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1.  Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls 
The AAPS Journal  2015;17(4):948-964.
The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of “what if” scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug’s F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or paracellular transporters). Although there are limitations to the approach used in this study, the results of our assessment strongly suggest that the human BCS classification system requires substantial modification before it can be reliably applied to dogs.
doi:10.1208/s12248-015-9743-7
PMCID: PMC4476996  PMID: 25916691
BCS; dogs; canine; permeability; solubility
2.  Demonstrating Comparative In Vitro Bioequivalence for Animal Drug Products Through Chemistry and Manufacturing Controls and Physicochemical Characterization: A Proposal 
The AAPS Journal  2015;17(2):307-312.
The assessment of in vivo bioequivalence (BE) of nonsystemically absorbed drug products has been a longstanding challenge facing drug manufacturers and regulators of human or animal health products. Typically, in situations where blood level BE studies are not feasible, clinical endpoint BE trials have provided the only option for generating interproduct comparisons. Given the imprecision and logistic challenges associated with these studies, there has been an effort to identify alternative pathways that can reliably ensure the equivalence of product performance and quality. This commentary provides a proposal for an in vitro approach for evaluating the in vivo BE of veterinary drug products that are either nonsystemically absorbed or that act both locally and systemically but where the local site of action is proximal to the absorption window. The assumption underlying this approach is that equivalence in product physicochemical attributes and in vitro product performance translates to equivalence in product in vivo behavior. For sponsors with a right of reference to underlying safety and effectiveness data, this approach could be used to support pre and post-approval changes. When comparing a generic test product to the pioneer (reference listed new animal drug, RLNAD) product, a demonstration of sameness across a battery of in vitro test procedures could be used to confirm that the test and RLNAD products are bioequivalent.
doi:10.1208/s12248-014-9702-8
PMCID: PMC4365090  PMID: 25609223
bioequivalence; critical quality attributes; in vitro dissolution; veterinary drug products
3.  Quality-by-Design III: Application of Near-Infrared Spectroscopy to Monitor Roller Compaction In-process and Product Quality Attributes of Immediate Release Tablets 
AAPS PharmSciTech  2014;16(1):202-216.
The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller compaction process parameters, compression force (CFt), and formulation variables identified from our earlier studies were evaluated in more detail. Multivariate principal component analysis (PCA) and partial least square (PLS) models were developed during the development stage and used as a control tool to predict the quality of granules and tablets. Validated models were used to monitor and control batches manufactured at different sites to assess their robustness to change. The results showed that roll pressure (RP) and CFt played a critical role in the quality of the granules and the finished product within the range tested. Replacing binder source did not statistically influence the quality attributes of the granules and tablets. However, lubricant type has significantly impacted the granule size. Blend uniformity, crushing force, disintegration time during the manufacturing was predicted using validated PLS regression models with acceptable standard error of prediction (SEP) values, whereas the models resulted in higher SEP for batches obtained from different manufacturing site. From this study, we were able to identify critical factors which could impact the quality attributes of the CIP IR tablets. In summary, we demonstrated the ability of near-infrared spectroscopy coupled with chemometrics as a powerful tool to monitor critical quality attributes (CQA) identified during formulation development.
doi:10.1208/s12249-014-0180-1
PMCID: PMC4309813  PMID: 25319052
chemometrics; crushing force; disintegration; near-infrared spectroscopy; partial least square; principal component analysis; quality by design; roller compaction
4.  Dosing Regimen Matters: the Importance of Early Intervention and Rapid Attainment of the Pharmacokinetic/Pharmacodynamic Target 
To date, the majority of pharmacokinetic/pharmacodynamic (PK/PD) discussions have focused on PK/PD relationships evaluated at steady-state drug concentrations. However, a concern with reliance upon steady-state drug concentrations is that it ignores events occurring while the pathogen is exposed to intermittent suboptimal systemic drug concentrations prior to the attainment of a steady state. Suboptimal (inadequate) exposure can produce amplification of resistant bacteria. This minireview provides an overview of published evidence supporting the positions that, in most situations, it is the exposure achieved during the first dose that is relevant for determining the therapeutic outcome of an infection, therapeutic intervention should be initiated as soon as possible to minimize the size of the bacterial burden at the infection site, and the duration of drug administration should be kept as brief as clinically appropriate to reduce the risk of selecting for resistant (or phenotypically nonresponsive) microbial strains. To support these recommendations, we briefly discuss data on inoculum effects, persister cells, and the concept of time within some defined mutation selection window.
doi:10.1128/AAC.05360-11
PMCID: PMC3370717  PMID: 22371890
5.  Factors Influencing the Use and Interpretation of Animal Models in the Development of Parenteral Drug Delivery Systems 
The AAPS Journal  2011;13(4):632-649.
Depending upon the drug and drug delivery platform, species-specific physiological differences can lead to errors in the interspecies extrapolation of drug performance. This manuscript provides an overview of the species-specific physiological variables that can influence the performance of parenteral dosage forms such as in situ forming delivery systems, nanoparticles, microspheres, liposomes, targeted delivery systems, lipophilic solutions, and aqueous suspensions. Also discussed are those factors that can influence the partitioning of therapeutic compounds into tumors, the central nervous system and the lymphatics. Understanding interspecies differences in the movement and absorption of molecules is important to the interpretation of data generated through the use of animal models when studying parenteral drug delivery.
doi:10.1208/s12248-011-9303-8
PMCID: PMC3231859  PMID: 21971647
animal model; interspecies differences; parenteral drug delivery; pharmacokinetics
6.  Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model 
The AAPS journal  2008;10(1):110-119.
There is limited information describing species related pharmacogenetic differences in animals. Despite the lack of genetic information in veterinary medicine, breed specific responses to endogenous and exogenous substances have been reported across many species. This finding underscores the importance of obtaining insight into the genotypic and phenotypic variation present across breeds. This article provides a summary of the literature pertaining to canine breed differences in physiology, drug response, drug pharmacokinetics, and metabolic idiosyncrasies. The existing knowledge of pedigrees and the known phenotypes and genotypes of dogs provides important information for determining mode of inheritance, penetration, and other major characteristics of heritable traits. Understanding these breed differences will improve canine population predictions (for canine drug products) and may be of value when extrapolating toxicology data from dogs to humans.
doi:10.1208/s12248-008-9011-1
PMCID: PMC2747081  PMID: 18446511
bioavailability; breed-related differences; canine pharmacodynamics; canine pharmacogenetics; canine pharmacokinetics; drug response; population diversity
7.  Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model 
The AAPS Journal  2008;10(1):110-119.
There is limited information describing species related pharmacogenetic differences in animals. Despite the lack of genetic information in veterinary medicine, breed specific responses to endogenous and exogenous substances have been reported across many species. This finding underscores the importance of obtaining insight into the genotypic and phenotypic variation present across breeds. This article provides a summary of the literature pertaining to canine breed differences in physiology, drug response, drug pharmacokinetics, and metabolic idiosyncrasies. The existing knowledge of pedigrees and the known phenotypes and genotypes of dogs provides important information for determining mode of inheritance, penetration, and other major characteristics of heritable traits. Understanding these breed differences will improve canine population predictions (for canine drug products) and may be of value when extrapolating toxicology data from dogs to humans.
doi:10.1208/s12248-008-9011-1
PMCID: PMC2747081  PMID: 18446511
bioavailability; breed-related differences; canine pharmacodynamics; canine pharmacogenetics; canine pharmacokinetics; drug response; population diversity
9.  2007 highlights of advances in the pharmaceutical sciences: An American Association of Pharmaceutical Scientists (AAPS) perspective 
The AAPS Journal  2007;9(2):E219-E226.
The American Association of Pharmaceutical Scientists (AAPS) covers the full range of areas of expertise associated with the resolution of concerns pertaining to drugs and drug products. This editorial highlights the initiatives, issues, and challenges that are the forefront of the pharmaceutical sciences in 2007. It also provides an overview of how these difficult questions are being addressed through the programs and events associated with the AAPS 2007 Annual Meeting that will be held at the San Diego, California, Convention Center from November 11 to 15, 2007.
doi:10.1208/aapsj0902024
PMCID: PMC2751411
dose predictions; product design; product quality control; population kinetics; dose individualization; regulatory sciences; pharmacostatistics; process analytical technology; medical imagining; quantitative pharmacology; dissolution; biotechnology
10.  Challenges and issues in veterinary pharmacology and animal health 2004—Preface 
The AAPS Journal  2005;7(2):E266-E271.
doi:10.1208/aapsj070226
PMCID: PMC2750963  PMID: 16353907
11.  AAPS/RAPS/CAPRA collaborative program: Exploring the challenges of drug regulation in a global environment: Clinical concerns 
AAPS PharmSci  2003;5(4):13-40.
Globalization of the pharmaceutical industry has led to a need to harmonize the regulatory requirements governing the marketing of medicinal products. To minimize the barriers impeding global drug product registration, the International Conference on the Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) was established in 1990. The ICH has developed a series of guidelines that reflect agreements reached by participating nations on aspects of the chemistry and clinical technical sections that will fulfill the regulatory requirements of these various jurisdications. Nevertheless, there continue to be points of divergent perspectives and barriers that can impede the use of foreign clinical data. Given the importance of these issues, the Regulatory Science (RS) section of the American Association of Pharmaceutical Scientists (AAPS), in conjunction with the Regulatory Affairs Professional Society (RAPS) and the Canadian Association of Professional Regulatory Affairs (CAPRA) cosponsored a public forum on this topic. This manuscript provides a summary of the speaker presentations and audience discussions regarding the design of clinical trials and the extrapolation of results from these trials to support international drug registration.
doi:10.1208/ps050427
PMCID: PMC2750989  PMID: 15198515
clinical trials; regulatory requirements; international harmonization; foreign clinical data
12.  Introduction: A welcome to the first special animal health issue of AAPS PharmSci 
AAPS PharmSci  2002;4(4):189-192.
The goal of this special volume is to provide veterinary scientists with state-of-the art reviews in animal health and to inform human health scientists of the various challenges and collaborative opportunities associated with their animal health counterparts. The contributors are highly respected experts, providing invaluable insights into current issues and state-of-the-art advances within veterinary medicine.
doi:10.1208/ps040439
PMCID: PMC2751328  PMID: 12647740
Veterinary medicine; harmonization
13.  Linking human and veterinary health: Trends, directions and initiatives 
AAPS PharmSci  2002;4(4):112-118.
The objective of this brief article is to provide an overview of some of the important harmonization efforts that are currently under way within the animal health community. Topics include: scientific networks and interdisciplinary communication: organizations that address animal-related public health concerns; the role of the veterinary pharmaceutical scientist within human health-oriented professional organizations; recent publications pertaining to veterinary pharmacology, pharmaceutics and therapeutics; and the role of global networking in veterinary product research and development.
doi:10.1208/ps040432
PMCID: PMC2751321  PMID: 12646004
communication; globalization; veterinary medicine

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