28 results on '"Rademaker CMA"'
Search Results
2. Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen
- Author
-
Favie, LMA, Huitema, ADR, Broek, MPB, Rademaker, CMA, de Haan, TR, van Straaten, HL, Simons, SHP (Sinno), Rijken, M, Nuytemans, D, Egberts, TC, Groenendaal, F, Brouwer, MJ, Tollenaer, SM, Jebbink-Akkerman, L, Dudink, J, de Jonge, RCJ, Bos, AA, Pediatrics, Neonatology, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, and Amsterdam Reproduction & Development (AR&D)
- Subjects
Lidocaine ,medicine.medical_treatment ,Population ,030226 pharmacology & pharmacy ,neonatology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Hypothermia, Induced ,Seizures ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Adverse effect ,education ,pharmacometrics ,mass spectrometry ,Pharmacology ,education.field_of_study ,Epilepsy ,business.industry ,Infant, Newborn ,Original Articles ,Hypothermia ,Pharmacometrics ,Confidence interval ,Anticonvulsant ,Anesthesia ,modelling and simulation ,Anticonvulsants ,Original Article ,clinical pharmacology ,medicine.symptom ,business ,drug utilization ,medicine.drug - Abstract
Aims: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. Methods: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred. Results: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54–0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63–11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed. Conclusion: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures.
- Published
- 2020
3. Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia
- Author
-
Favie, LMA, Groenendaal, F, Broek, MPB, Rademaker, CMA, de Haan, TR, van Straaten, HL, Dijk, PH, van Heijst, A, Simons, SHP (Sinno), Dijkman, KP, Rijken, M, Zonnenberg, IA, Cools, F, Zecic, A, v.d. Lee, JH, Nuytemans, D, van Bel, F, Egberts, TC, Huitema, ADR, Brouwer, MJ, Tollenaer, SM, Jebbink-Akkerman, L, Liem, D, Steiner, K, Dudink, J, de Jonge, RCJ, Bos, Annelies, Sonnaert, M, Camfferman, FA, Favie, LMA, Groenendaal, F, Broek, MPB, Rademaker, CMA, de Haan, TR, van Straaten, HL, Dijk, PH, van Heijst, A, Simons, SHP (Sinno), Dijkman, KP, Rijken, M, Zonnenberg, IA, Cools, F, Zecic, A, v.d. Lee, JH, Nuytemans, D, van Bel, F, Egberts, TC, Huitema, ADR, Brouwer, MJ, Tollenaer, SM, Jebbink-Akkerman, L, Liem, D, Steiner, K, Dudink, J, de Jonge, RCJ, Bos, Annelies, Sonnaert, M, and Camfferman, FA
- Published
- 2019
4. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
- Author
-
Favie, LMA, Groenendaal, F, van den Broek, MPH, Rademaker, CMA, de Haan, TR, van Straaten, HLM (Henrica / Henriette), Dijk, PH, van Heijst, A, Dudink, J, Dijkman, KP, Rijken, M, Zonnenberg, IA, Cools, F, Zecic, A, v.d. Lee, JH, Nuytemans, D, van Bel, F, Egberts, TCG (Toine), Huitema, ADR, Brouwer, MJ, Tollenaer, SM, Jebbink-Akkerman, L, Liem, D, Steiner, K, Simons, SHP (Sinno), de Jonge, RCJ, Bos, AA (Annelies), Sonnaert, M, Camfferman, FA, Favie, LMA, Groenendaal, F, van den Broek, MPH, Rademaker, CMA, de Haan, TR, van Straaten, HLM (Henrica / Henriette), Dijk, PH, van Heijst, A, Dudink, J, Dijkman, KP, Rijken, M, Zonnenberg, IA, Cools, F, Zecic, A, v.d. Lee, JH, Nuytemans, D, van Bel, F, Egberts, TCG (Toine), Huitema, ADR, Brouwer, MJ, Tollenaer, SM, Jebbink-Akkerman, L, Liem, D, Steiner, K, Simons, SHP (Sinno), de Jonge, RCJ, Bos, AA (Annelies), Sonnaert, M, and Camfferman, FA
- Published
- 2019
5. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis
- Author
-
Bulatovic, M, Heijstek, MW, Verkaaik, M, van Dijkhuizen, EHP, Armbrust, W, Hoppenreijs, EPAH, Kamphuis, Sylvia, Kuis, W, Egberts, TCG (Toine), Sinnema, G, Rademaker, CMA, Wulffraat, NM, and Pediatrics
- Published
- 2011
6. Guidelines on pediatric dosing on the basis of developmental physiology and harmacokinetic considerations
- Author
-
Bartelink, IH, Rademaker, CMA, Schobben, AFAM, van den Anker, John, and Pediatrics
- Published
- 2006
7. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations
- Author
-
Bartelink, A, Rademaker, CMA, Schobben, AFAM, van den Anker, John, and Pediatrics
- Published
- 2006
8. Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates
- Author
-
van Leuven, K, Groenendaal, F, Toet, MC, Schobben, AFAM, Bos, SAJ, de Vries, LS, Rademaker, CMA, and University of Groningen
- Subjects
RISK ,PHARMACOKINETICS ,genetic structures ,BIRTH ,INFANTS ,CEREBRAL FUNCTION ,encephalopathy ,METABOLITES ,surgical procedures, operative ,midazolam ,mental disorders ,ELECTROENCEPHALOGRAPHY ,heterocyclic compounds ,SEIZURES ,EEG ,neonate ,HYPOXIC-ISCHEMIC ENCEPHALOPATHY ,psychological phenomena and processes ,NEWBORN - Abstract
Aim: In the present, prospective study, the relation between the levels of midazolam, its two active metabolites-1-hydroxy-midazolam (OH-midazolam) and 1-hydroxy-midazolam-glucuronide (glumidazolam)-and the aEEG were examined. Patients and methods: Fifteen full-term neonates with seizures due to hypoxic-ischaemic encephalopathy admitted to our NICU were included. Midazolam (loading dose 0.05 mg/kg in 10 min, maintenance dose 0.15 mg/kg/h) was used as an add-on anti-convulsant after phenobarbital and lidocaine because of continuing seizures. Amplitude-integrated EEG background pattern was scored at the start of midazolam and at the time of blood sampling as continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage (CLV) or flat trace (FT). Serum levels of midazolam, OH-midazolam and glu-midazolam were measured at least 8 h after the start with HPLC. Results: In 11/15 patients, seizures were abolished with the addition of midazolam. In the remaining patients, seizure frequency was reduced in one and unchanged in three. Amplitude-integrated EEG background pattern at the start of midazolam was CNV in two, DNV in six, BS in five and CLV in two. Moderate, temporary suppression of the aEEG background pattern lasting less than 2 h was seen in four neonates. Amplitude-integrated EEG at midazolam sampling was CNV in two, DNV in seven, CLV in two and FT in four. Serum levels of midazolam ranged from 0.10 to 1.76 mg/l, OH-midazolam from 0.05 to 0.28 mg/l and glu-midazolam from 0.85 to 4.36 mg/l. Conclusions: A brief and moderate suppression of the aEEG background pattern immediately after midazolam was seen in four neonates for less than 2 h. Suppression at a later time point, i.e. after more than 8 h of midazolam infusion, was demonstrated almost exclusively in neonates with a poor background pattern, and therefore these patterns appear to be determined mainly by the severity of hypoxic-ischaemic encephalopathy.
- Published
- 2004
9. Pharmacokinetics and pharmacodynamics of medication in asphyciated newborns during controlled hypothermia. The PharmaCool multicenter study
- Author
-
de Haan, TR, Bijleveld, YA, v.d. Lee, JH, Groenendaal, F, van den Broek, MPH, Rademaker, CMA, van Straaten, HLM (Henrica / Henriette), van Weissenbruch, MM, Vermeulen, JR, Dijk, PH, Dudink, J, Rijken, M, van Heijst, A, Dijkman, KP, Gavilanes, D, Kaam, AH, Offringa, M (Martin), Mathot, RAA, de Haan, TR, Bijleveld, YA, v.d. Lee, JH, Groenendaal, F, van den Broek, MPH, Rademaker, CMA, van Straaten, HLM (Henrica / Henriette), van Weissenbruch, MM, Vermeulen, JR, Dijk, PH, Dudink, J, Rijken, M, van Heijst, A, Dijkman, KP, Gavilanes, D, Kaam, AH, Offringa, M (Martin), and Mathot, RAA
- Published
- 2012
10. Farmacotherapie in de kindergeneeskunde
- Author
-
Rademaker, CMA, van den Anker, John, Roord, JJ, and Pediatrics
- Published
- 1997
11. Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates
- Author
-
Leuven, K, primary, Groenendaal, F, additional, Toet, MC, additional, Schobben, AFAM, additional, Bos, SAJ, additional, Vries, LS, additional, and Rademaker, CMA, additional
- Published
- 2007
- Full Text
- View/download PDF
12. Effects of magnesium sulphate on amplitude‐integrated continuous EEG in asphyxiated term neonates
- Author
-
Groenendaal, F, primary, Rademaker, CMA, additional, Toet, MC, additional, and de Vries, LS, additional
- Published
- 2002
- Full Text
- View/download PDF
13. Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir.
- Author
-
Jansen CFM, Toet MC, Rademaker CMA, Ververs TFF, Gerards LJ, and van Loon AM
- Abstract
Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. Some congenitally infected infants will develop sequelae later in life, especially sensorineural hearing loss (SNHL) and mental retardation. There is no generally accepted antiviral therapy for the treatment of symptomatic congenital CMV infections yet. We present a neonate with symptomatic congenital CMV infection, who was treated with intravenous (iv) ganciclovir (GCV) during 18 days and subsequently with oral valganciclovir (VGCV) for 5.5 months, in an attempt to prevent development of SNHL. GCV was given intravenously 10 mg/kg/day in two doses and VGCV doses ranged from 280-850 mg/m2 bidaily (bid). Our experience shows that it is not possible to give a fixed dosing regime for VGCV in neonates and that continuous adaptation of dose is necessary to achieve stable target levels of GCV and to keep the viral load in urine at undetectable level. At 18 months of age no hearing deterioration has occurred. While the current findings are encouraging, the limitations of a single case report with a relatively short follow-up emphasizes the need for further prospective randomized studies to evaluate pharmacokinetics, efficacy and safety of VGCV therapy in neonates with congenital CMV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2005
14. Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia.
- Author
-
Benders MJN, Bos AF, Rademaker CMA, Rijken M, Torrance HL, Groenendaal F, and van Bel F
- Abstract
OBJECTIVE: To investigate whether postnatal allopurinol would reduce free radical induced reperfusion/reoxygenation injury of the brain in severely asphyxiated neonates. METHOD: In an interim analysis of a randomised, double blind, placebo controlled study, 32 severely asphyxiated infants were given allopurinol or a vehicle within four hours of birth. RESULTS: The analysis showed an unaltered (high) mortality and morbidity in the infants treated with allopurinol. CONCLUSION: Allopurinol treatment started postnatally was too late to reduce the early reperfusion induced free radical surge. Allopurinol administration to the fetus with (imminent) hypoxia via the mother during labour may be more effective in reducing free radical induced post-asphyxial brain damage. [ABSTRACT FROM AUTHOR]
- Published
- 2006
15. Effects of the pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes: a systematic literature review.
- Author
-
van Riet-Nales DA, Schobben AFA, Egberts TCG, and Rademaker CMA
- Abstract
Background: In view of the high rates of off-label and unlicensed prescribing of drugs in children, the US Food and Drug Administration and the European Union have implemented legislative regulations for the pharmaceutical industry to increase the number of drugs with approved pediatric labeling. However, the extent to which the effects of pharmaceutical technologic aspects of pediatric oral drugs (eg, taste, route and frequency of administration, user instructions) on patient-related outcomes (eg, efficacy, tolerability, preference, adherence) can be based on clinical evidence from the available literature is unknown. Objective: This systematic literature review aimed to identify the nature, volume, and quality of comparative studies that have assessed the effects of pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes. Methods: The Cochrane, EMBASE, and MEDLINE databases were searched from their start through December 31, 2009. Studies were eligible for inclusion if they were published in English; included search terms for child, study design, medicine, formulation aspects, dosage form, routes of administration, patient acceptance, adherence, side effects and tolerability, and/or efficacy; reported on >/=10 children aged 0 to <18 years; and described the effects of >/=1 of 3 pharmaceutical technologic aspects of an oral pediatric drug (formulation and dosage form; route and frequency of administration; and/or packaging, administration device, and user instruction) on >/=1 of 6 patient-related outcomes (clinical efficacy, side effects and tolerability, patient preference, patient acceptance, administration errors, and/or adherence). Studies were excluded if they concerned a nonallopathic drug (ie, homeopathic remedy, anthroposophic drug, herbal supplement, or food supplement); related to asthma (because modern asthma treatment protocols strongly favor the use of drug inhalation above oral medication); and/or related to analgesics. The characteristics of each of the included publications were assessed with respect to pharmaceutical technologic aspect studied; patient-related outcomes studied; pharmacotherapeutic indication; year of publication; geographic location; number and age of the included subjects; and sponsorship by industry and/or author affiliation with the pharmaceutical industry. The electronic search was supplemented with a manual search of the cited references. Results: Ninety-four publications were identified as eligible for inclusion. These publications reported on 176 assessments of the effects of >/=1 pharmaceutical technologic aspect on >/=1 patient-related outcome. Fiftyfive percent of the studies were conducted in children aged 2 or 3 years, and 69% in children aged 4 or 5 years. Forty-three percent of the publications included >/=100 patients. Fifty-one percent of the studies were conducted in the United States or Canada, and 29% in Europe. Antibacterials for systemic use were the subject of 30% of the included publications. Two of the 94 publications were of appropriate méthodologie quality (Jadad score >/=4). Forty-nine percent of the studies were sponsored by the pharmaceutical industry or were written by >/=1 author affiliated with the industry. Sixty-eight percent of the included studies had Jadad scores of 0 or 1 (poor quality). The proportion of industry-sponsored or industry-authored studies with a Jadad score >/=2 or in >/=100 children was not significantly different from that of non-industry-sponsored or-authored studies. The proportion of industry-sponsored or industry-authored studies conducted in the United States/Canada (48 [51%]) was not significantly different from that of studies conducted elsewhere (46 [49%]). The distribution of technologic aspects assessed in the included studies were formulation and dosage form, 48%; route and frequency of administration, 44%; and packaging, administration device, and user instruction, 8%. Seventy-six assessments included >/=100 patients. Twenty-one of these assessments addressed patient acceptance or patient preference; 17, clinical efficacy; and 14, side effects and tolerability. Conclusions: This systematic review identified 94 articles on oral drugs for use in children and adolescents, which reported on a total 176 assessments of the effects of 3 pharmaceutical technologic aspects (formulation and dosage form; route and frequency of administration; and packaging, administration device, and user instruction) on 6 patient-related outcomes (clinical efficacy, side effects and tolerability, patient preference, patient acceptance, administration errors, and adherence). Only 2 of the 94 publications were of appropriate methodologic quality. These results suggest that published clinical evidence to support pharmaceutical development programs is limited. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
16. The efficacy of the entire-vial dosing of emicizumab: Real-world evidence on plasma concentrations, bleeds, and drug waste.
- Author
-
Donners AAMT, van der Zwet K, Rademaker CMA, Egberts TCG, Schutgens REG, and Fischer K
- Abstract
Background: Prophylaxis with emicizumab provides effective bleeding protection in persons with hemophilia A (PwHA) but pressures healthcare budgets. The body weight-adjusted dosing at 7-, 14-, or 28-day intervals, according to the label, often mismatches the vial content. Entire-vial dosing resulted in therapeutic concentrations according to pharmacokinetic simulations and was introduced to avoid waste., Objectives: The objective of this study was to evaluate the efficacy of entire-vial dosing of emicizumab by investigating real-world evidence of plasma concentrations, bleeds, and drug waste., Methods: This is a single-center, observational study with PwHA receiving emicizumab in mg/kg doses according to label but dosing interval extrapolated to the nearest vial size. Patient characteristics and bleeds were compared 1 year before starting emicizumab and during emicizumab until January 2022. Concentrations were assessed at weeks 4, 12, and annually. The mean (95% CI) annualized bleed rates were compared by using negative binomial regression. Drug waste between label-based dosing and entire-vial dosing was compared., Results: A total of 112 individuals (94% severe phenotype and 9% positive FVIII inhibitors) were followed for a median of 56 weeks (interquartile range [IQR] 52-68) before and 51 weeks (IQR 29-75) after starting emicizumab. The median emicizumab dose was 5.9 (IQR 5.5-6.2) mg/kg/4 wk with median concentrations of 63 (IQR 51-80) μg/mL. The annualized bleed rate of treated bleeds before emicizumab was 3.6 (95% CI 2.9-4.4) and was 0.8 (95% CI 0.6-1.1) during emicizumab ( P < .001). Drug waste was reduced by 9%., Conclusion: The entire-vial dosing of emicizumab is an attractive treatment option for PwHA leading to therapeutic plasma concentrations, good bleeding control, and drug waste avoidance., (© 2023 The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
17. Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation.
- Author
-
Bognàr T, Bartelink IH, Egberts TCG, Rademaker CMA, Versluys AB, Slatter MA, Kletzel M, Nath CE, Cuvelier GDE, Savic RM, Dvorak C, Long-Boyle JR, Cowan MJ, Bittencourt H, Bredius RGM, Güngör T, Shaw PJ, Ansari M, Hassan M, Krajinovic M, Hempel G, Marktel S, Chiesa R, Théoret Y, Lund T, Orchard PJ, Wynn RF, Boelens JJ, and Lalmohamed A
- Subjects
- Administration, Intravenous, Busulfan adverse effects, Child, Humans, Transplantation Conditioning adverse effects, Young Adult, Hematopoietic Stem Cell Transplantation, Hepatic Veno-Occlusive Disease epidemiology
- Abstract
Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
18. Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review.
- Author
-
Donners AAMT, Rademaker CMA, Bevers LAH, Huitema ADR, Schutgens REG, Egberts TCG, and Fischer K
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal, Humanized, Child, Factor VIII, Humans, Antibodies, Bispecific, Hemophilia A drug therapy
- Abstract
Introduction: Emicizumab is an effective new treatment option for people with hemophilia A (PwHA). The approved dosing regimens are based on body weight, without the necessity for laboratory monitoring. This assumes a clear dose-concentration-response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted., Methods: The EMBASE, Pubmed and CENTRAL databases were systematically searched to November 2020 to identify studies on the PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modeling was performed using non-linear least squares regression in a maximum effect (E
max ) model., Results: The 15 included studies reported on data for 140 volunteers and 467 PwHA, including children (0 to <12 years) and adolescents and adults (≥12 years), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The interindividual variability of trough concentrations was moderate (32%) and was similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA., Conclusion: This review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
19. Comparison between coagulation factor VIII quantified with one-stage activity assay and with mass spectrometry in haemophilia A patients: Proof of principle.
- Author
-
Donners AAMT, van Maarseveen EM, Weetink YRJ, El Amrani M, Fischer K, Rademaker CMA, Egberts TCG, Huisman A, and Musson REA
- Subjects
- Adult, Biomarkers blood, Blood Coagulation Tests, Cross-Sectional Studies, Female, Humans, Male, Proof of Concept Study, Factor VIII metabolism, Hemophilia A blood, Tandem Mass Spectrometry
- Abstract
Introduction: Haemophilia A is a hereditary bleeding disorder caused by a factor VIII (FVIII) deficiency. As biomarker, FVIII activity is used to classify disease severity and to monitor treatment. The one-stage clotting assay (OSA) is performed to measure FVIII activity, but OSA's limitations may result in misclassification of disease severity or suboptimal monitoring of treatment. Measurement of FVIII plasma concentration with liquid chromatography-tandem mass spectrometry (LC-MS/MS) might overcome these challenges. The objective is to investigate the correlation between FVIII activity and concentration, and determinants for differences between the two methods., Methods: In this cross-sectional study, all haemophilia A patients receiving standard-of-care were eligible for inclusion. Within the activity categories of <1 IU/dL, 1-5 IU/dL, >5-40 IU/dL, >40-150 IU/dL and >150-600 IU/dL, we randomly selected 15-20 plasma samples and compared FVIII concentration (LC-MS/MS) to FVIII activity (OSA) with linear regression and Bland-Altman analysis. Potential determinants for differences were analysed with linear regression., Results: Inclusion was 87 samples. Bland-Altman analysis demonstrated an overall mean difference of -1% with an SD of 64% between the two methods. Large differences were correlated with the presence of anti-FVIII antibodies (133% [95% CI: 81, 185] n = 5) and use of exogenous FVIII products (-37% [95% CI: -65,-9] n = 58), for example plasma-derived and B-domain-modified FVIII products., Conclusions: Despite good overall correlation between the two methods, relative differences were large, especially for samples with anti-FVIII antibodies or exogenous FVIII products. These differences may have clinical impact. More research is needed to determine the value of FVIII plasma concentration in comparison with FVIII activity., (© 2020 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
20. Translation from animal to clinical studies, choosing the optimal moment.
- Author
-
Favié LMA, Peeters-Scholte CMPCD, Bakker A, Tjabbes H, Egberts TCG, van Bel F, Rademaker CMA, Vis P, and Groenendaal F
- Subjects
- Animals, Biomechanical Phenomena, Humans, Infant, Newborn, Biotin analogs & derivatives, Hypothermia, Induced
- Published
- 2020
- Full Text
- View/download PDF
21. Prediction of Drug Exposure in Critically Ill Encephalopathic Neonates Treated With Therapeutic Hypothermia Based on a Pooled Population Pharmacokinetic Analysis of Seven Drugs and Five Metabolites.
- Author
-
Favié LMA, de Haan TR, Bijleveld YA, Rademaker CMA, Egberts TCG, Nuytemans DHGM, Mathôt RAA, Groenendaal F, and Huitema ADR
- Subjects
- Age Factors, Belgium, Body Size, Body Temperature Regulation, Brain Diseases blood, Brain Diseases diagnosis, Brain Diseases physiopathology, Critical Illness, Drug Dosage Calculations, Female, Humans, Infant, Newborn, Male, Models, Biological, Netherlands, Pharmaceutical Preparations administration & dosage, Prospective Studies, Brain Diseases therapy, Hypothermia, Induced adverse effects, Pharmaceutical Preparations metabolism, Pharmacokinetics
- Abstract
Drug dosing in encephalopathic neonates treated with therapeutic hypothermia is challenging; exposure is dependent on body size and maturation but can also be influenced by factors related to disease and treatment. A better understanding of underlying pharmacokinetic principles is essential to guide drug dosing in this population. The prospective multicenter cohort study PharmaCool was designed to investigate the pharmacokinetics of commonly used drugs in neonatal encephalopathy. In the present study, all data obtained in the PharmaCool study were combined to study the structural system specific effects of body size, maturation, recovery of organ function, and temperature on drug clearance using nonlinear mixed effects modeling. Data collected during the first 5 days of life from 192 neonates treated with therapeutic hypothermia were included. An integrated population pharmacokinetic model of seven drugs (morphine, midazolam, lidocaine, phenobarbital, amoxicillin, gentamicin, and benzylpenicillin) and five metabolites (morphine-3-glucuronide, morphine-6-glucuronide, 1-hydroxymidazolam, hydroxymidazolam glucuronide, and monoethylglycylxylidide) was successfully developed based on previously developed models for the individual drugs. For all compounds, body size was related to clearance using allometric relationships and maturation was described with gestational age in a fixed sigmoidal Hill equation. Organ recovery after birth was incorporated using postnatal age. Clearance increased by 1.23%/hours of life (95% confidence interval (CI) 1.03-1.43) and by 0.54%/hours of life (95% CI 0.371-0.750) for high and intermediate clearance compounds, respectively. Therapeutic hypothermia reduced clearance of intermediate clearance compounds only, by 6.83%/°C (95% CI 5.16%/°C-8.34%/°C). This integrated model can be used to facilitate drug dosing and future pharmacokinetic studies in this population., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
- Full Text
- View/download PDF
22. Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia.
- Author
-
Favié LMA, Peeters-Scholte CMPCD, Bakker A, Tjabbes H, Egberts TCG, van Bel F, Rademaker CMA, Vis P, and Groenendaal F
- Subjects
- Asphyxia Neonatorum diagnosis, Asphyxia Neonatorum enzymology, Biotin administration & dosage, Biotin adverse effects, Biotin pharmacokinetics, Drug Administration Schedule, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Female, Humans, Hypoxia-Ischemia, Brain diagnosis, Hypoxia-Ischemia, Brain enzymology, Infant, Newborn, Infusions, Intravenous, Male, Netherlands, Nitric Oxide Synthase metabolism, Prospective Studies, Treatment Outcome, Asphyxia Neonatorum therapy, Biotin analogs & derivatives, Enzyme Inhibitors pharmacokinetics, Hypothermia, Induced adverse effects, Hypoxia-Ischemia, Brain prevention & control, Nitric Oxide Synthase antagonists & inhibitors
- Abstract
Background: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising neuroprotective agent additional to therapeutic hypothermia to improve the outcome of these neonates., Methods: In an open-label study, pharmacokinetics and short-term safety of 2-iminobiotin were investigated in neonates treated with therapeutic hypothermia. Group A (n = 6) received four doses of 0.16 mg/kg intravenously q6h. Blood sampling for pharmacokinetic analysis and monitoring of vital signs for short-term safety analysis were performed. Data from group A was used to determine the dose for group B, aiming at an AUC
0-48 h of 4800 ng*h/mL., Results: Exposure in group A was higher than targeted (median AUC0-48 h 9522 ng*h/mL); subsequently, group B (n = 6) received eight doses of 0.08 mg/kg q6h (median AUC0-48 h 4465 ng*h/mL). No changes in vital signs were observed and no adverse events related to 2-iminobiotin occurred., Conclusion: This study indicates that 2-iminobiotin is well tolerated and not associated with any adverse events in neonates treated with therapeutic hypothermia after perinatal asphyxia. Target exposure was achieved with eight doses of 0.08 mg/kg q6h. Optimal duration of therapy for clinical efficacy needs to be determined in future clinical trials.- Published
- 2020
- Full Text
- View/download PDF
23. Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen.
- Author
-
Favié LMA, Huitema ADR, van den Broek MPH, Rademaker CMA, de Haan TR, van Straaten HLM, Simons SHP, Rijken M, Nuytemans DHGM, Egberts TCG, and Groenendaal F
- Subjects
- Anticonvulsants therapeutic use, Humans, Infant, Newborn, Lidocaine therapeutic use, Seizures drug therapy, Epilepsy drug therapy, Hypothermia, Induced
- Abstract
Aims: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed., Methods: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred., Results: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54-0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63-11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed., Conclusion: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Published
- 2020
- Full Text
- View/download PDF
24. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.
- Author
-
Favié LMA, Groenendaal F, van den Broek MPH, Rademaker CMA, de Haan TR, van Straaten HLM, Dijk PH, van Heijst A, Dudink J, Dijkman KP, Rijken M, Zonnenberg IA, Cools F, Zecic A, van der Lee JH, Nuytemans DHGM, van Bel F, Egberts TCG, and Huitema ADR
- Subjects
- Female, Humans, Infant, Newborn, Male, Prospective Studies, Asphyxia Neonatorum blood, Asphyxia Neonatorum therapy, Brain Diseases blood, Brain Diseases therapy, Hypothermia, Induced, Morphine administration & dosage, Morphine pharmacokinetics
- Abstract
Objective: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population., Study Design: Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants., Results: 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia., Conclusions: Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect., Trial Registration: www.trialregister.nl NTR2529., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
- Full Text
- View/download PDF
25. Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia.
- Author
-
Favié LMA, Groenendaal F, van den Broek MPH, Rademaker CMA, de Haan TR, van Straaten HLM, Dijk PH, van Heijst A, Simons SHP, Dijkman KP, Rijken M, Zonnenberg IA, Cools F, Zecic A, van der Lee JH, Nuytemans DHGM, van Bel F, Egberts TCG, and Huitema ADR
- Subjects
- Anticonvulsants administration & dosage, Anticonvulsants blood, Drug Interactions, Drug Therapy, Combination, Female, Humans, Infant, Newborn, Male, Metabolic Clearance Rate, Midazolam administration & dosage, Midazolam blood, Phenobarbital administration & dosage, Phenobarbital blood, Practice Guidelines as Topic, Prospective Studies, Anticonvulsants pharmacokinetics, Asphyxia Neonatorum therapy, Hypothermia, Induced, Hypoxia-Ischemia, Brain therapy, Midazolam pharmacokinetics, Phenobarbital pharmacokinetics
- Abstract
Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance., Objectives: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines., Methods: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs., Results: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam., Conclusions: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth., (© 2019 The Author(s) Published by S. Karger AG, Basel.)
- Published
- 2019
- Full Text
- View/download PDF
26. Nitric Oxide Synthase Inhibition as a Neuroprotective Strategy Following Hypoxic-Ischemic Encephalopathy: Evidence From Animal Studies.
- Author
-
Favié LMA, Cox AR, van den Hoogen A, Nijboer CHA, Peeters-Scholte CMPCD, van Bel F, Egberts TCG, Rademaker CMA, and Groenendaal F
- Abstract
Background: Hypoxic-ischemic encephalopathy following perinatal asphyxia is a leading cause of neonatal death and disability worldwide. Treatment with therapeutic hypothermia reduced adverse outcomes from 60 to 45%. Additional strategies are urgently needed to further improve the outcome for these neonates. Inhibition of nitric oxide synthase (NOS) is a potential neuroprotective target. This article reviews the evidence of neuroprotection by nitric oxide (NO) synthesis inhibition in animal models., Methods: Literature search using the EMBASE, Medline, Cochrane, and PubMed databases. Studies comparing NOS inhibition to placebo, with neuroprotective outcome measures, in relevant animal models were included. Methodologic quality of the included studies was assessed., Results: 26 studies were included using non-selective or selective NOS inhibition in rat, piglet, sheep, or rabbit animal models. A large variety in outcome measures was reported. Outcome measures were grouped as histological, biological, or neurobehavioral. Both non-selective and selective inhibitors show neuroprotective properties in one or more outcome measures. Methodologic quality was either low or moderate for all studies., Conclusion: Inhibition of NO synthesis is a promising strategy for additional neuroprotection. In humans, intervention can only take place after the onset of the hypoxic-ischemic event. Therefore, combined inhibition of neuronal and inducible NOS seems the most likely candidate for human clinical trials. Future studies should determine its safety and effectiveness in neonates, as well as a potential sex-specific neuroprotective effect. Researchers should strive to improve methodologic quality of animal intervention studies by using a systematic approach in conducting and reporting of these studies.
- Published
- 2018
- Full Text
- View/download PDF
27. Comparison of antibiotic dosing recommendations for neonatal sepsis from established reference sources.
- Author
-
Liem TBY, Slob EMA, Termote JUM, Wolfs TFW, Egberts ACG, and Rademaker CMA
- Subjects
- Drug Administration Schedule, Humans, Infant, Newborn, Neonatal Sepsis epidemiology, Netherlands epidemiology, Anti-Bacterial Agents administration & dosage, Decision Support Systems, Clinical standards, Intensive Care Units, Neonatal standards, Medical Order Entry Systems standards, Medication Errors prevention & control, Neonatal Sepsis drug therapy
- Abstract
Background Incorrect dosing is the most frequent prescribing error in neonatology, with antibiotics being the most frequently prescribed medicines. Computer physician order entry and clinical decision support systems can create consistency contributing to a reduction of medication errors. Although evidence-based dosing recommendations should be included in such systems, the evidence is not always available and subsequently, dosing recommendations mentioned in guidelines and textbooks are often based on expert opinion. Objective To compare dosage recommendations for antibiotics in neonates with sepsis provided by eight commonly used and well-established international reference sources. Setting An expert team from our Dutch tertiary care neonatal intensive care unit selected eight well-established international reference sources. Method Daily doses of the seven most frequently used antibiotics in the treatment of neonatal sepsis, classified by categories for birth weight and gestational age, were identified from eight well-respected reference sources in neonatology/pediatric infectious diseases. Main outcome measure Standardized average daily dosage. Results A substantial variation in dosage recommendations of antibiotics for neonatal sepsis between the reference sources was shown. Dosage recommendations of ampicillin, ceftazidime, meropenem and vancomycin varied more than recommendations for benzylpenicillin, cefotaxime and gentamicin. One reference source showed a larger variation in dosage recommendations in comparison to the average recommended daily dosage, compared to the other reference sources. Conclusion Antibiotic dosage recommendations for neonates with sepsis can be derived from important reference sources and guidelines. Further exploration to overcome variation in dosage recommendations is necessary to obtain standardized dosage regimens.
- Published
- 2018
- Full Text
- View/download PDF
28. Long-Term Melatonin Therapy for Adolescents and Young Adults with Chronic Sleep Onset Insomnia and Late Melatonin Onset: Evaluation of Sleep Quality, Chronotype, and Lifestyle Factors Compared to Age-Related Randomly Selected Population Cohorts.
- Author
-
Zwart TC, Smits MG, Egberts TCG, Rademaker CMA, and van Geijlswijk IM
- Abstract
The extent of continuance of melatonin therapy initiated in pre-pubertal children with chronic sleep onset insomnia (CSOI) was investigated in young adult life. Sleep timing, sleep quality, adverse events, reasons for cessation of therapy, and patient characteristics with regard to therapy regimen, chronotype and lifestyle factors possibly influencing sleeping behavior were assessed. With an online survey using questionnaires (Pittsburgh Sleep Quality Index, Insomnia Severity Index, Morningness-Eveningness Questionnaire, and Munich Chronotype Questionnaire), outcomes were measured and compared with age-related controls. These controls were extracted from published epidemiological research programs applying the same questionnaires. At the moment of the survey, melatonin was still continued by 27.3% of the patients, with a mean treatment duration of 10.8 years. The overall average treatment duration was 7.1 years. Sleep quality of both discontinued and persistent melatonin users did not deviate from controls. Sleep timing and chronotype scores indicated evening type preference in all responders. Adverse events were scarce but the perceived timing of pubertal development suggested a tendency towards delayed puberty in former and current users of melatonin. This study may underestimate the number of children that are able to stop using melatonin due to the response rate (47.8%) and appeal for continuing users. Sleep timing parameters were based on self-reported estimates. Control populations were predominantly students and were of varying nationalities. The statistical power of this study is low due to the limited sample size. Melatonin therapy sustained for 7.1 years does not result in substantial deviations of sleep quality as compared to controls and appears to be safe. The evening type preference suggests a causal relation with CSOI. This study shows that ten years after initiation of treatment with melatonin for CSOI, approximately 75% of the patients will have normal sleep quality without medication., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.