This thesis concerns five studies where the statistical consequences of violations of modeling assumptions are assessed using experimental and simulated pharmacokinetic-pharmacodynamic data. The... Show moreThis thesis concerns five studies where the statistical consequences of violations of modeling assumptions are assessed using experimental and simulated pharmacokinetic-pharmacodynamic data. The first study describes the development of an open source web application for Bland-Altman analysis of comparison data, which is able to take into account both intra- and interindividual variability. In the second study the behavior of Akaike's information theoretic criterion is investigated in the presence of interindividual variability. The effects of neglecting or allowing for process noise are described in the third and fourth studies, for surrogate measures of clinical endpoints such depth of anesthesia and analgesia. In the fifth study pharmacodynamic model parameter estimates are compared when these are based on venous versus arterial blood samples. Show less
Drug 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.... Show moreDrug 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). Show less
Dahan, A.; Olofsen, E.; Sigtermans, M.; Noppers, I.; Niesters, M.; Aarts, L.; ... ; Sarton, E. 2011
Parkinson__s disease (PD) is an age-related neurodegenerative disorder. Pharmacotherapy is the first line symptomatic treatment of this neurological disease. Currently Levodopa (L-DOPA) is still... Show moreParkinson__s disease (PD) is an age-related neurodegenerative disorder. Pharmacotherapy is the first line symptomatic treatment of this neurological disease. Currently Levodopa (L-DOPA) is still considered the drug of first choice, but its possible neurotoxicity and the induction of movement disability after chronic use demand for alternative therapies. An attractive alternative is the use of (semi-)synthetic dopamine agonists. It has been suggested that continuous dopamine receptor stimulation is the best symptomatic treatment of Parkinson__s disease. Therefore the administration of dopamine agonists in a continuous, well-controlled manner by transdermal iontophoresis is an attractive therapeutic strategy in the symptomatic treatment of PD. This dissertation describes the administration of a series of dopamine agonists across the skin using iontophoresis. With iontophoresis a small current is applied across the skin to enhance the transdermal transport of charged molecules. With transdermal iontophoresis a continuous drug administration is achieved. And by adjusting the applied current density it is possible to titrate the dose to the requirements of the patient. In addition, continuous administration results in a continuous stimulation of the dopamine receptors in the striatum. These results demonstrate that transdermal iontophoresis of dopamine agonist is a promising method for the symptomatic treatment of PD. Show less
The objective of the investigations described in this thesis was to characterize the in vivo pharmacological and PK-PD properties of buprenorphine relative to fentanyl with respect to: 1) kinetics... Show moreThe objective of the investigations described in this thesis was to characterize the in vivo pharmacological and PK-PD properties of buprenorphine relative to fentanyl with respect to: 1) kinetics of onset and offset of the pharmacological effects at the mu-opioid receptor, 2) selectivity of action (antinociception versus respiratory depression), 3) the interspecies extrapolation of the PK-PD correlation of the antinociceptive and respiratory depressant effect, 4) the role of active metabolites, 5) kinetics of antagonism of the respiratory depressant effect. Preclinical investigations were performed to develop and validate mechanism-based PK-PD models for the effects of opioids on antinociception and respiration. These PK-PD models were subsequently applied to characterize the effects of buprenorphine and fentanyl in humans. It was shown that the developed PK-PD model can be used to predict the efficacy and safety outcome of opioids in animals. Furthermore, the PK-PD model had excellent properties to enable animal-to-human extrapolation of the efficacy and safety outcome. Show less
