Marilyn N. Martinez

A Mechanistic Approach to Understanding the Factors Affecting Drug Absorption: A Review of Fundamentals

This article provides an overview of the patient‐specific and drug‐specific variables that can affect drug absorption following oral product administration. The oral absorption of any chemical entity reflects a complex spectrum of events. Factors influencing product bioavailability include drug solubility, permeability, and the rate of in vivo dissolution. In this regard, the Biopharmaceutics Classification System has proven to be an important tool for predicting compounds likely to be associated with bioavailability problems. It also helps in identifying those factors that may alter the rate and extent of drug absorption. Product bioavailability can also be markedly influenced by patient attributes such as the integrity of the gastrointestinal tract, physiological status, site of drug absorption, membrane transporters, presystemic drug metabolism (intrinsic variables), and extrinsic variables such as the effect of food or concomitant medication. Through an awareness of a drugs physicochemical properties and the physiological processes affecting drug absorption, the skilled pharmaceutical scientist can develop formulations that will maximize product availability. By appreciating the potential impact of patient physiological status, phenotype, age, gender, and lifestyle, dosing regimens can be tailored to better meet the needs of the individual patient.

Dosing Regimen Matters: the Importance of Early Intervention and Rapid Attainment of the Pharmacokinetic/Pharmacodynamic Target

ABSTRACT 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.

Applying the biopharmaceutics classification system to veterinary pharmaceutical products: Part II. Physiological considerations

In comparing product bioavailability across animal species, it is not unusual to observe marked interspecies differences. For many compounds, these differences reflect presystemic drug metabolism. However, a host of other variables must also be considered such as in vivo drug solubility, gastric transit time, intestinal permeability, diet, and species-by-formulation interactions. By combining information on drug solubility and intestinal permeability with an understanding of the interrelationship between pH, product dissolution and gastrointestinal physiology, we attempt to define those conditions under which in vitro dissolution data may be used as a surrogate for data on in vivo bioavailability. We consider the likely physiological causes for species-related differences in the absolute and relative bioavailability of orally administered pharmaceuticals, and examine the potential for these normal interspecies differences to reflect bioavailability changes that can occur with various human pathologies.

Applying the Biopharmaceutics Classification System to veterinary pharmaceutical products: Part I: Biopharmaceutics and formulation considerations

The complexity of multiple species approvals continues throughout the life of a product as post-approval manufacturing changes, as well as all generic versions of approved products, are evaluated for each of the approved target animal species. In comparing product bioavailability across animal species, it is not unusual to observe marked interspecies differences. For many compounds, these differences reflect species-specific presystemic metabolism. However, a host of other variables must also be considered, including in vivo drug solubility, gastric transit time, intestinal permeability, diet, and species-by-formulation interactions. To predict potential species-by-formulation interactions, one must consider the solubility and intestinal permeability of the drug entity, the type of formulation, nature of the excipients, and the physiological characteristics of the animal recipient. In this paper, we examine manufacturing and formulation variables that can affect drug bioavailability, and the potential for species-specific differences in the responses to these formulations.

The pharmacogenomics of P‐glycoprotein and its role in veterinary medicine

Despite advancements in pharmacogenetics in human medicine, the incorporation of pharmacogenetics into veterinary medicine is still in its early stages of development. To date, efforts to understand the pharmacologic impact of genetic variation in veterinary species have largely focused on genes encoding for the membrane transporter, P-glycoprotein (P-gp). The emphasis on the role of P-gp is largely because of safety concerns associated with the use of some macrocyclic lactones in dogs. Because of the body of information available on this topic, we use P-gp as a platform for understanding the importance of population diversity in veterinary medicine. The impact of P-gp on drug pharmacokinetics and pharmacodynamics is considered, along with endogenous and exogenous factors that can modulate P-gp activity. The review includes discussion of how population diversity in P-gp activity can lead to susceptibility to certain diseases or alter patient response to environmental stress or pharmaceutical intervention. In addition, phenotypic diversity also needs to be considered, as demonstrated by the impact of P-gp up-regulation and drug resistance. The aim of this review was to set the stage for further exploration into the impact of genetic and phenotypic variability on drug pharmacokinetics, disease propensity, product formulation and drug response in both companion and food-producing animals.

Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model

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.

Factors Influencing the Gastric Residence of Dosage Forms in Dogs

An appreciation of the variables influencing canine gastric transit time is of interest both because of the push to develop pharmaceutical products that meet the therapeutic needs of the veterinary patient and because of efforts to improve our understanding of the strengths and weaknesses associated with the use of the dog as a preclinical model to support human product development. The gastric transit time of monogastric species is influenced by many factors. Physiological variables include the time of dosing relative to the phase of the interdigestive migrating myoelectric current (IMMC), the sieving properties of the pylorus, the presence or absence of food, and the inherent crushing force of the stomach. Pharmacological factors include particle size, shape and density, drug solubility, and the hardness of the tablet. Despite the importance of understanding the factors influencing gastric residence time in dogs, an in-depth examination of currently available information on this topic has not as yet been published. Therefore, this review provides an examination of each of these factors and their potential impact on canine oral drug absorption characteristics.

Antimicrobial drug resistance.

This chapter provides an overview of our current understanding of the mechanisms associated with the development of antimicrobial drug resistance, international differences in definitions of resistance, ongoing efforts to track shifts in drug susceptibility, and factors that can influence the selection of therapeutic intervention. The latter presents a matrix of complex variables that includes the mechanism of drug action, the pharmacokinetics (PK) of the antimicrobial agent in the targeted patient population, the pharmacodynamics (PD) of the bacterial response to the antimicrobial agent, the PK/PD relationship that will influence dose selection, and the integrity of the host immune system. Finally, the differences between bacterial tolerance and bacterial resistance are considered, and the potential for non-traditional anti-infective therapies is discussed.

Prediction of xenobiotic clearance in avian species using mammalian or avian data: how accurate is the prediction?

*Elanco Animal Health, A Division of Eli Lilly and Company, Greenfield, IN, USA; Office of Blood Review & Research (OBRR), Center forBiologic Evaluation and Research, Food and Drug Administration, Rockville, MD, USA; Division of Therapeutic Drugs for Food Animals (HFV-130), Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food & Drug Administration, Rockville, MD, USA

Modified release drug delivery in veterinary medicine.

To successfully research and develop an animal pharmaceutical dosage form, a diverse array of issues covering basic medicine, pharmacology and technology must be addressed. Societal concerns regarding animal and public health, as well as the rapidly changing farming and economic environments, provide additional challenges that require integration into an already complex web of issues. Here, we examine the drive towards reducing the frequency of administration to animals and the closing of gaps between the human and veterinary drug product development.