The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific ...impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown. In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes. This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N-acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults. Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology.
Sparse information is available on pharmacokinetic changes of drugs over time after bariatric surgery. By reviewing the literature on the short- and long-term pharmacokinetic changes of drugs, ...several patterns were identified for 39 drugs. No relevant pharmacokinetic changes were identified for roughly a third of the drugs. Of the remaining drugs, levels were variable and partly unpredictable shortly after the surgery. In the long term, most of the drug levels remain altered, but in some cases they returned to preoperative values. Based on the changes and the efficacy-safety balance of each drug, clinicians may need to perform additional clinical monitoring for specific drugs, including measuring drug levels. This review provides suggestions for clinicians and pharmacists for specific time-dependent drug dosing advice.
Purpose
To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children.
Methods
In this multicenter randomized controlled ...trial in three pediatric intensive care units in the Netherlands, mechanically ventilated critically ill children with need for sedative drugs were included. They were randomly assigned to either DSI + PS or PS only. Children in both study arms received sedation adjusted on the basis of validated sedation scores. Provided a safety screen was passed, children in the DSI + PS group received daily blinded infusions of saline; children in the PS group received blinded infusions of the previous sedatives/analgesics. If a patient’s sedation score indicated distress, the blinded infusions were discontinued, a bolus dose of midazolam was given and the ‘open’ infusions were resumed: DSI + PS at half of infusion rate, PS at previous infusion rate. The primary endpoint was the number of ventilator-free days at day 28. Data were analyzed by intention to treat.
Results
From October 2009 to August 2014, 129 children were randomly assigned to DSI + PS (
n
= 66) or PS (
n
= 63). The study was terminated prematurely due to slow recruitment rates. Median number of ventilator-free days did not differ: DSI + PS 24.0 days (IQR 21.6–25.8) versus PS 24.0 days (IQR 20.6–26.0); median difference 0.02 days (95 % CI −0.91 to 1.09),
p
= 0.90. Median ICU and hospital length of stay were similar in both groups: DSI + PS 6.9 days (IQR 5.2–11.0) versus PS 7.4 days (IQR 5.3–12.8),
p
= 0.47, and DSI + PS 13.3 days (IQR 8.6–26.7) versus PS 15.7 days (IQR 9.3–33.2),
p
= 0.19, respectively. Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 versus 0/63,
p
= 0.03), though no causal relationship to the intervention could be established. Median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6–22.6) versus PS 17.0 mg/kg (IQR 8.2–39.8),
p
= 0.11.
Conclusion
In critically ill children, daily sedation interruption in addition to protocolized sedation did not improve clinical outcome and was associated with increased mortality compared with protocolized sedation only.
During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the ...GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin.
Population pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24-43 weeks; postnatal age 1-30 days; birthweight 385-4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally.
Postmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived.
Amikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates.
Introduction: The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the ...pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known.
Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed.
Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.
Obesity and morbid obesity are associated with many physiological changes affecting pharmacokinetics, such as increased blood volume, cardiac output, splanchnic blood flow, and hepatic blood flow. In ...obesity, drug absorption appears unaltered, although recent evidence suggests that this conclusion may be premature. Volume of distribution may vary largely, but the magnitude and direction of changes seem difficult to predict, with extrapolation on the basis of total body weight being the best approach to date. Changes in clearance may be smaller than in distribution, whereas there is growing evidence that the influence of obesity on clearance can be predicted on the basis of reported changes in the metabolic or elimination pathways involved. For obese children, we propose two methods to distinguish between developmental and obesity-related changes. Future research should focus on the characterization of physiological concepts to predict the optimal dose for each drug in the obese population.
IMPORTANCE Continuous morphine infusion as standard postoperative analgesic therapy in young infants is associated with unwanted adverse effects such as respiratory depression. OBJECTIVE To determine ...whether intravenous paracetamol (acetaminophen) would significantly (>30%) reduce morphine requirements in neonates and infants after major surgery. DESIGN, SETTING, AND PATIENTS Single-center, randomized, double-blind study conducted in a level 3 pediatric intensive care unit in Rotterdam, the Netherlands. Patients were 71 neonates or infants younger than 1 year undergoing major thoracic (noncardiac) or abdominal surgery between March 2008 and July 2010, with follow-up of 48 hours. INTERVENTIONS All patients received a loading dose of morphine 30 minutes before the end of surgery, followed by continuous morphine or intermittent intravenous paracetamol up to 48 hours postsurgery. Infants in both study groups received morphine (boluses and/or continuous infusion) as rescue medication on the guidance of the validated pain assessment instruments. MAIN OUTCOME MEASURES Primary outcome was cumulative morphine dose (study and rescue dose). Secondary outcomes were pain scores and morphine-related adverse effects. RESULTS The cumulative median morphine dose in the first 48 hours postoperatively was 121 (interquartile range, 99-264) μg/kg in the paracetamol group (n = 33) and 357 (interquartile range, 220-605) μg/kg in the morphine group (n = 38), P < .001, with a between-group difference that was 66% (95% CI, 34%-109%) lower in the paracetamol group. Pain scores and adverse effects were not significantly different between groups. CONCLUSION AND RELEVANCE Among infants undergoing major surgery, postoperative use of intermittent intravenous paracetamol compared with continuous morphine resulted in a lower cumulative morphine dose over 48 hours. TRIAL REGISTRATION trialregister.nl Identifier: NTR1438
Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are ...warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.
As a result of the rising prevalence of childhood obesity, there is an increasing interest in the type 2 diabetes mellitus precursor insulin resistance (IR). The aim of this study is to review ...definitions (methods and cutoff values) to define IR in children and to apply these definitions to a previously described obese pediatric population.
A systematic literature review on prevalence and/or incidence rates in children was performed. The extracted definitions were applied to an obese pediatric population.
In the 103 identified articles, 146 IR definitions were reported based on 14 different methods. Fasted definitions were used 137 times, whereas oral/intravenous glucose tolerance test-derived methods were used nine times. The homeostasis model for the assessment of insulin resistance (HOMA-IR) and fasted plasma insulin (FPI) were the most frequently used fasted methods (83 and 37 times, respectively). A wide range in cutoff values to define IR was observed, resulting in prevalence rates in the predefined obese pediatric population between 5.5% (FPI>30 mU/L) and 72.3% (insulin sensitivity indexMatsuda≤7.2).
To compare IR incidence and prevalence rates in pediatric populations, a uniform definition of IR should be defined.
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® 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 < 10 versus > 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
https://www.trialregister.nl/trial/1913
.
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