Population variability in animal health: Influence on dose-exposure-response relationships: Part II: Modelling and simulation.

During the 2017 Biennial meeting, the American Academy of Veterinary Pharmacology and Therapeutics hosted a 1-day session on the influence of population variability on dose-exposure-response relationships. In Part I, we highlighted some of the sources of population variability. Part II provides a summary of discussions on modelling and simulation tools that utilize existing pharmacokinetic data, can integrate drug physicochemical characteristics with species physiological characteristics and dosing information or that combine observed with predicted and in vitro information to explore and describe sources of variability that may influence the safe and effective use of veterinary pharmaceuticals.

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. Furthermore, recognizing these differences also supports a reverse PK extrapolations from humans to dogs. To appreciate the canine-human differences that can affect drug absorption, distribution, metabolism, and elimination, this review provides a comparison of the physiology, drug transporter/enzyme location, abundance, activity, and specificity between dogs and humans. Supplemental material provides an in-depth discussion of certain topics, offering additional critical points to consider. Based upon an assessment of available state-of-the-art information, data gaps were identified. The hope is that this manuscript will encourage the research needed to support an understanding of similarities and differences in human versus canine drug PK.

Pharmacokinetics of caffeic acid phenethyl ester and its catechol-ring fluorinated derivative following intravenous administration to rats.

The pharmacokinetic profiles of caffeic acid phenethyl ester (CAPE) and its catechol-ring fluorinated derivative (FCAPE) were determined in rats after intravenous administration of 5, 10 or 20 mg/kg for CAPE and 20 mg/kg for FCAPE, respectively. The plasma concentrations of CAPE and FCAPE were measured using a validated liquid chromatography tandem mass spectrometric method. The pharmacokinetic parameters were estimated using non compartmental analysis (NCA) and biexponential fit. The results showed that the area under the plasma concentration-time curve for CAPE treatment increased in a proportion greater than the increase in dose from 5 to 20 mg/kg of CAPE. Total body clearance values for CAPE ranged from 42.1 to 172 ml/min/kg (NCA) and decreased with the increasing dose of CAPE. Similarly, the volume of distribution values for CAPE ranged from 1555 to 5209 ml/kg, decreasing with increasing dose. The elimination half-life for CAPE ranged from 21.2 to 26.7 min and was independent of dose. That FCAPE was distributed extensively into rat tissues and eliminated rapidly was indicated by a high value of volume of distribution and similar short elimination half-life as that of CAPE.

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. In this work, we detail the development and application of the Simcyp canine ADAM model to nine danazol oral formulations and compare the model predictions to caninein vivo pharmacokinetic data from published literature. The application of this mechanistic approach revealed insights suggesting: (1) complete danazol solubilization in vitro may lead to an over-estimation of oral bioavailability when predictions are not corrected for the in vivo conditions promoting gut luminal precipitation; (2) some solubilizing excipients can influence intestinal physiology in a manner that may reduce danazol absorption; (3) danazol-formulation-luminal bile salts interplay can result in the formation of mixed micelles that negatively impact danazol intestinal permeability; and (4) the magnitude of danazol bioavailability enhancement associated with the use of solubilizing agents can be affected by the presence of saturable gut metabolism that can lead to concentration-dependent differences in its influence in vivo formulation behaviour at high versus low doses.

Canine gastrointestinal physiology: Breeds variations that can influence drug absorption.

Although all dogs belong to Canis lupus familiaris, the physiological diversity resulting from selective breeding can lead to wide interbreed variability in drug pharmacokinetics (PK) or in oral drug product performance. It is important to understand this diversity in order to predict the impact of drug product formulation attributes on in vivo dissolution and absorption characteristics across the canine population when the dog represents the targeted patient population. Based upon published information, this review addresses breed differences in gastrointestinal (GI) physiology and discusses the in vivo implications of these differences. In addition to the importance of such information for understanding the variability that may exist in the performance of oral dosage forms in dogs for the purpose of developing canine therapeutics, an appreciation of breed differences in GI physiology can improve our prediction of oral drug formulation performance when we extrapolate bioavailability results from the dog to the humans, and vice versa. In this literature review, we examine reports of breed associated diversity in GI anatomy and morphology, gastric emptying time (GET), oro-cecal transit time (OCTT), small intestinal transit time (SITT), large intestinal transit time (LITT), intestinal permeability, sodium/potassium fecal concentrations, intestinal flora, and fecal moisture content.

A mechanistic pharmacokinetic model to assess modified oral drug bioavailability post bariatric surgery in morbidly obese patients: interplay between CYP3A gut wall metabolism, permeability and dissolution.

OBJECTIVES: Due to the multi-factorial physiological implications of bariatric surgery, attempts to explain trends in oral bioavailability following bariatric surgery using singular attributes of drugs or simplified categorisations such as the biopharmaceutics classification system have been unsuccessful. So we have attempted to use mechanistic models to assess changes to bioavailability of model drugs. METHODS: Pharmacokinetic post bariatric surgery models were created for Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, sleeve gastrectomy and jejunoileal bypass, through altering the 'Advanced Dissolution Absorption and Metabolism' (ADAM) model incorporated into the Simcyp® Simulator. Post to pre surgical simulations were carried out for five drugs with varying characteristics regarding their gut wall metabolism, dissolution and permeability (simvastatin, omeprazole, diclofenac, fluconazole and ciprofloxacin). KEY FINDINGS: The trends in oral bioavailability pre to post surgery were found to be dependent on a combination of drug parameters, including solubility, permeability and gastrointestinal metabolism as well as the surgical procedure carried out. CONCLUSIONS: In the absence of clinical studies, the ability to project the direction and the magnitude of changes in bioavailability of drug therapy, using evidence-based mechanistic pharmacokinetic in silico models would be of significant value in guiding prescribers to make the necessary adjustments to dosage regimens for an increasing population of patients who are undergoing bariatric surgery.

Selection of bioavailability markers for herbal extracts based on in silico descriptors and their correlation to in vitro permeability.

Bioavailability data for herbal supplements in humans is not readily available or is difficult to obtain, because of the complexity of the composition and the diversity of the constituents. Potency of an herbal extract is due to the synergistic interactions between several constituents. Thus, the use of in silico methods is an attractive alternative to predict the qualitative intestinal permeability of the active constituents for the selection of appropriate bioavailability markers. Molecular descriptors such as CLogP, minimal cross-sectional area and polar surface area of 37 active components from selected herbal extracts such as milk thistle, kava, ginkgo, ginseng, valerian, black cohosh and garlic were estimated. In vitro permeability of the compounds was determined by SimBioDAS an in vitro epithelial cell permeability assay. Based on the in silico descriptors and their relationship with the in vitro permeability, the qualitative intestinal permeability of the active compounds was predicted. Bioavailability and bioequivalence markers were predicted for kava, Ginkgo biloba and milk thistle. Choosing a compound which has the least intestinal permeability as a marker is the most conservative approach toward ensuring the bioavailability of the entire extract.