This dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded... Show moreThis dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded matter. Unblinding might partially mitigate the limitation, but current measurement methods have gaps that we should remain aware of. Detailed measurements of subintervals with characterization of ion channel profiles, concentration QTc modelling, or machine learning might help physicians in their decision making in the future. Show less
Prematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are... Show morePrematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are not necessarily similar to prematurely born neonates. When suboptimal dosing guidelines are applied the neonates are at risk for under- or overdosing. In this thesis the pharmacokinetics and pharmacodynamics of a variety of drugs frequently used in preterm neonates were characterized, ultimately to optimize treatment. Specifically, caffeine, ibuprofen and fluconazole were studied which are drugs to treat apnea of prematurity, to close a patent ductus arteriosus and to treat or prevent infections with Candida in newborns, respectively. These drugs were introduced and used in clinical practice without sufficient knowledge, especially on appropriate dosing for this subpopulation. For caffeine and ibuprofen we found that the clearance rapidly increases with postnatal age, while for fluconazole clearance is better reflected by body weight and serum creatinine. For these drugs dosing guidelines were proposed based on identified covariates for their pharmacokinetics. Ibuprofen therapy was further investigated by examining the course of spontaneous closure of the ductus arteriosus, and evaluating the effects of ibuprofen exposure and patient characteristics simultaneously. Show less
Muehlan, C.; Brooks, S.; Zuiker, R.; Gerven, J. van; Dingemanse, J. 2019
ACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation,... Show moreACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability following multiple-ascending oral dose (MAD) administration in the morning, and next-day residual effects after repeated evening administration were investigated in a double-blind, placebo-controlled, randomized study. 31 healthy male and female subjects in 3 dose-groups (10, 25, and 75 mg) received study drug in the morning for 5 days (MAD part), and 20 healthy subjects received 25 mg in the evening for 1 week (evening part). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analogue scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), Digit Symbol Substitution Test (DSST), and Simple Reaction Time Test (SRTT), safety, and tolerability were assessed. ACT-541468 was absorbed with a median t(max) of 1.0-2.0 h across the 3 dose groups. The geometric mean elimination half-life (t(1/2)) on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality. No accumulation and no influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. No effects were observed at 10 mg. Administration of 25 and 75 mg during the day showed clear dose-dependent effects on the PD parameters, while next-day effects were absent after evening administration of 25 mg. The drug was safe and well tolerated. In conclusion, multiple-dose PK/PD of ACT-541468 were compatible with a drug designated to treat insomnia. (C) 2019 Elsevier B.V. and ECNP. All rights reserved. Show less
This thesis covers a variety of topics around the central theme of pharmacological research involving children, with a specific focus on the development of minimally invasive methodology that can... Show moreThis thesis covers a variety of topics around the central theme of pharmacological research involving children, with a specific focus on the development of minimally invasive methodology that can be employed in future studies involving children. Children form a unique group within the area of pharmacological research and pharmacotherapy. The heterogeneity even within this group is large, covering the range of preterm neonates weighing 500 grams up to adolescents. Obviously, therapeutic needs change across this range, as among others disease epidemiology, drug disposition, pharmacodynamic response, and suitable drug formulations change with age. The same holds true for the design of drug trials involving children: where pharmacokinetics in adults can be studied simply by recruiting a number of healthy volunteers, such a study with a number of healthy toddlers is clearly not feasible and not acceptable. Therefore, approaches and new methodology are needed to circumvent these issues. Show less
