Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral abnormalities in the areas of social interaction, communication, and restrictive and repetitive behaviors. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by xanthine oxidase (XO). Febuxostat is a new FDA approved XO-inhibitor that has been shown to be more selective and potent than allopurinol in patients with gout. The first study developed a computational model to calculate an effective diffusion constant (Deff) of lipophilic compounds, such as febuxostat, that can cross endothelial cells of the blood-brain barrier (BBB) by the transcellular pathway. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing and quantification of oxidative stress in brain tissue compared to controls. Results of the first study showed that the lipophilic tracer chosen, as a substitute for febuxostat, could be modeled under the assumption of passive diffusion while experimental controls did not fit this model. The second study revealed no significant differences between BTBR mice that received febuxostat or the drug vehicle in both behavioral testing and quantification of oxidative stress in brain tissue. In the final study, of the four models proposed, one model was selected as the most plausible that considered transport into the CNS. As there is currently no literature surrounding tissue and organ ADME for febuxostat the final proposed model would need to be updated as new information becomes available. / PhD / Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral abnormalities in the areas of (1) social interaction, how an individual acts and reacts to others around them, (2) communication, the use of and understanding of language and facial expressions, and (3) restrictive and repetitive behaviors where individuals may have focused interests on specific topics/subjects and stick to set routines. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by the enzyme xanthine oxidase (XO). Oxidative stress is noted as the imbalance between free radicals (pro-oxidant) and antioxidant defenses where the pro-oxidant levels are greater than the antioxidant defenses leading to cell and tissue damage. Febuxostat is a new FDA approved XO-inhibitor that has been shown to target and inhibit XO better than allopurinol (an older XO-inhibitor) in patients with gout. The first study developed a computational model to calculate an effective diffusion constant (Def f ) that explained the free movement of a compound (substance) across cells, also known as trancellular movement. The transcellular pathway is the direct movement of compounds into a cell that requires no additional cellular energy or specialized transport routes to get the compounds into the cell. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing to study social interaction and restrictive and repetitive behaviors in autistic mice compared to non- autistic mice. Next, oxidative stress levels were measured in the brain tissue of autistic mice and compared to non-autistic mice. The third study developed four hypothesis-based human pharmacokinetic (PK) multi-compartment models of drug absorption, distribution, metabolism, and excretion (ADME). Pharmacokinetics is the study of what the body does to a drug once it is given, i.e how it gets into the bloodstream, where it goes in the body, how it is broken down, and how it is removed from the body . Compartments in PK models can be used to represent parts of the body such as blood, tissues, and organs. Results of the first study showed that the compound chosen as a substitute for febuxostat could be modeled under the assumption of passive diffusion, free movement across cells without use of energy or specialized routes, while the other compounds did not fit this model. The second study revealed no significant differences between autistic (BTBR) mice, those that received febuxostat treatment, and non-autistic mice for behavioral testing and oxidative stress levels in brain tissue. In the final study, of the four models proposed, one model was selected as the most plausible that considered drug movement into the brain and spinal cord regions. As there is currently no literature surrounding tissue and organ ADME for febuxostat the final proposed model would need to be updated as new information becomes available.

No description available.

vii ABSTRACT David Čechlovský‡ , Stefanie Kraff*, Ulrich Jaehde* *Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Germany ‡ Department of social and clinical pharmacy, Faculty of pharmacy in Hradec Králové, Charles University in Prague Title of diploma thesis: Individualized pharmacokinetically guided dosage adjustment of fluorouracil (5-FU) using population pharmacokinetic modelling. Objectives: To develop a method to increase the efficacy and tolerability of fluorouracil (5-FU) with pharmacokinetically-guided dose adjustment based on a target AUC. Methods: Blood samples were collected from 90 patients with the diagnosis of colorectal carcinoma treated with fluorouracil (5-FU) administered at various infusion durations. Several versions of compartmental pharmacokinetic models were fitted to the plasma concentration data, using nonlinear mixed effect modelling (NONMEM). Different error models were evaluated. The potential effect of patient covariates was evaluated using a stepwise method. Model evaluation was performed by using the bootstrap method. Results: The one-compartment linear model was chosen as a base model as it was successful in fitting to the data collected..The final model contained Additive Residual Error. A covariate BSA>CL and IIV on CL were significantly correlated to the...

Class of 2005 Abstract / Objectives: Doses of vancomycin are frequently estimated using various predictor formulas aiming for trough concentrations between 5 and 15 mg/L and peak concentrations between 25 and 40 mg/L.1 There is however, some controversy about the relationship between vancomycin concentrations and therapeutic response. This project compares the ability of several methods to estimate serum concentrations of vancomycin. Methods: This project was a retrospective look at 243 patient records, the patients were given vancomycin and later had at least one concentration measured. Data collected while the patient was being treated was used in the nine predictor models to determine which model would best predict actual concentrations. The methods compared were Moellering, Matzke, Lake-Peterson, Rodvold, Abbott, Birt, Burton, Ambrose, and Bauer. Results: There were 188 patients included in the analysis, 97 males and 91 women. The method with the least bias (+ 1.0) was the Rodvold method using the actual body weight. None of the models were very precise, with most around 10 (high of 12.83, and a low of 9.35). The r- values for all the models were also low, none of the models had an r- value greater than 0.5. The Lake-Peterson method predicted within 20% and 50% the most often; the Ambrose method the least often within 50%, and both Ambrose and Bauer the least often within 20%. The Lake-Peterson method predicted concentrations within plus or minus 2.5 and 5.0 mg/L of measured concentrations most frequently. The Ambrose method predicted concentrations within plus or minus 2.5 mg/L of measured the least often; Burton and Rodvold the least often within 5.0 mg/L of measured. Implications: With the best model only accurate (defined as ± 20%) less than 25 percent of the time, there is too much error to make a good decision on dose and interval without the feedback of measured serum concentrations. The models may be a good starting point as which dose and interval to choose, but they are not a substitute for measuring steady state concentrations.

nÃo hà / Uma formulaÃÃo de talidomida comprimido 100mg foi avaliada quanto a sua biodisponibilidade (Talidomida, FundaÃÃo Ezequiel Dias - FUNED) em 24 voluntÃrios saudÃveis do sexo masculino. O estudo realizado foi aberto, randomizado, cruzado, com dois tratamentos, dois perÃodos (duas sequÃncias), nos quais os voluntÃrios recebem, em cada perÃodo distinto, 200mg ou 400mg da talidomida com intervalo de sete dias entre os internamentos. O plasma foi obtido de um intervalo de 36 horas. As concentraÃÃes de talidomida foram analisadas por combinaÃÃo de cromatografia lÃquida de alta eficiÃncia (HPLC) acoplada à espectrometria de massas (MS-MS), com ionizaÃÃo em electrospray positivo (MRM). Os dados farmacocinÃticos (mÃdia  desvio padrÃo) obtidos para as formulaÃÃes contendo talidomida de 200mg e 400mg foram 12663,54  2123,99 e 23056,11  3437,08ng*h/mL para AUC0-24, 13282,84  2065,91 e 26292,67  4187,85ng*h/mL para AUC0-∞, 861,58  187,30 e 1131,63  266,93ng/mL para CmÃx, 4,52  1,53 e 6,88  4,71h para TmÃx, 6,89  1,44 e 11,01  4,36 h para t1/2, 0,10  0,02 e 0,07  0,03 1/h para Ke, respectivamente. A comparaÃÃo dos parÃmetros farmacocinÃticos, nas doses de 200 e 400mg, apresentou curvas proporcionais. Quando comparado os parÃmetros farmacocinÃticos deste estudo e os encontrados nos estudos de TEO et al., 1999, NOORMOHAMED et al., 1999 e PAGANOTTO, 2002 foi evidenciado que a formulaÃÃo FUNED apresenta absorÃÃo menor e mais lenta que as demais / formulation of thalidomide 100mg tablet was evaluated for its bioavailability (Thalidomide, FundaÃÃo Ezequiel Dias - FUNED) in 24 healthy male volunteers. The study conducted was open, randomized, with two treatments, and with a two-period crossover design, during which the volunteers were administered 200mg or 400mg of thalidomide with a seven day washout period. Plasma was obtained over a 36h interval. The thalidomide concentrations were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using selected daughter ion monitoring (MRM). The pharmacokinetic data (mean  standard deviation) obtained from the formulations containing thalidomide 200mg and 400mg were 12663.54  23056.11 2123.99 and 3437.08ng * h/mL for AUC0-24, 13282.84  2065.91 and 26292.67  4187.85ng * h/mL for AUC0-∞, 861.58  187.30 and 1131.63  266.93ng/mL for CmÃx, 4.52  1.53 and 6.88  4.71h to TmÃx, 6.89  1.44 and 11.01  4.36h to t1/2, 0.10  0.02 and 0.07  0.03 1/h for Ke, respectively. The comparison between pharmacokinetic parameters, at doses of 200 and 400mg, presented proportional curves. When comparing the pharmacokinetic parameters of this study and those found in studies of TEO et al., 1999, NOORMOHAMED et al., 1999 and PAGANOTTO, 2002 it was observed that the FUNED formulation presents smaller and slower absorption than the others

Class of 2011 Abstract / OBJECTIVES: Five methods for estimating vancomycin pharmacokinetic parameters were studied to determine the accuracy of each method in predicting vancomycin concentration. METHODS Patient vancomycin pharmacokinetic data from a prior study were retrospectively reviewed and used in five methods to calculate vancomycin clearance and volume of distribution in order to determine the accuracy in prediction of the measured value. RESULTS: The coefficients of determination ranged from 0.167 to 0.224, bias ranged from -5.18 to 2.13, and precision ranged from 5.98 to 7.64. The Buelga method had the highest percentage of predictions within 2.5 and 5 mg/L of the measured trough at 42% and 65% respectively, while the Thomson method had the highest percentage of predictions within 50% of the measured trough at 52%. The highest percentage of predictions within 25% of the measured trough were found with both the Thomson and Yasuhara method at 29%. CONCLUSION: There was wide variation in the prediction of vancomycin trough concentrations from the five methods for estimating vancomycin pharmacokinetic parameters. None of the methods provided adequate reliability to recommend discontinuation of therapeutic drug monitoring for vancomycin.

Master of Philosophy / Clozapine is a drug of choice for treatment of refractory schizophrenia, which is primarily metabolized by Cytochrome P450 1A2 (CYP1A2). Norclozapine is its main metabolite. There are reports of wide ranging gastrointestinal side effects associated with clozapine therapy, that result in concomitant administration of proton pump inhibitors to treat acid-related disorders. Omeprazole is an established CYP1A2 inducer, while an in vitro study has shown that rabeprazole is much less potent in this regard. There is no available information about the impact of rabeprazole on CYP1A2 activity in patients. Firstly, this information is essential when prescriptions are changed from omeprazole to rabeprazole to reduce medication costs. Therefore, the aim of this study was to compare the effects of rabeprazole and omeprazole on CYP1A2-mediated clearance (CL/F) of clozapine. Secondly, the effective dosage of clozapine varies widely among patients, making it necessary to individualize drug therapy with clozapine. The reason for dosage variation could be due to the influence of patient-related variables on clozapine plasma concentrations. Therefore, another aim of this study was to investigate the relationship between patient variables, such as age, gender, cigarette smoke, weight and body mass index and clozapine clearance (CL/F). A cross-over study design was used for this study. Twenty patients from Macquarie hospital who were receiving clozapine and rabeprazole (with no other interacting medications) were recruited in this study. Blood samples were taken at 30 min, 1 hr, 2 hr and 12 hr after a dose of clozapine. Rabeprazole was then replaced with omeprazole. After at least 1 month blood samples were again collected at the above corresponding intervals after clozapine. The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography. Abbottbase Pharmacokinetic Systems Software, which utilizes Bayesian forecasting, was used to estimate pharmacokinetic parameters of clozapine. The ratio of plasma norclozapine/clozapine concentrations at trough level was used to reflect CYP1A2 activity. No difference was observed in clozapine clearance (CL/F) and CYP1A2 activity during concurrent therapy with either rabeprazole or omeprazole. According to some studies CYP1A2 induction by omeprazole is dose dependent. Furthermore, since rabeprazole is a weak CYP1A2 inducer in vitro, we conclude that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40 mg/day). Hence, replacement of omeprazole with rabeprazole at conventional therapeutic dosages (20 or 40 mg daily) offers no advantages in the management of patients with schizophrenia on clozapine and no dose adjustment is required. Consistent with previous studies, clozapine concentrations were found to be significantly lower in cigarette smokers due to CYP1A2 induction. No relationship was found between age, gender, or weight and clozapine clearance (CL/F). However, body mass index showed a significant negative correlation with clozapine clearance (CL/F). Since weight gain and lipid accumulation are common side effects of clozapine they may be associated with a reduction of CYP1A2 activity and clozapine clearance (CL/F). Moreover, high lipoprotein levels may decrease the unbound fraction of clozapine and decrease the availability of clozapine for oxidation by cytochrome P450 enzymes. Therefore, it is concluded that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40mg/day). Hence, replacement of omeprazole with rabeprazole does not require the dose of clozapine to be adjusted. Moreover, the negative correlation between clozapine clearance (CL/F) and BMI is informative. Further studies are now required to clarify the relationship between BMI, lipoprotein levels and clozapine clearance in patients with schizophrenia.

Master of Philosophy / Clozapine is a drug of choice for treatment of refractory schizophrenia, which is primarily metabolized by Cytochrome P450 1A2 (CYP1A2). Norclozapine is its main metabolite. There are reports of wide ranging gastrointestinal side effects associated with clozapine therapy, that result in concomitant administration of proton pump inhibitors to treat acid-related disorders. Omeprazole is an established CYP1A2 inducer, while an in vitro study has shown that rabeprazole is much less potent in this regard. There is no available information about the impact of rabeprazole on CYP1A2 activity in patients. Firstly, this information is essential when prescriptions are changed from omeprazole to rabeprazole to reduce medication costs. Therefore, the aim of this study was to compare the effects of rabeprazole and omeprazole on CYP1A2-mediated clearance (CL/F) of clozapine. Secondly, the effective dosage of clozapine varies widely among patients, making it necessary to individualize drug therapy with clozapine. The reason for dosage variation could be due to the influence of patient-related variables on clozapine plasma concentrations. Therefore, another aim of this study was to investigate the relationship between patient variables, such as age, gender, cigarette smoke, weight and body mass index and clozapine clearance (CL/F). A cross-over study design was used for this study. Twenty patients from Macquarie hospital who were receiving clozapine and rabeprazole (with no other interacting medications) were recruited in this study. Blood samples were taken at 30 min, 1 hr, 2 hr and 12 hr after a dose of clozapine. Rabeprazole was then replaced with omeprazole. After at least 1 month blood samples were again collected at the above corresponding intervals after clozapine. The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography. Abbottbase Pharmacokinetic Systems Software, which utilizes Bayesian forecasting, was used to estimate pharmacokinetic parameters of clozapine. The ratio of plasma norclozapine/clozapine concentrations at trough level was used to reflect CYP1A2 activity. No difference was observed in clozapine clearance (CL/F) and CYP1A2 activity during concurrent therapy with either rabeprazole or omeprazole. According to some studies CYP1A2 induction by omeprazole is dose dependent. Furthermore, since rabeprazole is a weak CYP1A2 inducer in vitro, we conclude that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40 mg/day). Hence, replacement of omeprazole with rabeprazole at conventional therapeutic dosages (20 or 40 mg daily) offers no advantages in the management of patients with schizophrenia on clozapine and no dose adjustment is required. Consistent with previous studies, clozapine concentrations were found to be significantly lower in cigarette smokers due to CYP1A2 induction. No relationship was found between age, gender, or weight and clozapine clearance (CL/F). However, body mass index showed a significant negative correlation with clozapine clearance (CL/F). Since weight gain and lipid accumulation are common side effects of clozapine they may be associated with a reduction of CYP1A2 activity and clozapine clearance (CL/F). Moreover, high lipoprotein levels may decrease the unbound fraction of clozapine and decrease the availability of clozapine for oxidation by cytochrome P450 enzymes. Therefore, it is concluded that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40mg/day). Hence, replacement of omeprazole with rabeprazole does not require the dose of clozapine to be adjusted. Moreover, the negative correlation between clozapine clearance (CL/F) and BMI is informative. Further studies are now required to clarify the relationship between BMI, lipoprotein levels and clozapine clearance in patients with schizophrenia.

Compliance, the extent to which patients follow a medication regimen, has been recognized as one of the most serious problems facing medical practice today. Recent developments in assessing compliance include electronic compliance monitors (ECM), devices that record the date and time of the release of medication from its original container. This allows utilizing ECM compliance data in statistical analyses related to clinical trials. This thesis proposes ways of dealing with the time-varying nature of compliance. We examine the compliance behaviour from real ECM data through statistical analysis of compliance rate, followed by a time-to-event analysis with respect to first noncompliance event. Then, using discrete event simulation and proportional hazards models we compare analyses using a fixed treatment covariate and time-varying compliance covariate based on pharmacokinetic principles in estimating treatment effect. We observe a reduction of up to 40% in EMSE in favour of the latter model for treatment effect estimation.

Since the introduction of the lipid emulsion formulation in 1986, propofol has become established for induction as well as for maintenance of anaesthesia in veterinary practice1 including cats2;3-8. Propofol is rapidly metabolized by hepatic glucuronidation in most species and it has also been shown to undergo extrahepatic metabolism9-13, so that total body clearance may exceed liver blood flow in certain species. Because of their highly carniverous diet, cats are little exposed to antiherbivory compounds so that they have become deficient in UGP-glucuronosyltransferase (UGT)14. Consequently, a number of drugs are eliminated slowly15;16, often giving rise to prolonged half-lives of the parent drugs. Cats are therefore sensitive to the adverse effects of many drugs and toxins that are normally glucuronidated before elimination. It is therefore likely that the disposition of propofol may differ markedly from that of humans and other animal species17. Adam et al18 reported that for the cremophor propofol formulation in cats, volumes of distribution were smaller and elimination halflives were longer than those of pigs, rats and rabbits. In addition, pulmonary uptake has been demonstrated to occur in cats,19 however propofol’s pharmacokinetics have not been studied formally. The purpose of this study was to determine the pharmacokinetic behaviour of propofol after single intravenous injections. In comparison with man, the apparent central volume of distribution in domestic cats is small (0.56L.kg-1 body weight vs. 0.228L.kg-1) for the human pharmacokinetic parameter set of Marsh et al20 and the clearance (0.0086 L.kg-1.min-1 vs. 0.027 L.kg- 1.min-1) is approximately 2½ times slower in cats when compared with humans. Slow clearance should not influence recovery from anaesthesia following standard induction doses, because the early decreases in blood concentrations are predominantly due to redistribution of drug to various tissues (similar to the disposition of thiopentone which exhibits a slow total body clearance21. However it is possible that drug may accumulate within the body after prolonged infusions, resulting in delayed recovery times. This phenomenon is best described by calculating “context-sensitive” decrement-times by computer simulation22-24. Computer software♣ were used to calculate the 20%, 50% and 80% context-sensitive decrement times for the cat pharmacokinetic model. For comparative purposes, similar calculations were performed for an adult human male (weight 70 kg) using the pharmacokinetic parameter-set of Marsh et al20. Assuming that recovery from anaesthesia occurs after a 50% decrease in blood concentrations has taken place, it is apparent from the 50% context-senstive decrement-time graph that for infusions lasting up to 20 minutes (during which concentrations are kept constant), recovery can be expected to be rapid and predictable. However if infusions are administered for longer than 20 minutes, the recovery times of the “average” cat increase rapidly, reaching a plateau of 36 minutes, while recovery times of the human remain short, albeit increasing slowly. Awakening times become dramatically prolonged and unpredictable in both cats and humans if propofol concentrations are required to decrease by 80% for recovery to occur. Under these circumstances the 80% decrement time after a two-hour infusion is approximately two hours in cats and 45 minutes in humans. On the other hand, if dosing is conservative, so that blood concentrations need to decrease by only 20% for awakening to occur, then recovery times are short and predictable, being only a few minutes, regardless of the duration of the preceding infusion. These findings are in accordance with those of Pascoe et al25 who reported that cats took longer to recover after a short (30 min) infusion than after a long (150 min) infusion. In their crossover study, the propofol infusion rates were adjusted so that the cats were maintained at a light level of anaesthesia at which they responded sluggishly to pedal stimulation. It is therefore likely that propofol concentrations were kept steady and were similar during the 30-minute as well as during the 150-minute infusions. Delayed recovery has also been reported when propofol was administered to cats on consecutive days26. Conclusions and clinical relevance: We recommend that propofol infusions be administered to cats only for fairly short procedures and that for prolonged surgery, maintenance of anaesthesia should be accomplished using other drugs. In order to decrease the propofol dose, premedication and analgesic supplements should be co-administered to provide “balanced” anaesthesia. ♣ TIVA Trainer version 8, author Frank Engbers, Leiden University Medical Centre Copyright / Dissertation (MMedVet)--University of Pretoria, 2009. / Companion Animal Clinical Studies / unrestricted