PBPK used in modeling water medications effectively

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Although water medications have been used in the United States for over 40 years, the pharmacokinetics of these drugs have not been clearly discerned using compartmental pharmacokinetics techniques. No repeated dosing pharmacokinetic studies have been published on water medications in swine. Therefore we proposed to use three proven techniques in veterinary medicine to model water medications in swine. Non-compartmental modeling, physiologically based pharmacokinetic modeling and population based pharmacokinetic modeling have improved veterinary medicine pharmacology over the last decade. The applications of these techniques to the pharmacokinetics of water medications, however, have not been published. Therefore two in vivo studies were performed to collect pharmacokinetic information on these drugs and then pharmacokinetic modeling was performed to test these techniques and their applications to characterize the disposition characteristics of water medications in swine production settings. In vivo experiments were performed in pigs based on the age and dosing schedules of those treated in commercial production units with tetracycline and sulfamethazine. Non-compartmental analysis techniques were initially applied to these populations. PBPK and population pharmacokinetic techniques were also applied where relevant to these medications to provide insight into situations that traditional modeling techniques were unable to elucidate. For sulfamethazine, the use of PBPK modeling
proved useful in characterizing the potentially small exposure concentrations that have been documented in the literature for over 25 years. In contrast to sulfamethazine which is chemically very stable, tetracycline has been shown to degrade over time with exposure to high temperatures and sunlight. Ancillary experiments were performed to characterize the bioactivity of tetracycline water medication as dosed in a production setting. Furthermore, basic pharmacokinetic studies on tetracycline administered in water was collected and analyzed. Finally population based modeling was applied to data collected from commercial farm settings to determine factors that may apply to all water medication administration in the swine industry. This mixed effect modeling technique was able to provide increased support for the non-compartmental pharmacokinetic findings and to identify factors important to plasma concentrations of medications administered in water. PBPK and population based modeling techniques can be effectively used in modeling water medications in swine. Furthermore, they were able to determine dosing amounts and schedules as well as other factors that affect the concentration of water medications in swine where traditional pharmacokinetic modeling is inadequate.

Pharmacokinetics of ceftiofur crystalline free acid challenged with PRRSv

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Antimicrobial treatment regimens are generally based on pharmacokinetic analysis established in healthy animals. Likewise, in food animals, antimicrobial withdrawal times are based on pharmacokinetic data from healthy animals. In clinical practice, antimicrobials are therapeutically used in disease challenged animals. There is limited literature addressing the question of pharmacokinetic changes in diseased animals. Considering swine, there are approximately 17 searchable peer reviewed studies addressing disease influence on antimicrobial pharmacokinetics. Across those studies there are about 28 diseaseantimicrobial interactions evaluated, of which 21 find that disease changes the pharmacokinetics of the evaluated antimicrobial. None of the current studies address the influence vaccination may have on preserving antibiotic pharmacokinetics in the face of disease challenge.
Original research was performed to evaluate the pharmacokinetics of ceftiofur crystalline free acid in pigs vaccinated against, challenged with, or vaccinated against and challenged with PRRSv. The original research hypothesized that PRRSv wild-type challenge would change pharmacokinetics and previous vaccination would have no effect on pharmacokinetic variables. Previous research had shown ceftiofur pharmacokinetics change with PRRSv infection. The PRRSv vaccine investigated is a commonly used and commercially available modified live virus. The present work found that a wild-type PRRSv infection resulted in a lower AUC0-last, higher Cl/F and higher Vz/F. The present work also determined that the modified live virus used for vaccination did not result in any pharmacokinetic changes, and vaccination with the modified live virus prevented pharmacokinetic changes in pigs that were subsequently challenged with a wild-type virus.
Disease or infection of a virulent organism does not always change antimicrobial pharmacokinetics. Pharmacokinetic changes seem dependent on specific antimicrobial and specific organism. Available research demonstrates PRRSv infection does change pharmacokinetics of ceftiofur drugs. Original research reported in this thesis suggests a modified live PRRSv vaccination has the potential to prevent ceftiofur pharmacokinetic changes that occur in the face of a wild-type PRRSv challenges. This information may be clinically applied by following labeled pharmacokinetic analysis of ceftiofur crystalline free acid in pigs vaccinated with a modified live PRRSv, regardless of wild-type PRRSv challenge.

Some types of pharmacology and toxicology for Preclinical trials

Medicilon provides a full range of services to support our clients in discovering and evaluating new potential drug therapies. Our Pharmacology department functions in accordance with the needs of our customers for a variety of effective animal models used to detect drug effectiveness. We offer non-human primates, dogs, mice and rats, rabbits, guinea pigs and others in our services

Discovery Toxicology

Our early discovery screening and DMPK services enable clients to select candidates with the highest potential for successful development. Early toxicity evaluations enable confirmation of the selection. Expediency, accuracy and communication characterize the discovery toxicology unit at Medicilon.

In vivo and in vitro Metabolism

We understand your need for fast turnaround in drug metabolism studies. Medicilon provides rapid, accurate in vitro and in vivo metabolism services that provide information required to assess your candidate’s profile and determine appropriate next steps in the development cycle. Customized in vivo studies identify pharmacokinetic parameters in animals, including metabolite profiling, disposition across tissues and organs, and structural identification of metabolites. We also provide a complete package of in vitro studies to characterize your drug candidate’s intrinsic metabolic behavior, metabolic stability, and CYP involvement, thereby assisting in prediction of clinical responses and defining concerns for subsequent studies.
Kinetic profiling is essential to provide understanding of a candidate’s exposure in vivo and potential for successful development. Commonly, these studies conducted to survey or confirm species selection for preclinical development. Medicilon conducts a wide range of PK/TK studies in various species and uses state-of-the-art software modeling to determine parameters such as half-life, exposure, bioavailability, clearance, and volume of distribution. Discovery kinetic studies typically involve unlabeled drug administered by the intended clinical route to allow determination and modeling of circulating parent drug and metabolite exposures. Medicilon maintains stock colonies of acclimated and study-ready canines and primates for fast study start times.
Determination of maximally tolerated dosages (MTD) in two species provides an initial in vivo toxicity assessment that is often followed by a short-term dose range finding (DRF) study involving repeated administrations. Collectively, these studies provide considerable information regarding confirmation of candidate selection, circulating exposure levels and kinetics, and toxicity profiling. At Medicilon, our teams efficiently initiate, execute and analyze data from these studies to provide critical information to our clients as quickly as possible.

Recombinant Factor fusion protein in Toxicological testings

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The toxicological study effects of rFVIIIFc were measured through observations of in-life parameters (clinical observations, body weight, food consumption, and ophthalmic examination), laboratory evaluations (hematology, serum chemistry, and coagulation parameters), and post-mortem evaluation (gross necropsy, organ weights, and histopathology) in all studies. Cardiovascular evaluations were also performed for monkeys in the repeat-dose toxicology study. Electrocardiograms (ECGs) were recorded for all monkeys prior to dosing and on Day 23, as well as in the week prior to the scheduled core cohort necropsy (Day 26) and all recovery monkeys during the week prior (Day 54) to the recovery cohort necropsy; ECGs were analyzed qualitatively by a board-certified veterinary cardiologist. Heart rates were calculated from the ECG tracings. Local tolerance was evaluated through gross and microscopic evaluation of the intravenous infusion site in the repeat-dose studies in both rats and monkeys.
For the repeat-dose studies, assessments of in-life parameters, clinical pathology, and post-mortem evaluations were analyzed statistically when the number of animals was 3 or greater. Data were analyzed for effects of rFVIIIFc through an analysis of variance. For data with variances that were homogeneous across test groups, as determined by Bartlett’s test for homogeneity at the 0.05 level, tests for differences between experimental and control groups were made using Dunnett’s test. For non-homogenous data, tests for pair-wise differences between experimental and control groups were made using Cochran and Cox’s modified 2-sample t test. Statistical significance was set at the 0.05 level for all comparisons.
Rats and monkeys were pharmacologically relevant species for toxicological study, as the coagulation cascade is well conserved across species and rFVIIIFc is able to bind to FcRn in both species (unpublished data). The route of administration (intravenous) and formulations of rFVIIIFc used in this study were consistent with those used in clinical studies; the lyophilized formulation used in the repeat-dose monkey study was representative of the formulation intended for commercial use. Dosing frequency in the repeat-dose studies (every other day) was based on an elimination half-life of approximately 13 hours in both species. The doses of rFVIIIFc used in these studies (50-1000 IU/kg in the repeat-dose studies and 3000-20,000 IU/kg in the high-dose study) were greater than those indicated for use in humans.
rFVIIIFc was well tolerated in 2 relevant animal species, rats and monkeys. An adequate safety margin of 10-fold was demonstrated, based on a NOAEL of 1000 IU/kg in the repeat-dose toxicology studies compared with a highest anticipated clinical dose of 100 IU/kg. The nonclinical safety profile of rFVIIIFc shown here supported the observed clinical safety profile of rFVIIIFc [9] and. Furthermore, the A-LONG phase 3 clinical study demonstrated that rFVIIIFc was well tolerated and efficacious for the prevention and treatment of bleeding episodes in previously treated subjects with severe hemophilia.

Boric Acid Causes ER Stress and Activates the ATF4 and ATF6 Branches

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Nutritional chemoprevention is a growing area in the field of toxicology study. What we do and do not eat has a major impact on the development of cancer. However, it is difficult to show a causal relationship between a natural product and cancer prevention because mechanistic biochemical data are often missing and animals studies can be inconclusive. Both determining and elucidating molecular mechanisms that modulate pathological endpoints are necessary components in the risk assessment process used to determine if chemicals that show chemoprevention properties in the laboratory are safe for public use. The research presented in this dissertation focuses on chemoprevention through the consumption of a nutrient or the avoidance of toxic food additives. Part I presents research that elucidated a molecular pathway activated by boric acid (BA), an essential plant nutrient, which may provide insight into the inhibition of cell proliferation of prostate cancer cells and reduced risk of prostate cancer. Part II consists of molecular toxicology research in application to public interest and health. It is a critical analysis of two commonly consumed FDA-approved food additives, rebaudioside A, an artificial sweetener, and artificial food dyes. In Part I, it was shown that BA is not an isoform-specific antagonist to the ryanodine receptor (RyR), a calcium (Ca2+) channel, but is a RyR antagonist that functions by interacting and competing with the receptor's only known endogenous agonist. This results in altered Ca2+ signaling that induces ER stress and the eIF2α/ATF4 and ATF6 branches of the unfolded protein response (UPR) in DU-145 prostate cancer cells. ER stress and the UPR are tightly associated with cell proliferation. The specific pathway that we have unfolded in BA-treated DU-145 cells is correlated with cell survival and an inhibition of cell proliferation. In Part II, we describe how in vivo and in vitro studies on rebaudioside A and food dyes demonstrated their toxicity. The assessment of toxicology studies on food dyes showed they do present an increased health risk and this is important given their widespread use by the public. The research presented here thus presents both the molecular mechanistic and public health sides of molecular toxicology.