Purpose: Ivermectin (IVM) is a lipophilic BCS-II compound (molecular weight=875 g/mole, LogP=3.22, intrinsic solubility=700 ug/L). IVM is used as antiparasitic drug in both humans and animals. IVM is known to have a half-life of 12-56 hours in humans. Strongyloidiasis is a chronic parasitic infection of humans caused by Strongyloides stercoralis, with an estimated 30-100 million people infected worldwide. Infection may be severe and even life-threatening in cases of immunodeficiency. Patients with disseminated strongyloidiasis are usually bedridden hospitalized patients that show symptoms such as paralytic ileus and reduced plasma albumin and cholesterol. Oral IVM is the only FDA-approved treatment but may not be effective in patients with disseminated disease. Veterinary subcutaneous formulations have been used in severe infections. We hypothesized that IVM PK in patients with disseminated strongyloidiasis can be predicted using PBPK model originally built and refined in healthy human and animal species. This hypothesis was tested and shown to be valid. Methods:A systematic method was used to build and refine different parts of the PBPK model. The process involved construction of models, parameterization of these models, evaluation of the effect of uncertainty in model parameters on model prediction via local and global sensitivity analyses and finally, refinement of model predictions. Two disposition models that differ in the rate limiting step in drug distribution were constructed and include perfusion-limited and permeability-limited distribution models. The ability of each model to predict IVM disposition was evaluated using plasma PK data in rat after intra-arterial dosing and in dog after intravenous bolus dosing. Then the disposition model was scaled to humans and an oral input model was constructed as a modification on the well-known ACAT model. The oral input model was coupled with the disposition model and used to predict IVM plasma concentration-time profile in healthy fasted human subject after oral dosing. Two subcutaneous (SQ) input models were constructed and used to evaluate the effect of IVM precipitation at the injection site. Plasma PK data in dog after SQ dosing was used to refine the constructed SQ input models. The refined disposition, oral input and SQ input physiologically-based models were used to predict IVM PK in patients with disseminated strongyloidiasis after a complex dosing regimen. The physiological parameters of the model were modified to account for the effect of the disease-induced pathophysiological changes on the body physiology and hence on the drug PK. Plasma PK data from hospitalized subjects with disseminated strongylidiasis was used in this part. Results and conclusions:The disposition model with assumption of permeability-limited distribution was more capable of describing IVM disposition in rat after intra-arterial dosing compared to when perfusion-limited distribution was assumed. The model predicted that hepatic clearance is the most impactful parameter on model-predicted plasma concentration of the drug. Also, IVM was shown to have low hepatic extraction ratio along with high binding in plasma and large volume of distribution, which collectively may explain the long half-life in the plasma of 63 hours in rat after intra-arterial dosing. The oral input model predicted that the oral input is limited by drug dissolution in the GI lumen and that a very small fraction of oral tablet dose (0.03) is available in the systemic circulation in healthy fasted human subjects. Both of the studied SQ input models predicted that majority of IVM absorption after SQ dosing is via the lymphatic route and that drug precipitation at the injection site can further slowdown the drug absorption after SQ administration. The PBPK model was able achieve the main goal of this research which is to predict IVM pharmacokinetics in patients with disseminated strongyloidiasis after a complex dosing regimen of multiple oral and SQ dosing. This was achieved by modifying the most impactful physiological parameters of the model affected by the disease state and that are related to drug binding in the plasma (fraction unbound), the GI motility (gastric emptying rate) and the lymphatic flow rate. Based on our analysis, we recommend measurement of plasma IVM concentrations early after initiation of therapy to exclude treatment failure due to reduced oral and/or SQ absorption. Also, we recommend measurement of plasma lipoprotein levels and their composition in these patients to differentiate between low total plasma concentrations due to low binding plasma as opposed to low drug input. Finally, interventional procedures that enhance lymphatic flow rate to site of SQ injection are recommended to enhance SQ absorption.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.

No description available.

Dissolution testing and physiological based pharmacokinetic modeling are the essential methods during drug development. However, there is a lack of a sound approach and understanding of the parameter that controls dissolution and absorption of amorphous formulations. Robust dissolution conditions and setup and PBPK models that have a predictability of in vivo results will expedite and facilitate the drug development process. In this project, cefuroxime axetil, CA (Zinnat® as the amorphous formulations); itraconazole, ITR (Sporanox® as the amorphous formulation) and a compound undergoing clinical trial, Compound X, CX (CX tablet as the amorphous formulation) were chosen. The design of experiments for the in vitro dissolution studies using different apparatus, media and setup which closely simulate the physiological condition of humans (CA and ITR) and dogs (CX) were implemented. The dissolution of CA, ITR and CX formulations was successfully characterised using different dissolution apparatus, setting and media (compendial, biorelevant and modified media) to simulate the changes of pH, contents, hydrodynamic conditions (flow rate and rotation speed) in human gastrointestinal tract (fasted and fed state). The change of hydrodynamics combined with media change that corresponded to the physiological conditions created with USP apparatus 4 and biorelevant dissolution media were able to mimic the in vivo performance of the tested formulations. Furthermore, surface UV dissolution imaging methodology that could be used to understand the mechanism of CA and ITR (Active compounds and their amorphous formulations) dissolution were developed in this project. The UV images developed using surface UV imaging apparatus provided a visual representation and a means for the qualitative as well as quantitative assessment of the differences in dissolution rates and concentration for the model compounds used. In this project, validated PBPK models for fasted state (CA, ITR) and fed state (CA, ITR and CX) were developed. These models incorporated in vitro degradation, particle size distribution, in vitro solubility and dissolution data as well as in vivo human/ dog pharmacokinetics data. Similarly, the results showed that level A IVIVCs for all three model compounds were successfully established. Dissolution profiles with USP apparatus 4 combined with biorelevant media showed close correlation with the in vivo absorption profiles. Overall, this project successfully provides a comprehensive biorelevant methodology to develop PBPK models and IVIVCs for orally administered amorphous formulations.

Degradation product toxicity is a critical quality issue for a small group of useful drug products--e.g. lidocaine, isoniazid, chlorhexidine, gabapentin. In the traditional risk assessment approaches, a no-observed-adverse-effect level (NOAEL) derived from animal data is determined with the use of generic (and arbitrary) uncertainty factors to obtain an acceptable daily intake. The effects of compound-specific biological complexities and pharmacokinetics are typically not part of the risk calculations. The selection of uncertainty factors that account for interspecies or intraspecies difference concerning biokinetics and biodynamics has also generally failed to consider chemical-specific mechanism information or pharmacokinetics data. The use of combining in-vitro biopharmaceutical characterization methods and physiologically-based pharmacokinetic modeling has undergone extensive study and validation for predicting clinical drug blood level time profiles. The rationale for the proposed research is that a PBPK modeling utilizing rat to human scaling for target tissue toxicity in combination with the Monte Carlo method for estimating human target exposure distributions provides a rational basis for assessing drug stability safety issues for drug substances that potentially degrade to toxic compounds. PBPK models for rats and humans were developed to simulate drug exposure time profiles after oral administration of model compounds including aniline, p-chloroaniline, 2,6-dimethylaniline, o-toluidine and p-aminophenol. The PBPK models were parameterized using a combination of literature values, computational models and standard in vitro experiments. Microsomal and hepatocyte metabolism studies were used to estimate the metabolic constants, and ultrafiltration was used to measure protein binding. Intestinal permeability was predicted using a set of related compound data to correlate measured Caco-2 permeability with molecular descriptors by multivariate regression. Sensitivity analyses were conducted to evaluate the impact of PBPK model parameters on plasma level predictions. To evaluate patient population effects on exposure profiles, the PBPK model parameters were varied in meaningful ways using Monte Carlo methods. Based on population PBPK models, distributions of target tissue exposure in rats and humans were simulated and compared to derive human safe dose. As results, rat PBPK model-predicted aniline concentration time profiles were in reasonable agreement with published profiles. Distributions of target tissue exposure in rats and humans were generated and compared based on a criterion. A human reference dose was then selected at a value of 1% criteria. This approach was compared to traditional risk assessment calculations. In conclusion, the PBPK modeling approach resulted in drug degradation product risk specifications that were less stringent than those estimated by conventional risk assessment approach. The PBPK modeling approach provides a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.

The bioavailability of a drug can be described as the fraction of an orally administered dose that reaches the systemic circulation and is often limited by first-pass metabolism in the gut and the liver. It is important to have knowledge about these processes since the systemic blood drug concentration is tightly connected to the effect of the drug. The general aim of this project was to quantitatively examine the role of the intestine in relation to the liver in first-pass metabolism of orally administered drugs. The first-pass metabolism of verapamil and raloxifene was investigated in detail with in vivo, in vitro and simulation studies, using the pig as an experimental model. The intestine contributed to the same extent as the liver to first-pass metabolism of R/S-verapamil in vivo in pigs. The S-isomer of verapamil was found in lower plasma concentrations compared to the R-isomer after oral dosing. The in vitro metabolism of verapamil in pig and human liver showed interspecies similarity and indicated equal intrinsic clearance for R- and S-verapamil. Through physiologically based pharmacokinetic modeling the stereoselectivity was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut and liver tissue distribution. For raloxifene the intestine was the dominating organ in first-pass glucuronidation in vivo in pigs. Furthermore, the raloxifene concentration entering the intestine or the dose administered in the gut did not influence the plasma PK of raloxifene and indicated that the intestinal metabolism was not saturable with clinical relevant doses. For both verapamil and raloxifene, a time-dependent hepatic metabolism was noted with major consequences to the pharmacokinetic of the drugs. This project has pointed out the importance of intestinal metabolism in the overall first-pass extraction of drugs and indicates that intestinal metabolism should be considered and evaluated early in drug development.

abstract: During summer 2014, a study was conducted as part of the Landscape Architecture Foundation Case Study Investigation to analyze features of three sustainably designed landscapes. Each project was located in a southwest desert city: Civic Space Park in Phoenix, AZ, the Pete V. Domenici US Courthouse Sustainable Landscape Retrofit in Albuquerque, NM, and George "Doc" Cavalliere Park in Scottsdale, AZ. The principal components of each case study were performance benefits that quantified ongoing ecosystem services. Performance benefits were developed from data provided by the designers and collected by the research team. The functionality of environmental, social, and economic sustainable features was evaluated. In southwest desert cities achieving performance benefits such as microclimate cooling often come at the cost of water conservation. In each of these projects such tradeoffs were balanced by prioritizing the project goals and constraints. During summer 2015, a study was conducted to characterize effects of tree species and shade structures on outdoor human thermal comfort under hot, arid conditions. Motivating the research was the hypothesis that tree species and shade structures will vary in their capacity to improve thermal comfort due to their respective abilities to attenuate solar radiation. Micrometeorological data was collected in full sun and under shade of six landscape tree species and park ramadas in Phoenix, AZ during pre-monsoon summer afternoons. The six landscape tree species included: Arizona ash (Fraxinus velutina Torr.), Mexican palo verde (Parkinsonia aculeata L.), Aleppo pine (Pinus halepensis Mill.), South American mesquite (Prosopis spp. L.), Texas live oak (Quercus virginiana for. fusiformis Mill.), and Chinese elm (Ulmus parvifolia Jacq.). Results showed that the tree species and ramadas were not similarly effective at improving thermal comfort, represented by physiologically equivalent temperature (PET). The difference between PET in full sun and under shade was greater under Fraxinus and Quercus than under Parkinsonia, Prosopis, and ramadas by 2.9-4.3 °C. Radiation was a significant driver of PET (p<0.0001, R2=0.69) and with the exception of ramadas, lower radiation corresponded with lower PET. Variations observed in this study suggest selecting trees or structures that attenuate the most solar radiation is a potential strategy for optimizing PET. / Dissertation/Thesis / Masters Thesis Applied Biological Sciences 2016

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections and is part of a broader class of antibiotics called carbapenems. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. Previously, a physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose in normal height, normal weight males. Due to the absorption properties of ertapenem, the amount of fat in the body can influence how the drug binds, how quickly the drug passes through the body, and thus how effective the drug might be. Thus, we have revised the model so that it is applicable to males and females of differing body mass index (BMI). Simulations were performed to consider the distribution of the antibiotic in males and females with varying body mass indexes. These results could help to determine if there is a need for altered dosing regimens in the future.

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections, which is part of a broader class of antibiotics called carbapenem. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. A physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose. PBPK modeling incorporates known physiological parameters such as body weight, organ volumes, and blood ow rates in particular tissues. Furthermore, ertapenem is highly bound in human blood plasma; therefore, nonlinear binding is incorporated in the model since only the free portion of the drug can saturate tissues and, hence, is the only portion of the drug considered to be medicinally effective. Parameters in the model were estimated using a least squares inverse problem formulation with published data for blood concentrations of ertapenem for normal height, normal weight males. Finally, an uncertainty analysis of the parameter estimation and model predictions is presented.