The Use of Systemically Absorbed Drugs to Explore An In Vitro Bioequivalence Approach For Comparing Non-Systemically Absorbed Active Pharmaceutical Ingredients in Drug Products For Use in Dogs.

Purpose: Currently, for veterinary oral formulations containing one or more active pharmaceutical ingredient (API) that are not systemically absorbed and act locally within the gastrointestinal (GI) tract, the use of terminal clinical endpoint bioequivalence (BE) studies is the only option for evaluating product BE. This investigation explored the use of a totality of evidence approach as an alternative to these terminal studies.

Methods: Three formulations of tablets containing ivermectin plus praziquantel were manufactured to exhibit distinctly different in vitro release characteristics.

Development and Validation of Matrix of Chemistry, Manufacturing, and Control (MoCMC) System for Intramammary Drug Products (IMM).

Purpose: Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations.

Development and Validation of a Stability-indicating UPLC-DAD Method for the Simultaneous Determination of Ivermectin and Praziquantel in Pharmaceutical Tablets and Dissolution Media.

Currently, there is no single rapid and accurate stability-indicating quantitative method that can simultaneously determine both ivermectin and praziquantel and their related compounds. Thus, the goal of this research is to develop and validate a new rapid, accurate, and stability-indicating ultra-performance liquid chromatography (UPLC) method. The method uses a water, acetonitrile, and methanol gradient.

Development and Validation of Discriminatory In-vitro Release Method for Intramammary Drug Product.

Purpose: Intramammary (IMM) formulations are locally acting and delivered intracisternally into the udder. No pharmacopeial in-vitro release method is available to differentiate between the IMM formulations. Our research aim is to develop in-vitro release methods that discriminate different IMM formulations (SPECTRAMAST® LC and in-house formulations).

Evaluating the solubility of compounds intended for intramammary infusion based upon tests conducted across a range of milk matrices.

The ability to evaluate drug solubility in milk and milk-related products has relevance both to human and veterinary medicine. Model compounds explored in a previous investigation focused on drug solubility assessments when delivered in milk-associated vehicles for administration to human patients. In the current investigation, we focus on the solubility of drugs intended for delivery via intramammary infusion to cattle.

Canine Intestinal Organoids as a Novel In Vitro Model of Intestinal Drug Permeability: A Proof-of-Concept Study.

A key component of efforts to identify the biological and drug-specific aspects contributing to therapeutic failure or unexpected exposure-associated toxicity is the study of drug-intestinal barrier interactions. While methods supporting such assessments are widely described for human therapeutics, relatively little information is available for similar evaluations in support of veterinary pharmaceuticals. There is, therefore, a critical need to develop novel approaches for evaluating drug-gut interactions in veterinary medicine.

Evaluation of product bioequivalence when subject blood volume necessitates limited sampling strategies.

In a traditional blood level bioequivalence (BE) study, every subject provides drug concentrations at each blood sampling time. However, this approach is not suitable for animals whose blood volume limits or prohibits multiple sample collections. In our previous research, we presented an approach that can be applied to studies using a destructive sampling design where each animal provides only 1 blood sample that is then incorporated into a composite profile.

Using simulations to explore the potential effect of disease and inflammation on the frequency of violative flunixin residues in cattle.

The US Food and Drug Administration (FDA) assigns a tolerance and withdrawal period when evaluating new drugs for use in food-producing species. Because withdrawal periods are determined from data generated in normal, healthy animals, questions have been raised regarding whether disease and inflammation can be a factor associated with some residue violations. We explored this question using flunixin liver concentrations as a model situation.

Individualized Patient Care Through Model-Informed Precision Dosing: Reflections on Training Future Practitioners.

Prior to his passing, Dr. Roger Jelliffe, expressed the need for educating future physicians and clinical pharmacists on the availability of computer-based tools to support dose optimization in patients in stable or unstable physiological states. His perspectives were to be captured in a commentary for the AAPS J with a focus on incorporating population pharmacokinetic (PK)/pharmacodynamic (PD) models that are designed to hit the therapeutic target with maximal precision.

Application of pharmacokinetic/pharmacodynamic concepts to the development of treatment regimens for sporadic canine urinary tract infections: Challenges and paths forward.

Antimicrobial efficacy can be predicted based on infection site exposure to the antimicrobial agent relative to the in vitro susceptibility of the pathogen to that agent. When infections occur in soft tissues (e.g.

A Critical Overview of the Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption.

Traditionally, excipients have been considered in drug development from the perspective of their influence on drug solubility, manufacturability, and ability to control in vitro and in vivo drug release. These effects have been largely evaluated through studies involving in vitro dissolution methods. However, there is a growing awareness that what had previously been considered biologically inert excipients can exert numerous in vivo effects.

A Critical Overview of the Biological Effects of Excipients (Part II): Scientific Considerations and Tools for Oral Product Development.

It is now recognized that a number of excipients previously considered to be "inert" have the capacity to alter drug oral bioavailability through a range of in vivo effects. The various mechanisms through which an excipient can affect in vivo gastrointestinal physiology and drug absorption characteristics were explored in "A Critical Overview of The Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption." The next critical issue that needs to be discussed is how these biological effects are evaluated.

Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics.

Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid composition and the associated impact of food intake and dietary composition on in vivo drug solubilization. This information gap can lead to uncertainties with regard to how best to formulate pharmaceuticals for veterinary use or the in vitro test conditions that will be most predictive of species-specific in vivo oral product performance. To address these challenges, this overview explores species-specific factors that can influence oral drug solubility and the formulation approaches that can be employed to overcome solubility-associated bioavailability difficulties.

Canine Intestinal Organoids in a Dual-Chamber Permeable Support System.

The permeable support system is typically used in conjunction with traditional two-dimensional (2D) cell lines as an in vitro tool for evaluating the oral permeability of new therapeutic drug candidates. However, the use of these conventional cell lines has limitations, such as altered expression of tight junctions, partial cell differentiation, and the absence of key nuclear receptors. Despite these shortcomings, the Caco-2 and MDCK models are widely accepted and validated for the prediction of human in vivo oral permeability.

Harnessing the Biology of Canine Intestinal Organoids to Heighten Understanding of Inflammatory Bowel Disease Pathogenesis and Accelerate Drug Discovery: A One Health Approach.

In a recent issue of the Lancet, the prevalence of Inflammatory Bowel Disease (IBD) was estimated at 7 million worldwide. Overall, the burden of IBD is rising globally, with direct and indirect healthcare costs ranging between $14.6 and $31.

Comparison of Canine and Human Physiological Factors: Understanding Interspecies Differences that Impact Drug Pharmacokinetics.

This review is a summary of factors affecting the drug pharmacokinetics (PK) of dogs versus humans. Identifying these interspecies differences can facilitate canine-human PK extrapolations while providing mechanistic insights into species-specific drug in vivo behavior. Such a cross-cutting perspective can be particularly useful when developing therapeutics targeting diseases shared between the two species such as cancer, diabetes, cognitive dysfunction, and inflammatory bowel disease.

Evaluation of partial area under the curve in bioequivalence studies using destructive sampling design.

Product blood-level in vivo bioequivalence (BE) studies typically involve complete blood concentration-time profiles generated for each subject. Accordingly, each subject provides the estimates of the rate and extent of drug absorption. However, repeated blood draws are not always feasible for studies using small animals because of handling or blood volume (e.

The Impact of Infection and Inflammation on Drug Metabolism, Active Transport, and Systemic Drug Concentrations in Veterinary Species.

Within human medicine, it is recognized that the pharmacokinetics (PK) of many compounds can be altered by the presence of inflammation or infection. Research into the reason for these changes has identified pathways that can influence drug absorption, clearance, and tissue distribution. In contrast, far less is known about these relationships within the framework of veterinary medicine.

Expert Discussion of the Role of Rate Constant Versus Clearance Approaches to Define Drug Pharmacokinetics: Theoretical and Clinical Considerations.

This article provides a dialogue covering an ongoing controversy on the use of clearance versus rate constant approaches for model parameterization when assessing pharmacokinetic (PK) data. It reflects the differences in opinions that can exist among PK experts. Importantly, this discussion extends beyond theoretical arguments to demonstrate how these different approaches impact the analysis and interpretation of data acquired in clinical situations.

Reconciling Human-Canine Differences in Oral Bioavailability: Looking beyond the Biopharmaceutics Classification System.

The extrapolation of oral bioavailability (F) information between dogs and humans has had an important role in the drug development process, whether it be to support an assessment of potential human pharmaceutical formulations or to identify the bioavailability challenges that may be encountered in dogs. Accordingly, these interspecies extrapolations could benefit from a tool that helps identify those drug characteristics consistent with species similarities in F. Our initial effort to find such a tool led to an exploration of species differences as it pertained to the biopharmaceutics classification system (BCS).

Impact of bovine respiratory disease on the pharmacokinetics of danofloxacin and tulathromycin in different ages of calves.

Pneumonia is one of the most economically important respiratory diseases of calves and knowledge of the impact of clinical disease on pharmacokinetics (PK) in young calves is limited. This study was undertaken to investigate the efficacy and PK of two antibiotics, tulathromycin and danofloxacin, in two age groups of calves experimentally infected with Pasteurella multocida. Both danofloxacin, a fluoroquinolone antibiotic, and tulathromycin, a macrolide antibiotic is approved for the treatment of bovine respiratory disease (BRD).

Danazol oral absorption modelling in the fasted dog: An example of mechanistic understanding of formulation effects on drug pharmacokinetics.

Oral bioavailability of poorly water soluble (BCS II) drugs like danazol can be minimal without the necessary formulation strategies. Availability of in vitro physicochemical and in vivo pharmacokinetic studies can be valuable when designing these strategies but cannot reveal the drug-formulation-gastrointestinal physiology interplay that impact the successful optimization of intestinal solubilization and resulting oral drug absorption. In silico mechanistic oral drug absorption models can serve as a tool for providing this important perspective and for integrating information generated across various in vivo and in vitro studies.