and active secretion: a simulation-based study

Glomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we systematically analyzed the influence of transporter ontogeny on the relative contribution of GF and ATS to renal clearance CL(R)for drugs with different properties in children. A physiology-based model for CL(R)in adults was extrapolated to the pediatric population by including maturation functions for the system-specific parameters. This model was used to predict GF and ATS for hypothetical drugs with a range of drug-specific properties, including transporter-mediated intrinsic clearance (CLint,T) values, that are substrates for renal secretion transporters with different ontogeny patterns. To assess the impact of transporter ontogeny on ATS and total CLR, a percentage prediction difference (%PD) was calculated between the predicted CL(R)in the presence and absence of transporter ontogeny. The contribution of ATS to CL(R)ranges between 41 and 90% in children depending on fraction unbound and CL(int,T)values. If ontogeny of renal transporters is 50%) for the majority of drugs regardless of the pediatric age. Ignoring ontogeny patterns of secretion transporters increasing with age in children younger than 2 years results in CL(R)predictions that are not systematically acceptable for all hypothetical drugs (%PD > 50% for some drugs). This analysis identified for what drug-specific properties and at what ages the contribution of ATS on total pediatric CL(R)cannot be ignored. Drugs with these properties may be sensitivein vivoprobes to investigate transporter ontogeny.Pharmacolog

Exploring the Relationship Between Morphine Concentration and Oversedation in Children After Cardiac Surgery

Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC50 was 46.3 ng/mL. At morphine concentrations below the EC50, the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (

Unraveling the effects of acute inflammation on pharmacokinetics: a model-based analysis focusing on renal glomerular filtration rate and cytochrome P450 3A4-mediated metabolism

UNLABELLED\nMETHODS\nRESULTS\nCONCLUSION\nBACKGROUND AND OBJECTIVES: Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute inflammation as represented by interleukin-6 (IL-6) levels on drug clearance, focusing on renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism.\nA physiologically based model incorporating renal and hepatic drug clearance was implemented. Functions correlating IL-6 levels with GFR and in vitro CYP3A4 activity were derived and incorporated into the modeling framework. We then simulated treatment scenarios for hypothetical drugs by varying the IL-6 levels, the contribution of renal and hepatic drug clearance, and protein binding. The relative change in observed area under the concentration-time curve (AUC) was computed for these scenarios.\nInflammation showed opposite effects on drug exposure for drugs eliminated via the liver and kidney, with the effect of inflammation being inversely proportional to the extraction ratio (ER). For renally cleared drugs, the relative decrease in AUC was close to 30% during severe inflammation. For CYP3A4 substrates, the relative increase in AUC could exceed 50% for low-ER drugs. Finally, the impact of inflammation-induced changes in drug clearance is smaller for drugs with a larger unbound fraction.\nThis analysis demonstrates differences in the impact of inflammation on drug clearance for different drug types. The effects of inflammation status on pharmacokinetics may explain the inter-individual variability in pharmacokinetics in critically ill patients. The proposed model-based analysis may be used to further evaluate the effect of inflammation, i.e., by incorporating the effect of inflammation on other drug-metabolizing enzymes or physiological processes.Pharmacolog

Systems pharmacology of hepatic metabolism in zebrafish larvae

Interspecies translation of pharmacological processes needs to improve to reduce attrition in drug development. Systems pharmacology integrates systems biology and pharmacometrics to characterise and quantify system-specific behaviour upon exposure to drugs in different species. The zebrafish is a suitable vertebrate model organism for systems pharmacology, combining high-throughput potential with high genetic homology to higher vertebrates. Zebrafish larvae have been increasingly used for drug screens, but the influence of internal drug and metabolite exposure is hardly studied. Quantifying this internal exposure is essential for establishing both exposure-response and dose-exposure relationships, needed for translation. The zebrafish may also serve as a suitable model species for translational studies on the occurrence of hepatotoxicity and the influence of hepatic dysfunction on drug metabolism. Pharmacolog

The role of population PK-PD modelling in paediatric clinical research

Pharmacolog

Midazolam infusion and disease severity affect the level of sedation in children: a parametric time-to-event analysis

Aim In critically ill mechanically ventilated children, midazolam is used first line for sedation, however its exact sedative effects have been difficult to quantify. In this analysis, we use parametric time-to-event (PTTE) analysis to quantify the effects of midazolam in critically ill children.Methods In the PTTE analysis, data was analyzed from a published study in mechanically ventilated children in which blinded midazolam or placebo infusions were administered during a sedation interruption phase until, based on COMFORT-B and NISS scores, patients became undersedated and unblinded midazolam was restarted. Using NONMEM (R) v.7.4.3., restart of unblinded midazolam was analysed as event. Patients in the trial were divided into internal and external validation cohorts prior to analysis.Results Data contained 138 events from 79 individuals (37 blinded midazolam; 42 blinded placebo). In the PTTE model, the baseline hazard was best described by a constant function. Midazolam reduced the hazard for restart of unblinded midazolam due to undersedation by 51%. In the blinded midazolam group, time to midazolam restart was 26 h versus 58 h in patients with low versus high disease severity upon admission (PRISM II 21), respectively. For blinded placebo, these times were 14 h and 33 h, respectively. The model performed well in an external validation with 42 individuals.Conclusion The PTTE analysis effectively quantified the effect of midazolam in prolonging sedation and also the influence of disease severity on sedation in mechanically ventilated critically ill children, and provides a valuable tool to quantify the effect of sedatives. Clinical trial number and registry URL: Netherlands Trial Register, Trial NL1913 (NTR2030), date registered 28 September 2009.Pharmacolog