Knibbe, C.A.

Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance (Article)

2012-01-23T00:00:00Z

Background and Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

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

2011-05-01T00:00:00Z

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child.

Systematic evaluation of the descriptive and predictive performance of Paediatric morphine population models (Article)

2011-04-01T00:00:00Z

Purpose: A framework for the evaluation of paediatric population models is proposed and applied to two different paediatric population pharmacokinetic models for morphine. One covariate model was based on a systematic covariate analysis, the other on fixed allometric scaling principles. Methods: The six evaluation criteria in the framework were 1) number of parameters and condition number, 2) numerical diagnostics, 3) prediction-based diagnostics, 4) η-shrinkage, 5) simulation-based diagnostics, 6) diagnostics of individual and population parameter estimates versus covariates, including measurements of bias and precision of the population values compared to the observed individual values. The framework entails both an internal and external model evaluation procedure. Results: The application of the framework to the two models resulted in the detection of overparameterization and misleading diagnostics based on individual predictions caused by high shrinkage. The diagnostic of individual and population parameter estimates versus covariates proved to be highly informative in assessing obtained covariate relationships. Based on the framework, the systematic covariate model proved to be superior over the fixed allometric model in terms of predictive performance. Conclusions: The proposed framework is suitable for the evaluation of paediatric (covariate) models and should be applied to corroborate the descriptive and predictive properties of these models.

Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children (Article)

2011-01-01T00:00:00Z

Background and Objective: Model validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model. Methods: Six external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model. Results: The original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the originalmodelwere in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH. Conclusion: The predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations - namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated.

Prediction of propofol clearance in children from an allometric model developed in rats, children and adults versus a 0.75 fixed-exponent allometric model (Article)

2010-03-19T00:00:00Z

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 maturation. Methods: The predictive value of the allometric equation, clearance (CL) is equal to 0.071 • bodyweight in kg0.78, 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 • (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; (ii) 22 postoperative infants aged 4-18 months; (iii) 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-CLi)/CLi• 100, where CLallometricis the predicted propofol clearance from the allometric equations for each individual and CLiis 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 individual 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 age of 2 years.

The use of the behavioral pain scale to assess pain in conscious sedated patients (Article)

2010-01-01T00:00:00Z

Background: Assessing pain in mechanically ventilated critically ill patients is a great challenge. There is a need for an adequate pain measurement tool for use in conscious sedated patients because of their questionable communicative abilities. In this study, we evaluated the use of the Behavioral Pain Scale (BPS) in conscious sedated patients in comparison with its use in deeply sedated patients, for whom the BPS was developed. Additionally, in conscious sedated patients, the combination of the BPS and the patient-rated Verbal Rating Scale (VRS-4) was evaluated. Methods: We performed a prospective evaluation study in 80 nonparalyzed critically ill adult intensive care unit patients. Over 2 mo, nurses performed 175 observation series: 126 in deeply sedated patients and 49 in conscious sedated patients. Each observation series consisted of BPS ratings (range 3-12) at 4 points: at rest, during a nonpainful procedure, at retest rest, and during a routine painful procedure. Patients in the conscious sedated state also self-reported their pain using the 4-point VRS-4. Results: BPS scores during painful procedures were significantly higher than those at rest, both in deeply sedated patients (5.1 [4.8-5.5] vs 3.4 [3.3-3.5], respectively) and conscious sedated patients (5.4 [4.9-5.9] vs 3.8 [3.5-4.1], respectively) (mean [95% confidence interval]). For both groups, scores obtained during the nonpainful procedure and at rest did not significantly differ. There was a strong correlation between nurses' BPS ratings and conscious sedated patients' VRS-4 ratings during the painful procedure (rs = 0.67, P < 0.001). At rest and during nonpainful procedures, 98% of the observations were rated as acceptable pain (VRS 1 or 2) by both nurses and patients. During painful procedures, nurses rated the pain higher than patients did in 16% of the observations and lower in 12% of the observations. Conclusion: The BPS is a valid tool for measuring pain in conscious sedated patients during painful procedures. Thus, for noncommunicative and mechanically ventilated patients, it may be regarded as a bridge between the observational scale used by nurses and the VRS-4 used by patients who are able to self-report pain. Copyright

Morphine glucuronidation in preterm neonates, infants and children younger than 3 years (Article)

2009-08-12T00:00:00Z

Background and objective: A considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug. Methods: A population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM® V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors. Results: Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight. Conclusions: Model-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in μg/kg and a maintenance dose expressed in μg/kg1.5/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made.

Knowledge of developmental pharmacology and modeling approaches should be used to avoid useless trials in children (Article)

2009-08-01T00:00:00Z

Tailor-made drug treatment for children. Creation of an infrastructure for data-sharing and population PK-PD modeling (Article)

2009-03-01T00:00:00Z

Rational dosing guidelines for drugs in pediatrics are urgently needed. To develop these guidelines, we use population pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation by: (i) optimization of clinical trial designs based on preliminary data; (ii) development and internal validation of population PK-PD models using sparse data; (iii) external validation using independent data; and (iv) prospective clinical evaluation. Optimized dosing regimens for specific drugs may then serve as a basis to develop dosing guidelines for existing or newly developed drugs with similar disposition and/or effect. In addition to modeling of drug disposition (PK) pathways, we emphasize the need for modeling of effect (PD) pathways and the use of a multidisciplinary infrastructure for data-sharing.

Defining off-label and unlicensed use of medicines for children: Results of a Delphi survey (Article)

2008-11-01T00:00:00Z

The aim of this Delphi survey is to develop common definitions for unlicensed and off-label drug use in children to be used for research and regulatory purposes. After a literature review on the current status of unlicensed/off-label definitions, a two-stage, web-based Delphi survey was conducted among experts in Europe. Their opinion on concerns, rules and scenarios regarding the unlicensed and off-label use of medicines were obtained. Results were then consulted with the European Medicines Agency (EMEA) before the final proposal was circulated to participants. Eighty-four experts were invited to participate (scientists, health professionals, pharmaceutical companies, regulatory agencies), 34 responded to the first round questionnaire and participated in subsequent rounds. Consensus was reached for the majority of questions. The lowest level of consensus reached was for questions related to a different formulation or if a drug was given although contraindicated. At the final step, 85% of the responding experts agreed on the proposed definition for off-label (use of a drug already covered by a Marketing Authorisation, in an unapproved way) and 80% on the definition for unlicensed (use of a drug not covered by a Marketing Authorisation as medicinal for human use), respectively. Results will facilitate the conduct of pharmacoepidemiological studies and allow comparison between different countries. The Delphi panel agreed that the definitions should be circulated within the scientific community and recommended to be adopted by relevant regulatory authorities.

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

2008-03-01T00:00:00Z

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.

Comparison of different pain scoring systems in critically ill patients in a general ICU (Article)

2008-02-16T00:00:00Z

Background: Pain in critically ill patients in the intensive care unit (ICU) is common. However, pain assessment in critically ill patients often is complicated because these patients are unable to communicate effectively. Therefore, we designed a study (a) to determine the inter-rater reliability of the Numerical Rating Scale (NRS) and the Behavioral Pain Scale (BPS), (b) to compare pain scores of different observers and the patient, and (c) to compare NRS, BPS, and the Visual Analog Scale (VAS) for measuring pain in patients in the ICU. Methods: We performed a prospective observational study in 113 non-paralyzed critically ill patients. The attending nurses, two researchers, and the patient (when possible) obtained 371 independent observation series of NRS, BPS, and VAS. Data analyses were performed on the sample size of patients (n = 113). Results: Inter-rater reliability of the NRS and BPS proved to be adequate (kappa = 0.71 and 0.67, respectively). The level of agreement within one scale point between NRS rated by the patient and NRS scored by attending nurses was 73%. However, high patient scores (NRS ≥4) were underestimated by nurses (patients 33% versus nurses 18%). In responsive patients, a high correlation between NRS and VAS was found (rs= 0.84, P < 0.001). In ventilated patients, a moderate positive correlation was found between the NRS and the BPS (rs= 0.55, P < 0.001). However, whereas 6% of the observations were NRS of greater than or equal to 4, BPS scores were all very low (median 3.0, range 3.0 to 5.0). Conclusion: The different scales show a high reliability, but observer-based evaluation often underestimates the pain, particularly in the case of high NRS values (≥4) rated by the patient. Therefore, whenever this is possible, ICU patients should rate their pain. In unresponsive patients, primarily the attending nurse involved in daily care should score the patient's pain. In ventilated patients, the BPS should be used only in conjunction with the NRS nurse to measure pain levels in the absence of painful stimuli.

Inter-individual variability in propofol pharmacokinetics in preterm and term neonates (Article)

2007-12-01T00:00:00Z

Background. To document covariates which contribute to inter-individual variability in propofol pharmacokinetics in preterm and term neonates. Methods. Population pharmacokinetics were estimated (non-linear mixed effect modelling) based on the arterial blood samples collected in (pre)term neonates after i.v. bolus administration of propofol (3 mg kg-1, 10 s). Covariate analysis included postmenstrual age (PMA), postnatal age (PNA), gestational age, weight, and serum creatinine. Results. Two hundred and thirty-five arterial concentration-time points were collected in 25 neonates. Median weight was 2930 (range 680-4030) g, PMA 38 (27-43) weeks, and PNA 8 (1-25) days. In a three-compartment model, PMA was the most predictive covariate for clearance (P<0.001) when parameterized as [CLstd·(PMA/38)11.5]. Standardized propofol clearance (CLstd) at 38 weeks PMA was 0.029 litre min-1. The addition of a fixed value in neonates with a PNA of ≥10 days further improved the model (P<0.001) and resulted in the equation [CLstd·(PMA/38)11.5+0.03] for neonates ≥10 days. Values for central volume (1.32 litre), peripheral volume 1 (15.4 litre), and peripheral volume 2 (1.29 litre) were not significantly influenced by any of the covariates (P>0.001). Conclusions. PMA and PNA contribute to the inter-individual variability of propofol clearance with very fast maturation of clearance in neonatal life. This implicates that preterm neonates and neonates in the first week of postnatal life are at an increased risk for accumulation during either intermittent bolus or continuous administration of propofol.

Propofol 6% as sedative in children under 2 years of age following major craniofacial surgery. (Article)

2005-05-01T00:00:00Z

BACKGROUND: After alarming reports concerning deaths after sedation with propofol, infusion of this drug was contraindicated by the US Food and Drug Administration in children <18 yr receiving intensive care. We describe our experiences with propofol 6%, a new formula, during postoperative sedation in non-ventilated children following craniofacial surgery. METHODS: In a prospective cohort study, children admitted to the paediatric surgical intensive care unit following major craniofacial surgery were randomly allocated to sedation with propofol 6% or midazolam, if judged necessary on the basis of a COMFORT behaviour score. Exclusion criteria were respiratory infection, allergy for proteins, propofol or midazolam, hypertriglyceridaemia, familial hypercholesterolaemia or epilepsy. We assessed the safety of propofol 6% with triglycerides (TG) and creatine phosphokinase (CPK) levels, blood gases and physiological parameters. Efficacy was assessed using the COMFORT behaviour scale, Visual Analogue Scale and Bispectral Index monitor. RESULTS: Twenty-two children were treated with propofol 6%, 23 were treated with midazolam and 10 other children did not need sedation. The median age was 10 (IQR 3-17) months in all groups. Median duration of infusion was 11 (range 6-18) h for propofol 6% and 14 (range 5-17) h for midazolam. TG levels remained normal and no metabolic acidosis or adverse events were observed during propofol or midazolam infusion. Four patients had increased CPK levels. CONCLUSION: We did not encounter any problems using propofol 6% as a sedative in children with a median age of 10 (IQR 3-17) months, with dosages <4 mg kg(-1) h(-1) during a median period of 11 (range 6-18) h.