Target Drug Exposure Attainment in Children: How to Get from Better to Best

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Evidence-Based Pharmacotherapy in Preterm Infants : Aiming at a moving target

Premature born infants require intensive care with many drugs. For most drugs knowledge is lacking on the correct dosage, the effects and the side-effects. This leads to large differences in prescribed drugs for treatment of premature born infants, found by comparing four Dutch hospitals as part of this dissertation. This could be improved through more consensus between hospitals on the optimal treatment, and through extensive research into optimal dosage regimens for preterm born infants. ZonMw has granted this research to close the knowledge gap with four Dutch hospitals; Máxima MC - Veldhoven, Radboudumc - Nijmegen, MaastrichtUMC - Maastricht, ErasmusMC – Rotterdam. This enabled to study 9 frequently prescribed drugs in preterm born infants; paracetamol, fentanyl, phenobarbital, doxapram, ibuprofen, midazolam, fluconazole, sildenafil and levetiracetam. The first five have been described in this dissertation. The drug amounts could be measured in a very small blood volume, and the effects were studied with appropriate instruments for these patients. Premature born infants showed to eliminate paracetamol, fentanyl, phenobarbital, doxapram and ibuprofen slower at lower gestational age than at higher gestational age. After birth, the elimination of drugs increased with age. This means that it is no longer appropriate to prescribe one dose per kilogram bodyweight for all premature born infants, but dosage regimens should take gestational age into account, as well as bodyweight, and age after birth. Consequently, the smallest premature born infants may have been overtreated with drugs. This study defined improved dosage regimens of the studied drugs for treatment of premature born infants. Furthermore, good tools for effect measurement in premature born infants have been used successfully, despite the fact that the measurement of effects and side-effects is very complicated in these patients

Ibuprofen treatment after the first days of life in preterm neonates with patent ductus arteriosus

Aim: Patent ductus arteriosus (PDA) is treated with ibuprofen and it is known that the clearance of ibuprofen increases with postnatal age. We aimed to study whether postnatal age-adjusted ibuprofen dosages improve the effectiveness of treatment compared to standard ibuprofen dosages after the first days of life. Methods: A historical cohort of 207 preterm neonates treated with standard ibuprofen dosages (Group A; 2011–2015) was compared to a prospective cohort of 66 preterm neonates treated with postnatal age-adjusted ibuprofen dosages (Group B; 2015–2016). Results: Both groups had comparable background characteristics. Treatment was started after median 6 (25–75th percentile: 4–11) and 5 (25–75th percentile: 4–11) days and effectiveness was 33.2 and 44.7% (p =.17) in groups A and B, respectively. No hemodynamically significant PDA was found in 23/49 (46.9%) of the patients born before 28 weeks after adjusted ibuprofen dosages compared to 48/162 (29.6%) after standard ibuprofen dosages (p =.04). There were significantly more reversible side effects with the postnatal age-adjusted ibuprofen dosages (p =.04). Conclusions: There seems to be a trend to higher effectiveness with the adjusted ibuprofen dosages in preterm neonates before 28 weeks, but it is associated with more reversible side effects

Simultaneous quantification of fentanyl, sufentanil, cefazolin, doxapram and keto-doxapram in plasma using liquid chromatography–tandem mass spectrometry

A simple and specific UPLC–MS/MS method was developed and validated for simultaneous quantification of fentanyl, sufentanil, cefazolin, doxapram and its active metabolite keto-doxapram. The internal standard was fentanyl-d5 for all analytes. Chromatographic separation was achieved with a reversed-phase Acquity UPLC HSS T3 column with a run-time of only 5.0 min per injected sample. Gradient elution was performed with a mobile phase consisting of ammonium acetate or formic acid in Milli-Q ultrapure water or in methanol with a total flow rate of 0.4 mL min−1. A plasma volume of only 50 μL was required to achieve adequate accuracy and precision. Calibration curves of all five analytes were linear. All analytes were stable for at least 48 h in the autosampler. The method was validated according to US Food and Drug Administration guidelines. This method allows quantification of fentanyl, sufentanil, cefazolin, doxapram and keto-doxapram, which is useful for research as we

Pre- and postnatal maturation are important for fentanyl exposure in preterm and term newborns: a pooled population pharmacokinetic study

Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9-42.3), birthweight of 1055 g (range 390-4245), and postnatal age (PNA) of 1 day (range 0-68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 μg/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 μg/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM® 7.4. Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12-48 h. As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered.Pharmacolog

Prediction of glomerular filtration rate maturation across preterm and term neonates and young infants using inulin as marker

Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of preterm and term neonates and infants is important to predict the clearance of renally cleared drugs. This study aims to describe the GFR maturation in (pre)term neonates and young infants (PNA < 90 days) using individual inulin clearance data (CLinulin). To this end, published GFR maturation models were evaluated by comparing their predicted GFR with CLinulin retrieved from literature. The best model was subsequently optimized in NONMEM V7.43 to better fit the CLinulin values. Our study evaluated seven models and collected 381 individual CLinulin values from 333 subjects with median (range) birthweight (BWb) 1880 g (580-4950), gestational age (GA) 34 weeks (25-43), current weight (CW) 1890 g (480-6200), postnatal age (PNA) 3 days (0-75), and CLinulin 2.20 ml/min (0.43-17.90). The De Cock 2014 model (covariates: BWb and PNA) performed the best in predicting CLinulin followed by the Rhodin 2009 model (covariates: CW and postmenstrual age). The final optimized model shows that GFR at birth is determined by BWb, thereafter the maturation rate of GFR is dependent on PNA and GA, with a higher GA showing an overall faster maturation. To conclude, using individual CLinulin data, we found that a model for neonatal GFR requires a distinction between prenatal maturation quantified by BWb and postnatal maturation. To capture postnatal GFR maturation in (pre)term neonates and young infants, we developed an optimized model in which PNA-related maturation was dependent on GA.Pharmacolog

Precision dosing of doxapram in preterm infants using continuous pharmacodynamic data and model-based pharmacokinetics: an illustrative case series

IntroductionCurrent drug dosing in preterm infants is standardized, mostly based on bodyweight. Still, covariates such as gestational and postnatal age may importantly alter pharmacokinetics and pharmacodynamics. Evaluation of drug therapy in these patients is very difficult because objective pharmacodynamic parameters are generally lacking. By integrating continuous physiological data with model-based drug exposure and data on adverse drug reactions (ADRs), we aimed to show the potential benefit for optimized individual pharmacotherapy.Materials and MethodsContinuous data on oxygen saturation (SpO(2)), fraction of inspired oxygen (FiO(2)) and composite parameters, including the SpO(2)/FiO(2) ratio and the cumulative oxygen shortage under the 89% SpO(2) limit, served as indicators for doxapram effectiveness. We analyzed these continuous effect data, integrated with doxapram exposure and ADR parameters, obtained in preterm infants around the start of doxapram therapy. The exposures to doxapram and the active metabolite keto-doxapram were simulated using a population pharmacokinetic model. Infants were selected and retrospectively compared on the indication to start doxapram, the first response to doxapram, a potential dose-response relationship, and the administered dosage over time. Recommendations were made for individual improvements of therapy.ResultsWe provide eight cases of continuous doxapram administration that illustrate a correct and incorrect indication to start doxapram, responders and non-responders to therapy, and unnecessary over-exposure with ADRs. Recommendations for improvement of therapy include: objective evaluation of added effect of doxapram after start, prevention of overdosing by earlier down-titration or termination of therapy, and the prevention of hypoxia and agitation by measuring specific parameters at strategical time-points.ConclusionReal-time and non-invasive effect monitoring of drug therapy combined with model-based exposure provides relevant information to clinicians and can importantly improve therapy. The variability between and within patients emphasizes the importance of individual, objective evaluation of pharmacotherapy. These measurements, together with data on ADRs, allow for precision medicine in neonatology that should be brought to the bedside.Pharmacolog

Knowledge gaps in late-onset neonatal sepsis in preterm neonates: a roadmap for future research

Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. Impact This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts. Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use. Methods to personalize medicine and technologies feasible for bedside clinical use are described.Pharmacolog