Danhof, M.

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.

Pharmacokinetics of clindamycin in pregnant women in the peripartum period (Article)

2010-05-01T00:00:00Z

The study presented here was performed to determine the pharmacokinetics of intravenously administered clindamycin in pregnant women. Seven pregnant women treated with clindamycin were recruited. Maternal blood and arterial and venous umbilical cord blood samples were obtained. Maternal clindamycin concentrations were analyzed by nonlinear mixed-effects modeling with the NONMEM program. The data were best described by a linear three-compartment model. The clearance and the volume of distribution at steady state were 10.0 liters/h and 6.32 × 103liters, respectively. Monte Carlo simulations were performed to determine the area under the concentration curve (AUC) for the free (unbound) drug (f) in maternal serum for 24 h divided by the MIC (fAUC0-24/MIC) . At a MIC of 0.5 mg/liter, which is the EUCAST breakpoint, the attainment at the lower 95% confidence interval (CI) was 24.6 if the level of protein binding was 65%, and this value concurred well with the target value of 27. However, for higher degrees of protein binding, as has been described in the literature, the attainment was lower, down to 10.2 for a protein binding level of 85% (lower 95% CI). The concentrations in umbilical cord blood were lower than those in maternal blood. The concentration-time profiles in maternal serum indicate that the level of exposure to clindamycin may be too low in these patients. Together with the lower concentrations in umbilical cord blood, this finding suggests that the current dosing regimen may not be adequate to protect all neonates from group B streptococcal disease. Copyright

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.

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.

Pharmacokinetics of amoxicillin in maternal, umbilical cord, and neonatal sera (Article)

2009-04-01T00:00:00Z

The pharmacokinetics of amoxicillin were studied in umbilical cord and neonatal sera relative to maternal concentrations in prevention of neonatal group B streptococcus infection. The subjects were 44 pregnant women receiving amoxicillin as 1 or 2 g as an intravenous infusion. To measure the concentrations, blood samples were obtained from the mother, the arterial and venous umbilical cord, and the neonate. The pharmacokinetics were characterized by a five-compartment model by using nonlinear mixed-effects (population) modeling. The population estimates for the clearance, central volume of distribution, and the two peripheral maternal volumes of distribution were 19.7 ± 0.99 liters/h, 6.40 ± 0.61 liters, and 5.88 ± 0.83 liters (mean ± standard error), respectively. The volume of distribution of the venous umbilical cord and the neonatal volume of distribution were 3.40 liters and 11.9 liters, respectively. The pharmacokinetic parameter estimates were used to simulate the concentration-time profiles in maternal, venous umbilical cord, and neonatal sera. The peak concentration in the venous umbilical cord serum was 18% of the maternal peak concentration. It was reached 3.3 min after the maternal peak concentration. The concentration-time profile in neonatal serum was determined by the profile in venous umbilical cord serum, which in turn depended on the profile in maternal serum. Furthermore, the simulated concentrations in maternal, venous umbilical cord, and neonatal sera exceeded the MIC for group B streptococcus for more than 90% of the 4-h dosing interval. In a first approximation, the 2-g infusion to the mother appears to be adequate for the prevention of group B streptococcal disease. However, to Investigate the efficacy of the prophylaxis, further studies of the interlndi-vidual variability in pharmacokinetics are indicated.

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.

The influence of labour on the pharmacokinetics of intravenously administered amoxicillin in pregnant women (Article)

2008-12-01T00:00:00Z

AIMS: Many physiological changes take place during pregnancy and labour. These might change the pharmacokinetics of amoxicillin, necessitating adjustment of the dose for prevention of neonatal infections. We investigated the influence of labour on the pharmacokinetics of amoxicillin. METHODS: Pregnant women before and during labour were recruited and treated with amoxicillin intravenously. A postpartum dose was offered. Blood samples were obtained and amoxicillin concentrations were determined using high-pressure liquid chromatography. The pharmacokinetics were characterized by nonlinear mixed-effects modelling using NONMEM. RESULTS: The pharmacokinetics of amoxicillin in 34 patients was best described by a three-compartment model. Moderate interindividual variability was identified in CL, central and peripheral volumes of distribution. The volume of distribution (V) increased with an increasing amount of oedema. Labour influenced the parameter estimate of peripheral volume of distribution (V2). V2 was decreased during labour, and even more in the immediate postpartum period. For all patients the population estimates (mean ± SE) for CL and V were 21.1 ± 4.1 l h-1 (CL), 8.7 ± 6.6 l (V1), 11.8 ± 7.7 l (V2) and 20.5 ± 15.4 l (V3) respectively. CONCLUSIONS: The peripheral distribution volume of amoxicillin in pregnant women during labour and immediately postpartum is decreased. However, these changes are not clinically relevant and do not warrant deviations from the recommended dosing regimen for amoxicillin during labour in healthy pregnant patients.

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.

Pharmacokinetics of penicillin G in infants with a gestational age of less than 32 weeks (Article)

2007-10-01T00:00:00Z

The pharmacokinetics of penicillin G were studied in 20 preterm neonates with a gestational age of less than 32 weeks on day 3 of life by using a population approach performed with the nonlinear mixed effects modeling program NONMEM. The derived population estimates and the correlation matrix of these estimates were used to perform Monte Carlo simulations and obtain the probability of target'attainment (PTA). The pharmacokinetics of penicillin G were best described by a two-compartment pharmacokinetic model. The population estimates of the central volume of distribution, the peripheral volume of distribution, the intercompartmental clearance, and the total body clearance were 0.359 ± 0.06 liter, 0.152 ± 0.03 liter, 0.774 ± 0.28 liter/h, and 0.103 ± 0.01 liter/h (mean ± standard error), respectively. The terminal half-life was 3.9 h. Clearance increased significantly with increasing birth weight. Assuming the percentage of time that the concentration of unbound drug remained above the MIC of 50% for preterm neonates, the susceptibility breakpoint based on a 100% PTA was ≤4 mg/liter, simulating the current dosing regimen of 50,000 U/kg every 12 h. This regimen is therefore adequate for the treatment of common infections in neonates on the third day of life. Copyright

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.