303 research outputs found
Antifungal pharmacokinetics in the era of the obesity pandemic
No full textContains fulltext :
214242.pdf (Publisher’s version ) (Open Access)Radboud University, 15 november 2019Promotores : Burger, D.M., Knibbe, C.A.J. Co-promotor : Bruggemann, R.J.M
Size does matter : drug glucuronidation in children
No full textThe maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was developed for morphine, which was used as a paradigm compound. In this model, the maturation of morphine glucuronidation is described by a bodyweight-based exponential relationship with an exponent of 1.44. The model-derived dosing algorithm was evaluated prospectively in a clinical trial and it was shown that this dosing algorithm may reduce overdosing of neonates and exposure to ineffective doses in older infants. Additionally, it was found that the bodyweight-based exponential relationship that describes the maturation of morphine glucuronidation can be directly applied to the maturation of zidovudine, which is also a UGT2B7 substrate. This expedites the development of paediatric pharmacokinetic models and evidence-based paediatric drug dosing algorithms. Based on a study using physiologically-based pharmacokinetic modeling it was concluded that the equation for maturation of morphine glucuronidation could be applicable to all small molecular drugs and to paediatric patient populations with normal hepatic function. Finally, a framework was developed to properly validate paediatric pharmacokinetic population models and the validation of paediatric pharmacokinetic models for morphine in literature were investigated.TI PharmaUBL - phd migration 201
Novel approach to characterize developmental changes in pharmacokinetics across the human lifespan: application to the prediction of clearance in children
No full textThis book focuses on novel approach to characterize developmental changes in pharmacokinetics across human lifespan with the up-to-date Nonlinear Mixed Effect Modeling techniques.UBL - phd migration 201
Concepts and applications for evidence-based dosing in morbidly obese patients before and after weight loss surgery
No full textDrug concentrations and effects may be different in morbidly obese patients (body mass index > 40 kg/m2). In addition, also such changes may be expected in patients after a weight loss surgery. This thesis aims to develop evidence-based dosing recommendations for these patient groups and focuses on two drugs: cefazolin and midazolam. Cefazolin is an antibiotic that is often used as a prophylactic before surgery in order to prevent surgical wound infections. This research demonstrates that in morbidly obese patients, cefazolin subcutaneous tissue penetration in lower in comparison to non-obese patients and dosing adjustments are needed. Midazolam is a commonly used drug for short term or long term sedation. This thesis shows that in particular the distribution of midazolam is strongly influenced by obesity requiring dosing adjustments. Furthermore, it was found that midazolam metabolism (through cytochrome P450 3A enzymes, CYP3A) appears to be lower in comparison to non-obese healthy volunteers, while the total clearance was the same for both groups. After weight loss surgery, midazolam clearance increased, probably because the CYP3A enzyme activity is restored. In the future, these results may be used for other drugs which also undergo CYP3A metabolism (approximately 25% of all clinical used drugs).The research described in this thesis was supported by the St. Antonius Hospital Nieuwegein, a research grant from Fonds Nuts OHRA (1002-026) and by ZonMW (The Netherlands Organisation for Health Research and Development, project number 836011008).UBL - phd migration 201
Pharmacokinetics and/or pharmacodynamics of propofol, atracurium and cefazolin in morbidly obese patients
No full textIn this thesis we initiated pharmacokinetic and/or pharmacodynamic studies in morbidly obese patients undergoing bariatric surgery in order to study propofol, atracurium and cefazolin in this population. The studies in this thesis show that these types of investigation in morbidly obese patients can most adequately be performed in a large teaching hospital by a multidisciplinary team working closely with a university centre. In the bariatric centre in the St. Antonius Hospital in Nieuwegein a large number of bariatric procedures (300 yearly) are carried out and all patients remain in a life-long follow-up program within a multidisciplinary team of medical specialists and nurses. While this program also allows for longterm studies, we have shown in this thesis the suitability of the infrastructure for pharmacokinetic and/or pharmacodynamic studies for different kind of drugs. The pilot study (chapter 3) on propofol for induction of anaesthesia shows that a dose based on ideal body weight (i.e. 200 mg) is an inadequate induction dose for morbidly obese patients in terms of efficacy of induction of anaesthesia measured using Bispectral Index values, haemodynamic parameters and clinical observations. While propofol 200 mg typically is an adequate dose for induction of anaesthesia in non-obese patients, it seems that the higher induction dose in morbidly obese patients (i.e. 350 mg) may be explained by the increased blood volume and cardiac output that can be expected in morbidly obese patients. Upton and co workers also showed in sheep that a higher cardiac output resulted in lower initial arterial concentrations of propofol, as upon a dose of 100 mg over two minutes, arterial concentrations of propofol were found to be inversely related to cardiac output. This implies that cardiac output may be a determinant of the induction of anaesthesia with propofol. In our pilot study, an induction dose of 350 mg seemed adequate, although temporary cardiovascular instability was observed in one patient, which was attributed to the start of the propofol maintenance infusion of 10 mg/kg/hour within five minutes after induction of anaesthesia. On the basis of these results, it was concluded that for future studies, a dose based on total body weight with or without a dose cap at 350 mg or a dose based on lean body mass in a larger sample of morbidly obese patients seems appropriate. More recently, the study of Ingrande et al. showed that lean body mass is a more appropriate weight based scalar for propofol infusion for induction of anaesthesia in morbidly obese patients compared to total body weight. These recent findings seem consistent with a report on the correlation of cardiac output with lean body mass. In the study evaluating propofol for maintenance of anaesthesia in morbidly obese patients (chapter 4), a dosing regimen of 4-6 mg/kg/hr was proposed for both the combination of propofol with remifentanil and the combination of propofol with epidural analgesia because no difference was observed in the propofol concentration __ Bispectral Index relation between the two groups. Although in this study Bispectral Index values are influenced to the same extend by adding remifentanil compared to epidural analgesia to propofol anaesthesia, the current opinion is that opioids such as remifentanil do exert a propofol-sparing effect when given in combination with propofol. Some studies did show reductions in Bispectral Index values when an opioid was given during anaesthesia with propofol, which may potentially be explained by a decrease in blood pressure, heart rate or cerebral blood flow and thus a decrease in Bispectral Index values. Guignard et al. on the other hand demonstrated that remifentanil does not affect Bispectral Index values but that the increases in Bispectral Index values associated with laryngoscopy and orotracheal intubation are prevented by remifentanil in a dose-dependent fashion. Other studies did demonstrate a deeper level of anaesthesia when an opioid was co-administered with propofol which was not reflected by lower Bispectral Index values. As the use of the Bispectral Index can be questioned as an endpoint to evaluate propofol dosing in co-administration with remifentanil, we also used haemodynamic parameters as an endpoint for propofol dosing. The predefined range of the haemodynamic parameters, however, was easier to aim for compared to the predefined range of Bispectral Index values. It seems therefore that a propofol-sparing effect by remifentanil co-administration can not be excluded and that potentially other pharmacodynamic measures are required to answer this question. From the study evaluating the population pharmacokinetics and pharmacodynamics of propofol when used in combination with remifentanil in morbidly obese patients (chapter 5) it can be concluded that body weight is the major determinant for clearance of propofol using an allometric function with an exponent of 0.72. This conclusion indicates that propofol in morbidly obese patients should be dosed in mg kg-0.72 instead of mg/kg as was reported in chapter 4. In our opinion, this different conclusion can be explained by the difference in analysis techniques. In the study described in chapter 4 dosing of propofol was based on clinical practice and dosing was thus performed in mg/kg/ hr (linear). As a result, a dosing advice in mg/kg/hr was given for maintenance of anaesthesia with propofol. In chapter 5, though, a population pharmacokinetic and pharmacodynamic analysis was performed using NONMEM allowing for a systematic covariate analysis in which the influence of different measures of body weight on pharmacokinetic and pharmacodynamic parameters can be studied. Although Lemmens et al. concluded that dosing of propofol in morbidly obese patients should be based on lean body mass, this is not confirmed by our analysis. In our study total body weight was the major determinant for clearance of propofol in morbidly obese patients, with body mass index as a good alternative, while there was no basis for the use of lean body mass. This was confirmed by repeating the analysis with the inclusion of non-obese patients. As propofol clearance is mainly influenced by hepatic blood flow, it may be speculated that in morbidly obese patients hepatic blood flow is correlated to total body weight in an allometric function with an exponent of 0.72 instead of lean body mass. Using these techniques it was also found that there was no significant influence of body weight on any of the other pharmacokinetic and pharmacodynamic parameters. A non-significant trend was identified towards an increased central volume of distribution in morbidly obese patients. This result may be explained by an increased blood volume in morbidly obese patients and thereby explain part of the results of the pilot study described in chapter 3, in which a larger dose of propofol was reported for induction of anaesthesia in morbidly obese patients compared to non-obese patients. However, another explanation for the larger dose of propofol necessary for induction in morbidly obese patients described in chapter 3 may be an increase in cardiac output in morbidly obese patients. In the pharmacokinetic and pharmacodynamic analysis of propofol described in chapter 5 patients with body weights up to 167 kg were included. The non-linear dosing regimen that is derived from this pharmacokinetic and pharmacodynamic model should therefore primarily be used in patients up to this body weight. However, it also seems of interest to evaluate the extrapolation possibilities of the model and its dosing regimen by applying this dosing regimen in patients with larger body weights. A prospective study, in this respect, is of importance to show the predictive, clinical and practical value of the model in addition to its descriptive properties in morbidly obese patients. The study of atracurium (chapter 6) showed that dosing of this muscle relaxant when used at the time of induction of anaesthesia should be based on ideal body weight, as this results in a predictable profile of muscle relaxation allowing for adequate intubation conditions and recovery of muscle strength to a train-offour- ratio > 90% within 60 minutes with lack of need for antagonism. A dose-dependent prolongation of action is shown when dosing is based on total body weight. The relative decrease in the percentage of lean body mass and total body water together with the hydrophilic characteristics of atracurium may lead to the hypothesis that less atracurium is needed per kilogram of body weight in obese patients compared to non-obese patients. This is in accordance with the findings described in chapter 6. Whether this is applicable to other muscle relaxants as rocuronium remains uncertain, as the clearance of this agent is more dependent on liver and kidney function . For rocuronium, an antagonist (sugammadex) is on the market, and it would be of interest to study the dose requirements of both drugs in morbidly obese patients. As for atracurium, in the European drug information for rocuronium a dosing advice is given in mg/kg. In our study, this proved to be incorrect for atracurium, and provokes speculations on this advice for rocuronium and sugammadex, providing a basis for future research on this topic in morbidly obese patients. The study on cefazolin in this thesis (chapter 7) shows unbound plasma cefazolin concentrations above 1 mg/L (minimal inhibitory concentration for 90% (MIC90) of methicillin sensitive isolates of S. Aureus in Europe) during four hours after a dose of two gram intravenously in morbidly obese patients. Whether these unbound plasma cefazolin concentrations are adequate in specific hospitals or countries depends on the minimal inhibitory concentration for 90% of the isolates in the local setting. As discussed in the introduction of this thesis, cefazolin is mainly albumin-bound and it is not expected that obesity influences the plasma protein binding of cefazolin. This is in accordance to our study described in chapter 7, where we conclude that plasma protein binding of cefazolin in morbidly obese patients is 79%, which is the same as in non-obese patients. The negative correlation between peak cefazolin concentration and body weight described in our study may potentially be explained by the increased volume of distribution due to the increased blood volume described in morbidly obese patients. In addition, the positive correlation between age and trough plasma cefazolin concentrations described in our study may be explained by the increase in glomerular filtration and perfusion of the kidneys described in the early stages of obesity, while in the later stages of obesity these tend to normalize and subsequently decrease. As described in the introduction of this thesis, morbidly obese patients are exposed to an increased risk of developing post-operative wound infections compared to non-obese patients due to poorly perfused excess of adipose tissue. As cefazolin is excreted via the kidneys, an increase of glomerular filtration as well as perfusion as described in obesity may result in increased cefazolin clearance, necessitating a higher dose of cefazolin in morbidly obese patients. As was shown in our study, this particularly occurred in younger individuals, even though in all cases cefazolin concentrations remained above 1 mg/L. However, it is unknown if cefazolin can penetrate into the target organ, i.e. the subcutaneous tissue. Altogether, this may explain the wound infections that occurred despite adequate plasma cefazolin concentrations in two patients in our study, even though the statistical importance of the high infection rate in our study remains uncertain due to the small patient group (n=20). A future study evaluating plasma cefazolin concentrations together with tissue concentrations of cefazolin using a microdialysis catheter is in progress. In conclusion, we initiated pharmacokinetic and/or pharmacodynamic studies in morbidly obese patients undergoing bariatric surgery by investigating propofol, atracurium and cefazolin in this population. To allow for this type of research a large (teaching) hospital with a multidisciplinary team of medical specialists and nurses is essential. Pharmacokinetic and/or pharmacodynamics studies provide the basis for dosing regimen of medication used in morbidly obese patients and give insight into the pathophysiological changes in this special population. A large amount of future research in morbidly obese patients is yet to be performed and is essential as the body weights and body mass indices in this population are still increasing.UBL - phd migration 201
Don't be afraid! Population PK-PD modeling as the basis for individualized dosing in children and critically ill
No full textThe overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Both under- and oversedation significantly and adversely affects patient outcome. Due to the high intra- and interindividual variability in dose requirements dosing is complicated. In this thesis the interindividual variability in response has been examined by covariate analysis. In this analysis the effects of bodyweight, cardiac function, severity of illness and liver blood flow and the unexplained interindividual variability have been characterized. It was shown that infants require higher doses of propofol because of differences in pharmacokinetics rather than pharmacodynamics. When comparing the results of the PK-PD model of propofol and midazolam in infants, propofol is preferred over midazolam because of the lower interindividual variability in pharmacodynamics compared to midazolam. In critically ill patients severity of the illness was found to be a major determinant of the level of sedation, with lower propofol dosing requirements with increasing severity of illness. The PK-PD models can be used as a basis for individualized dosing of propofol and midazolam, which is essential for optimizing the quality of sedation in clinical practice and will improve patients__ outcome.UBL - phd migration 201
Towards a system-based pharmacology approach to predict developmental changes in renal drug clearance in children
No full textRenal clearance is responsible for the elimination of a large number of water-soluble drugs and metabolites and is therefore of large importance when characterizing the pharmacokinetics of drugs. Renal clearance includes glomerular filtration, tubular secretion and reabsorption and each of these processes is subject to different developmental changes. To estimate the renal clearance of drugs in children, a thorough understanding of these developmental changes in the different subprocesses contributing to renal function is needed. Therefore the aim of the research described in this thesis was to characterize the developmental changes in renal function over the entire pediatric age range. To this end, a system-based pharmacology approach was applied implicating that within the models for the different subprocesses contributing to renal function a distinction was made between system-specific and drug-specific properties. The transition to a more system-based pharmacology approach and the combination of different strategies (extrapolation to other drugs, adult data or non-clinical data) will result in an approach focusing on the underlying system instead of focusing on the drugs and may facilitate development of pharmacokinetic models and evidence-based dosing regimens in the pediatric population.LACDR University Hospitals Leuven, Belgium Bayer Healthcare, BelgiumUBL - phd migration 201
Towards an integral approach of sustainable housing in Indonesia: With an analysis of current practices in Java
No full textHow can the concept of sustainable housing be implemented in Indonesia? Prompted by various housing problems, especially in dense urban areas, this research proposes an integrated approach towards the sustainability of housing projects, which emphasizes the importance of community participation and the use of local solutions and resources. In general, existing guidelines and requirements for sustainable housing refer to efficient use of energy and material resources, while minimizing waste. This research analyzes existing examples of sustainable housing implementation in Indonesia (particularly on Java). On the basis of the results a set of requirements and guidelines for sustainable housing were developed, specifically for conditions in Indonesia. Furthermore, bamboo as a sustainable building material is evaluated, being a natural resource which is indigenous to Indonesia. And finally, as a supplement with this dissertation, a prototype of a communication tool is provided, which can be used by those involved in a housing project: an illustrated booklet which proposes four ambition levels of sustainability for all aspects of a housing project.Architectur
Acute and chronic pain after cardiac surgery
No full textPain management in the ICU can be difficult due to lack of patient self report. This thesis describes pain management, including procedural pain in patients in the ICU after cardiac surgery. Chronic pain one year after cardiac surgery is also evaluated and risk factors for the development of chronic pain are identified. Recommendations for the management of acute and procedural pain in patients in the ICU and for the follow-up of chronic pain after cardiac surgery are provided.UBL - phd migration 201
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