Browsing by Subject "Social, Administrative, and Clinical Pharmacy"
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Item Anti-virulence paradigm for development of staphylococcal therapies(2010-02) Lin, Ying-ChiStaphylococcus aureus is a major human pathogen capable of causing various diseases, from skin infections to life-threatening pneumonia and toxic shock syndrome (TSS). S. aureus exoproteins contribute significantly to S. aureus pathogenesis via causing inflammation, tissue disruption, and immune evasion. Antibiotics treat S. aureus disease by eliminating bacteria, but provide no protection from S. aureus exoproteins, once released. With the emergence of antibiotic-resistant S. aureus, new therapeutic options to treat/prevent S. aureus-associated disease are critical. Given most S. aureus diseases initiate locally on mucosal surfaces or the skin, it was hypothesized that S. aureus exoproteins that have pro-inflammatory and/or cytotoxic effects on epithelial cells, contributing directly to S. aureus pathogenesis. Therefore, anti-staphylococcal therapies that inhibit toxin production and/or prevent toxin effects on host cells could reduce or prevent S. aureus infections. A global approach was taken to characterize pro-inflammatory properties of exoproteins from two genetically close TSS S. aureus isolates, a pulmonary TSS isolate (MNPE) and a menstrual TSS isolate (CDC587), on epithelial cells. Cytolysins, alpha- and gamma-toxins, superantigens, and staphopain (protease) were determined as the most pro-inflammatory (via interleukin-8) to epithelial cells. MNPE, originating from skin, produced large amounts of alpha-toxin and SAgs, but little other virulence factors, whereas CDC587, a mucosal strain, produced gamma-toxin, small amounts of alpha-toxin, and large numbers of secreted virulence factors. These findings implied that pro-inflammatory S. aureus exoproteins play key roles in environmental selection and disease severity. As proof of principle, glycerol monolaurate (GML), a lauric acid monoester known to inhibit S. aureus exoprotein production and to have anti-inflammatory effects, was compared with its monoether, dodecylglycerol (DDG), as local anti-virulence agents to prevent S. aureus disease using a rabbit wiffleball abscess/TSS model. GML, but not DDG, significantly decreased TSST-1 and local inflammation (via tumor necrosis factor-alpha in the wiffleball and prevented rabbit death from TSS. In summary, these studies identified key exoproteins important in S. aureus mucosal pathogenesis and determined the potential for anti-toxin agents, such as GML, to treat and/or prevent S. aureus diseases. These studies also suggest the addition of anti-toxin components will improve the effectiveness of antistaphylococcal vaccines and immunotherapies.Item Application of an active comparator-based benefit-risk Assessment in evaluating clinical trial design features of a new chemical entity using a Bayesian decision-theoretic framework.(2010-06) Goel, VarunDuring the drug development process, drug candidates are screened for their efficacy and toxicity. Dose selection is a crucial part of drug development and specifying the right dose imparts pharmacological activity while minimizing side effects. Evaluation of the benefit/risk ratio is typically done by examining the effect of a drug on efficacy and safety endpoints. However, this comparison can be difficult when there are multiple endpoints that are clinically and commercially relevant. A decision-based clinical utility is proposed and evaluated to aid in dose selection. A dose is viable if it has higher efficacy and lower toxicity than the values specified in multi-attribute decision criteria. PD 0200390 is a ligand of the α2δ subunit of the voltage-gated calcium channel being investigated for the treatment of primary insomnia and non-restorative sleep. Wake after sleep onset and number of awakenings are the measures of sleep consolidation while ease of awakening and morning behavior following wakefulness are the measures of residual effects. The objective of this research is to select a dose that maximizes the probability of a decision criterion characterized over safety and efficacy attributes. Data is obtained from two phase II double blind, randomized, placebo controlled crossover studies in subjects with primary insomnia. Dose response models are developed as hierarchical nonlinear model using NONMEM® and WinBUGS®. A Sensitivity analysis is performed to test the robustness of the selected dose with varying decision attributes.Item Association of genetic and nongenetic variabilities with phenytoin and carbamazepine response phenotypes.(2012-05) Kijsanayotin, PornpimolIn spite of the availability of an increasing numbers of antiepileptic drugs (AEDs), drug treatment of epilepsy remains symptomatic with a manifestation of a large variability in drug response to AEDs among patients. At present, it is unclear how drug-resistant epilepsy as well as the variability in response among individuals to AEDs happens. Drug-resistance and variability to drug response are proposed to be a multifactorial and complex genetic trait. The variability is under the influence of several putative factors including patient’s genetic and nongenetic variability that affect drug disposition and action. Therefore, the objective of the two pharmacogenetic studies include in this dissertation was to investigate the combined associations of common genetic variations in genes encoding drug metabolizing enzymes, drug transporters and drug target along with nongenetic variations on the clinical phenotypes of drug response to phenytoin (PHT) and carbamazepine (CBZ) namely maintenance dose and drug exposure. These two studies were cross-sectional genetic association studies using a candidate gene approach. Retrospective data were used. The study populations were patients with epilepsy who were unrelated Caucasian Americans or African Americans that were enrolled in the P50 studies. For PHT pharmacogenetic study, a dataset of 54 adult Caucasian patients with epilepsy on PHT maintenance therapy was used. Demographic and clinical variables were retrieved. Genomic DNA samples were used to genotype for 5 candidate single nucleotide polymorphisms (SNPs): SCN1A c.IVSN5+5 G>A, ABCB1c.3435C>T, CYP2C9*2 (g.3608C>T), CYP2C9*3 (g.42614A>C) and CYP2C19*2 (g.19154G>A). Steady-state AUC0- 12 hr was determined from PHT plasma concentrations at 0, 0.08, 0.25, 0.5, 1, 2, 4, 6 and 12 hours after an oral dose. Bivariate analysis as well as stepwise multiple linear regression analysis were used to determine the association of genetic and nongenetic variants with PHT maintenance dose and AUC0-12 hr. This study identified two non-genetic factors (body weight and age) and three genetic variants (CYP2C9*2, CYP2C9*3 and CYP2C19*2) that were strongly associated with variability in PHT maintenance dose in adult Caucasian patients with epilepsy. These covariates explained about 40% of variability in PHT dose requirement in this sample. Moreover, PHT dose and a genetic factors including CYP2C9*3 and ABCB1c.3435C>T were found to be associated with increase in phenytoin AUC 0-12 hr in the same group of adult Caucasian patients. These covariates explained about 42% (R2= 0.422, P= 0.007) and 76% (R2= 0.760, p< 0.001) of variability in phenytoin AUC 0-12 hr in two different multiple linear regression models. For CBZ pharmacogenetic study, demographic and clinical variables were retrieved from datasets of 55 unrelated adult Caucasian American and 32 African American patients with epilepsy on CBZ maintenance therapy. Genomic DNA samples were used to genotype for 5 candidate SNPs including CYP3A5*3 (g.6986A>G), CYP3A5*6 (g.14690G>A), CYP3A5*7 (g.27131_27132insT), SCN1A c.IVSN5+5 G>A and ABCB1c.3435C>T. Steady-state AUC0-24 hr was determined from CBZ plasma concentrations at 0, 0.08, 0.25, 0.5, 1, 2, 4, 6, 12 and 24 hours after oral doses. Bivariate analysis as well as stepwise multiple linear regression analysis were used to determine the association of genetic and non-genetic variants with CBZ response phenotypes, namely CBZ maintenance dose and AUC0-24 hr -to-dose ratio (ADR) in Caucasians or African American patients. By using multiple linear regression analysis, this study found a significant association between CBZ maintenance dose and a non-genetic factor, age, and a genetic variant, CYP3A5*3. The two covariates explained about 9% (R2 = 0.089, P = 0.020) of inter-individual variability in CBZ maintenance dose. In line with that, carbamazepine AUC 0-24 hr -to- dose ratio was found to be associated with the presence of CYP3A5*3 alleles. The model explains about 32% of the variability in carbamazepine AUC 0-24 hr-to-dose ratio (R2= 0.324, P< 0.001). In addition, it was found that carbamazepine AUC 0-24 hr -to- dose ratio was significantly different between African and Caucasian American patients. In bivariate analysis, carbamazepine AUC 0-24 hr -to- dose ratio was found to be associated with race, CYP3A5*3, CYP3A5*7 or ABCB1c.3435C>T allele suggesting that there might be the influence of multiple polymorphisms on CBZ pharmacokinetics which may resulted in the different exposure to CBZ between African and Caucasian patients. These two pharmacogenetic studies clearly confirm that drug response is a complex multifactorial phenotype influenced by many genetic and nongenetic factors. However, the genes and variants identified so far explain only a small fraction of variability in response to AEDs, and still needed to be replicated by other independent study.Item Demonstration of pharmacometric applications to anti-infective chemotherapy.(2010-06) Salem, Ahmed Hamed AhmedWe developed a population pharmacokinetic model for efavirenz in pediatric HIV patients to guide dosing and decrease incidence of subtherapeutic levels. Data comprised of 3172 plasma concentrations collected over 4 years from 96 HIV-1 infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. A one compartment model adequately described the data and the allometric size model accounted for the effect of body size on oral clearance and apparent volume of distribution. A sigmoid Emax maturation model demonstrated an increase in oral clearance by age to reach 90% of its mature level by the age of 9 months. The bioavailability of oral liquid formulations relative to the capsule formulation was also found to increase by age to reach 90% of its mature value of 0.79 by the age of 8 years. CYP2B6-G516T polymorphism was associated with a 51% decrease in oral clearance while MDR1-C3435T polymorphism has shown no effect. The final model showed good predictability performance and its application to improve dosing in pediatrics warrants further investigation. Appropriate initial treatment choices for methicillin resistant Staphylococcus aureus (MRSA) infections are very critical especially in the intensive care units (ICU) settings. We compared the ability of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite PK/PD targets against MRSA isolates collected from ICU settings. Ceftobiprole and dalbavancin were found to have the highest probability of achieving favorable outcome against MRSA infections in the ICU. The susceptibility results suggested a further reduction of the vancomycin breakpoint to 1 μg/ml. We also employed a recently developed quantitative methodology to characterize the killing effect of vancomycin and rifampin combination against MRSA biofilm. The results suggest antagonism between vancomycin and rifampin against MRSA biofilm. The quantitative approach used provides a scientific rationale for further in vivo investigations which should allow a better understanding of the therapeutic potential of this combination in biofilm-associated MRSA infections. Finally, we compared the activities of moxifloxacin and vancomycin against MRSA and MRSE biofilms. Moxifloxacin exhibited a superior anti-biofilm activity suggesting potential benefit in treatment of MRSA and MRSE biofilm associated infections.Item Improving hematopoietic cell transplantation therapeutics:emphasis in pharmacokinetic-pharmacodynamic relationships and pharmacogenomics.(2009-12) Long-Boyle, Janel ReneeTreatment-related mortality and acute graft vs host disease remain prominent clinical problems in nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Hence, the need for improved preparative regimens and immunosuppressive strategies in HCT persists. The research presented in my dissertation will be focused on defining pharmacokinetic-pharmacodynamic relationships, and pharmacogenomics involving two antineoplastic agents, fludarabine and clofarabine, and the immunosuppressive agent, mycophenolate all of which are used in the setting of HCT. Fludarabine is a purine analog commonly used in both adult and pediatric nonmyeloablative allogeneic HCT. Although the pharmacokinetics of fludarabine have been extensively studied in a variety of malignant diseases, very little data is available in nonmyeloablative HCT and the relationship between fludarabine pharmacokinetic parameters and clinical outcomes such as treatment-related mortality have yet to be evaluated. Similarly, no PK data is available for clofarabine; a newer purine analog currently used pediatric patients undergoing HCT for non-hematologic malignancies. Finally, mycophenolic acid pharmacokinetics in HCT recipients displays wide inter- and intra-patient variability in plasma concentrations and low mycophenolate exposure is associated with lower rates of engraftment and greater risk of acute graft vs host disease. Patient characteristics such as weight or body surface area, or clinical markers for hepatic and renal function incompletely explain pharmacokinetic variability suggesting there may be genetic factors influencing mycophenolate metabolism or transport. The methodologies and techniques employed to evaluate each individual agent will differ, including pharmacokinetic and statistical analyses. However, all projects share the common goal of improving patient outcomes and reducing toxicity in this very complex patient population.Item Intranasal and rectal diazepam for rescue therapy: assessment of pharmacokinetics and tolerability.(2010-12) Ivaturi, Vijay DeepThe use of rectal diazepam has improved the management of acute repetitive seizures (ARS) outside a health care facility. Two placebo controlled trials have shown that rectal administration of diazepam is safe and effective for treatment of this condition. Diastat® is the only FDA approved treatment for ARS in the United States. Although some older children and adults are willing to use Diastat®, many patients in these age groups as well as physicians and caregivers object to the route of administration and instead use other therapies not approved for this purpose, receive no treatment, or use emergency medical services or acute care systems. We developed and evaluated three nasal spray formulations of diazepam which can be easily administered with rapid absorption characteristics intended as an alternative to rectal administration. One formulation used a supersaturated glycofurol based co-solvent system while the remaining two (Nas-A & Nas-B) used microemulsion based co-solvent systems. These formulations were studied for their pharmacokinetics and tolerability in healthy adult volunteers. Data from these studies were then compared to the pharmacokinetics after rectal administration using both model-based analysis (NONMEM) and graphical methods. The primary finding from this work was that, only the microemulsion-based formulations, particularly Nas-B could be used for further development as the glycofurol formulation was not well tolerated by subjects. The pharmacokinetic profiles after intranasal administration were associated with high variability. However, we are able to show that the dose-normalized partial area under the curve (AUC - an exposure parameter) after nasal administration, at times when the drug concentrations are most important, are 60-80 % of that when given via the rectal route. Given the ease and social acceptability of nasal administration compared to rectal, equivalent exposures can be easily attained by giving a second nasal dose, and we thus conclude that intranasal diazepam is a feasible and preferable alternative to rectal diazepam in the management of ARS outside a hospital. This work also provides some recommendations for future studies in the development of an intranasal product.Item Pharmacokinetics, pharmacodynamics, and dose optimization of fludarabine in nonmyeloablative hematopoietic stem cell transplantation.(2010-10) Baron, Kyle ThomasThe first goal of this research was to develop models describing pharmacokinetics and pharmacodynamics of fludarabine in a patient population undergoing nonmyeloablative hematopoietic stem cell transplantation. The second goal was to leverage model information to identify fludarabine doses that are most likely to achieve optimal outcomes after transplant. Datasets consisting of intensively sampled F-ara-A plasma concentrations after approximately 40 mg/m2 fludarabine as well as outcome data (treatment-related mortality, maximum acute graft-versus-host disease grade, and neutrophil engraftment) were available at the start of the modeling work. Population pharmacokinetic models were built using NONMEM. Covariate models for pharmacokinetic parameters were derived, including a model for the typical value of clearance in the population as a function of weight, creatinine clearance, and comorbidity score. Bayesian generalized linear models linking F-ara-A exposure to outcome probabilities were fit using OpenBUGS software. Both models were evaluated using predictive model checking methods. Fludarabine doses were optimized with respect to individual outcomes by finding the posterior probability that a certain dose would meet specific criteria defining treatment "success". Doses were optimized simultaneously across all three outcomes using a utility index defined as the product of the individual outcome success probabilities. In general, the results recommend a reduction of fludarabine doses to optimize outcomes after hematopoietic stem cell transplantation.Item Pharmacometric modeling of anti-cancer agents: application to gemcitabine, PQIP and irinotecan.(2010-07) Khatri, AmitWe performed pharmacometric modeling of irinotecan, PQIP and gemcitabine. Irinotecan is a DNA topoisomerase-I inhibitor used in colorectal and brain tumors. One of our aims was to show that that cranial radiation, delivered during irinotecan administration, can enhance uptake in to cerebral-spinal fluid (CSF), and also to characterize the pharmacokinetics of irinotecan and its metabolites SN38 and APC in plasma and CSF in rats. The concentration-time data in plasma and CSF were analyzed by nonlinear mixed-effects modeling using FOCE-I method in NONMEM. The analysis showed that cranial radiation delivered during irinotecan administration enhances uptake in to CSF. The second aim of dissertation was to quantitatively evaluate the drug administration sequence effects of insulin-like growth factor type-1 receptor inhibitors (IGF-1R) with gemcitabine in vitro . Gemcitabine is a nucleoside analogue approved for a variety of solid tumors, while PQIP is an investigational IGF-1R inhibitor. In vitro experiments were conducted in 24-well tissue culture plates using MCF-7, MDA-MB-231 and Hs-578T human breast cancer cell lines. Viable cells were counted every day following the day of drug exposure. The effect of sequence on cell-kill was analyzed by bayesian techniques using WinBUGS. We found that exposure with gemcitabine first, followed by PQIP (GP sequence) was either superior or equivalent to the reverse sequence (PG sequence) with these drugs. The third aim of dissertation was to perform a population pharmacokinetic analysis of gemcitabine and its metabolites dFdU and dFdCTP in patients with solid tumors and to determine patient specific covariates associated with their disposition. Concentration data were obtained in 40 patients with solid tumors. The concentration-time data were analyzed by nonlinear mixed-effects modeling using first-order conditional estimation method with interaction (FOCE-I) in NONMEM. We found that Body surface area (BSA) and age were significant covariates for the disposition of gemcitabine, while creatinine clearance (CL CR ) and BSA were found to be significant covariates for the disposition of dFdU. We also found that patients who received gemcitabine at a rate less that 25 mg/m 2 /min had higher formation of dFdCTP than those who received gemcitabine at a rate greater than 25 mg/m 2 /min.Item Pharmacometrics of antiepileptic drugs: modeling and simulation-based studies of lamotrigine and carbamazepine pharmacokinetics(2008-11) Prasittisopin, BaraleeThe population pharmacokinetic modeling plays a pivotal role in quantitative learning about drugs from sparse data collected in clinical studies. It provides crucial information needed for individualization of dosage regimens especially in special population in which the intensive pharmacokinetic studies are of ethical concern. Lamotrigine and carbamazepine are antiepileptic drugs commonly used in elderly patients; however, dosing these drugs is based largely on studies from adult patients. Pharmacokinetic information of these drugs in elderly patients is limited. The aims of the current dissertation were to determine the population pharmacokinetic parameters of lamotrigine and carbamazepine in the community-dwelling elderly patients, and to quantitatively identify factors that have significant effects on these parameters. The further aim was to characterize the time course of carbamazepine deinduction by an enzyme turnover model. Due to the presence of collinearity between covariates during the covariate model development of lamotrigine, the effect of collinearity on power, bias, and precision of the parameter estimates in the population covariate model was further investigated by means of simulations. The population pharmacokinetic models of lamotrigine and carbamazepine were successfully developed and the models adequately described the data sets. The important information of drugs' pharmacokinetics was obtained and it can be beneficial in developing dosing strategies for elderly patients receiving these drugs. The time course of carbamazepine deinduction was well described by an enzyme turnover model. This model allowed the estimation of the half-life of the induced enzymes involving carbamazepine metabolism which is the important parameter for characterizing the time course of carbamazepine deinduction process. The power of selecting the true covariates depends on sample size of the data set, the magnitude of covariate coefficient, and the degrees of correlation. The investigation of the effect of collinearity between two true covariates revealed that an increasing collinearity between two true covariates not only decreases the power of selecting the true covariate model, but also leads to the biased and imprecise parameter estimates. The results from this study improve the understanding of how and to what extent the collinearity affects the parameter estimates in the covariate model building.Item Role of equilibrative nucleoside transporters 1 and 2 in the transport and disposition of gemcitabine and its metabolites in cervical carcinoma.(2010-08) Hodge, Lucy SahrGemcitabine is a nucleoside analog used as a radiosensitizer for the treatment of locally advanced cervical carcinoma. Yet, despite its efficacy when administered concomitantly with radiation, gemcitabine therapy is not without side effects. The utility of delivering gemcitabine directly to the cervix was explored through the use of a novel drug delivery device, CerviPrep(TM). Local administration to the cervix led to clinically relevant concentrations of gemcitabine in cervical tissue and plasma, while no gemcitabine was detected in the systemic circulation and no side effects were reported. Our data suggest that targeting gemcitabine delivery to the cervix can limit systemic exposure and toxicity while achieving cytotoxic concentrations of drug at the target site. Despite its widespread use in cervical carcinoma, little is known about the disposition of gemcitabine in this tissue. As a nucleoside analog, gemcitabine is a substrate for the equilibrative nucleoside transporters (hENT), and patient response to gemcitabine therapy has been associated with the expression of these proteins. A characterization of hENT1 and hENT2 in both malignant and normal cervical tissue was undertaken, and while no effect of malignancy was observed on hENT1 protein expression, hENT2 protein was nearly three-fold higher in malignant cervical tissue when compared to normal tissue. Expression of hENT mRNA was highly variable and not associated with malignancy. We also examined the effect of dFdU on gemcitabine disposition, as this relatively inactive metabolite is present at much higher concentrations in the plasma than gemcitabine following intravenous administration of the parent compound. We report a novel interaction between dFdU and gemcitabine whereby dFdU competes with gemcitabine for transport via hENT1 and hENT2. The presence of dFdU appears to enhance the retention of gemcitabine intracellularly leading to an increase in the amount of active gemcitabine triphosphate. As more gemcitabine is phosphorylated in the presence of dFdU, a "metabolic sink" is created, further increasing gemcitabine uptake into the cell via hENT1 and hENT2. These data suggest that both transport and intracellular metabolism are equally important components of gemcitabine disposition and cytotoxic potential, and that the presence of dFdU increases intracellular exposure to this nucleoside analog.Item The role of social networks in medication information seeking behavior(2009-05) Kjos, Andrea LeeThe study purpose was to determine the role of social networks in medication information seeking behavior by describing the structure of social networks that provide information, the content provided, and the function of information in addition to individual characteristics of people who use various types of social networks to obtain medication information. This was an exploratory qualitative research study, which used volunteering participants who were at least eighteen years old. Forty subjects completed a personal interview that measured aspects of one's social network as a modality to seek medication information. Data were audio recorded and transcribed using theory and prior research driven themes as a basis for ethnographic content analysis. Phase I analysis found that social network structures used for obtaining medication information were made up of health professionals and lay social contacts. Content themes included factual information, personal experiences, and beliefs and attitudes. Function themes were identified as decision making, diagnosis, monitoring, prescriptive or recommendations, social support, staying informed, or validation. Phase II analysis used clustering of social network types and themes to create coding intersections within the data to explore co-occurring thematic concepts. Social network contacts displayed different roles for what content was provided and the subsequent function of the information. For health professionals, the strongest content related role was to provide factual information functioning to support patient decision making, monitoring, recommendations, staying informed, and validation of information. In contrast, the role of content provision from lay contacts was to provide factual information, personal experiences and beliefs and attitudes functioning to support decision making, monitoring, recommendations, social support, staying informed, or validation of information. Findings from this study described the role of social networks in medication information seeking behavior of patients as complex, dynamic, and important to the medication use experience. The study concluded that patients use social network contacts from both inside and outside of health care to satisfy all types of information needs. Finally, by coming to a more complete understanding of the social nature of the information environment, health professionals can better understand information needs from a patient's perspective.