Dosing Recommendations for Vancomycin in Children and Adolescents with Varying Levels of Obesity and Renal Dysfunction: a Population Pharmacokinetic Study in 1892 Children Aged 1–18 Years

Vancomycin is an effective but potentially nephrotoxic antibiotic commonly used for severe infections. Dosing guidelines for vancomycin in obese children and adolescents with or without renal impairment are currently lacking. This study describes the pharmacokinetics of vancomycin in a large pediatric cohort with varying degrees of obesity and renal function to design practical dosing guidelines for this population. A multi-center retrospective population pharmacokinetic study was conducted using data from patients aged 1−18 years who received \u3e1 dose of vancomycin and had ≥1 vancomycin concentration measured between January 2006 and December 2012. Besides pharmacokinetic data, age, gender, body weight, creatinine clearance (CLcr, bedside Schwartz equation), ward, race, and neutropenic status were collected. Population pharmacokinetic analysis and simulations were performed using NONMEM7.4. A total of 1892 patients (5524 samples) were included, with total body weight (TBW) ranging 6−188 kg (1344 normal weight, 247 overweight, and 301 obese patients) and CLcr down to 8.6 mL/min/1.73 m2. The two-compartment model, with clearance (CL) significantly increasing with TBW and CLcr, central and peripheral volume of distribution and inter-compartmental clearance increasing with TBW, performed well for all age, weight, and renal function ranges. A dosing guideline is proposed that integrates body weight and CLcr resulting in effective and safe exposures across all ages, body weight, and renal functions in the pediatric population. We have characterized the full pharmacokinetic profile of vancomycin in obese children and adolescents aged 1−18 years and propose a practical dosing guideline that integrates both body weight and renal function

Estimation of ontogeny functions for renal transporters using a combined population pharmacokinetic and physiology-based pharmacokinetic approach : application to OAT1,3

To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CLR) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CL(R)post-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CLR was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CLint,OAT1,3,invivo) and its ontogeny. CLint,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CLR predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months-15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within +/- 50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CLint,OAT1,3,invivo that yields accurate CLR predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters

Особливості розвитку освітнього потенціалу України в умовах глобалізації

BACKGROUND: Recommended screening to identify children at risk for diabetes and its precursors impaired glucose tolerance (IGT) and insulin resistance (IR) is fasted plasma glucose (FPG). This study evaluates the added value of fasted plasma insulin (FPI). METHODS: This study analyzed routinely collected data of an oral glucose tolerance test (OGTT) of 311 obese children (age 10.8 ± 3.2 years). Diabetes and IGT were defined according to the American Diabetes Association criteria, IR as homeostasis model assessment (HOMA)-IR ≥3.4. RESULTS: Cases diagnosed with an OGTT if FPG ≥5.6 mmol/L, compared with an OGTT performed if FPG ≥5.6 mmol/L or HOMA-IR ≥3.4, were, respectively, 4 (80%) versus 5 (100%) with diabetes, 7 (28%) versus 16 (64%) with IGT, and 0 (0%) versus 93 (100%) with IR. CONCLUSIONS: Screening with FPG and FPI has equal burden compared with screening with FPG alone, identifies all patients with diabetes, and identifies more patients with precursors of diabetes

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

Purpose: To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. Methods: 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. Results: 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 describing clearance of all individuals best. Conclusions: 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

Psychostimulants: Influence on Body Mass Index and Height in a Pediatric Population with Attention-Deficit/Hyperactivity Disorder?

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is often treated with psychostimulants. Psychostimulants' adverse effects on body mass index standard deviation score (BMI-sds) and height in children/adolescents with ADHD have been reported. However, literature is inconsistent, and it is unclear whether the observed effects are dosage- and/or BMI-dependent. Therefore, the aim of this retrospective observational study is to evaluate the influence of psychostimulants on BMI-sds and height-sds in a pediatric cohort with ADHD from an outpatient clinic, and to study the correlation between psychostimulant dosage and BMI-sds and height-sds change. METHOD: Participants ≤18 years of age diagnosed with ADHD who started with psychostimulants (methylphenidate) were studied. Changes in BMI-sds and height-sds over an 18-month treatment period were assessed in subgroups according to baseline BMI-sds, gender, and age. Furthermore, correlations between BMI-sds, height-sds, and psychostimulant dose were studied. RESULTS: In total, 298 participants [median age 9.8 years, height-sds 0.0, BMI-sds 0.5, psychostimulant dosage 0.5 (0.2-1.4) mg/kg/day] were analyzed, with an underweight, overweight, and obesity prevalence of 5%, 21%, and 7%, respectively. After 18 months of treatment a significant decline in BMI-sds (-0.4) and height-sds (-0.2) was observed. These effects were consistent in all subgroups except for no change in BMI-sds in the underweight subgroup and no change in height-sds in the overweight subgroup. Medication dosage was weakly correlated with change in BMI-sds [r = -0.3 (-0.9 to +0.5); p < 0.01] and height-sds [r = -0.2 (-0.4 to -0.1); p = 0.01]. CONCLUSION: After 18 months of psychostimulant treatment, a significant decline in BMI-sds and height-sds was observed. However, the correlation with psychostimulant dosage was weak, and the decline was not observed in all subgroups. Therefore, further studies on the etiology of BMI-change are warranted, particularly with regard to the ADHD symptoms

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

Oral Drug Dosing Following Bariatric Surgery: General Concepts and Specific Dosing Advice

Bariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased absorption surface in the small intestine, decreased exposure to bile acids and enterohepatic circulation, and decreased gastrointestinal transit time may be expected. In the years after bariatric surgery, patients will also substantially lose weight. As a result of these changes, the absorption, distribution, metabolism and/or elimination of drugs may be altered. The purpose of this article is to report the general influence of bariatric surgery on oral drug absorption, and to provide guidance for dosing of commonly used drugs in this special population. Upon oral drug administration, the time to maximum concentration is often earlier and this concentration may be higher with less consistent effects on trough concentrations and exposure. Additionally, prescription of liquid formulations to bariatric patients is supported by some reports, even though the high sugar load of these suspensions may be of concern. Studies on extended-release medications result in an unaltered exposure for a substantial number of drugs. Also, studies evaluating the influence of timing after surgery show dynamic absorption profiles. Although for this group specific advice can be proposed for many drugs, we conclude that there is insufficient evidence for general advice for oral drug therapy after bariatric surgery, implying that a risk assessment on a case-by-case basis is required for each drug

Daily interruption of sedation in critically ill children:study protocol for a randomized controlled trial

BACKGROUND: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and efficacy of daily sedation interruption in critically ill children. METHODS/DESIGN: Children between 0 and 18 years of age who require mechanical ventilation, with an expected duration of at least 48 h and need for sedative infusion, will be included. After enrollment patients will be randomly assigned to DSI in combination with protocolized sedation (intervention group) or protocolized continuous sedation (control group). A sedation protocol that contains an algorithm for increasing and weaning of sedatives and analgesics will be used. The sedative infusion will be restarted if the patient becomes uncomfortable or agitated according to the sedation protocol. The primary endpoint is the number of ventilator-free days at 28 days. TRIAL REGISTRATION: NTR203

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