Population variability in animal health: Influence on dose‐exposure‐response relationships: Part <scp>II</scp>: Modelling and simulation

Martinez, Marilyn N.; Gehring, Ronette; Mochel, Jonathan P.; Pade, D; Pelligand, Ludovic

doi:10.1111/jvp.12666

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…Body weight, sex, and the rate of drug metabolism are intrinsic physiological factors that can contribute to interindividual variability in the pharmacokinetic disposition of a drug (Martinez, Court, Fink‐Gremmels, & Mealey, ; Martinez, Gehring, Mochel, Pade, & Pelligand, ). Based on our data, weight does not appear to be a significant cause of variation in CAM‐D plasma concentrations in cats.…”

Section: Discussionmentioning

confidence: 99%

High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

Lee

Faus

Court

2018

Vet Pharm & Therapeutics

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Clopidogrel response variability has been identified in cats. In humans, evidence suggests that variable clopidogrel active metabolite (CAM) generation is the primary explanation for clopidogrel response variability with differences in body weight, sex, and variable metabolism of clopidogrel primarily due to polymorphisms of the gene encoding cytochrome P450 (CYP) 2C19 as some proposed mechanisms. The aim of this study was to evaluate whether variation in CAM concentrations exists in healthy cats and what the cause of such variation might be. Nineteen healthy cats were given 18.75 mg clopidogrel by mouth. Blood was collected 2 hr later. Plasma CAM concentrations were measured using high performance liquid chromatography and tandem mass spectrometry. Clopidogrel metabolism was estimated by calculating CAM metabolic ratio. DNA was collected, and feline CYP2C genotyping was performed. The cats demonstrated high interindividual variation of plasma CAM concentrations.Approximately 69% of this interindividual variation was primarily explained by differences in clopidogrel metabolism as measured by CAM metabolic ratio with some influence by sex but not by weight. A single nucleotide polymorphism was identified in the feline CYP2C gene that explained in part individual differences in CAM metabolic ratio and CAM plasma concentrations. K E Y W O R D S antiplatelet, antithrombotic, Plavix, thienopyridine, thromboprophylaxis | 17 LEE Et aL. response in cats is currently unknown. The aim of this study was to evaluate whether variations in CAM concentrations exist in healthy cats given the clinically used dose of 18.75 mg clopidogrel per os andwhat the cause of such variation might be. We hypothesized that interindividual variability in CAM plasma concentrations would be present and that this variability would be influenced by variability in cat weight, sex, metabolism, and/or CYP2C genetic polymorphisms. | MATERIAL S AND ME THODS | Animal inclusion criteriaEligible client-owned cats were required to be apparently healthy, between 2 and 8 years of age, and >3.4 kg in weight. Written informed owner consent was obtained prior to participation in the study. Apparent health was determined based on history, a normal physical examination, and normal laboratory values including complete blood count, serum biochemistry panel, urinalysis, negative feline leukemia virus and feline immunodeficiency virus testing, and a normal echocardiogram. All blood work and urinalyses were performed by the Washington State University Clinical Pathology Laboratory.All echocardiograms were performed by a single investigator (PML).Conventional 2D, M-mode, and Doppler examinations were performed using an echocardiographic system and transducers ranging from 4 to 10 MHz. This study was approved by the Washington State University Institutional Animal Care and Use Committee.

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Section: Discussionmentioning

confidence: 99%

High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

Lee

Faus

Court

2018

Vet Pharm & Therapeutics

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“…However, due to very limited drug depletion studies for penicillin G in heavy sows available and the high variabilities among the available data sets, the model still needs be improved with additional studies to better predict the tissue concentrations and WDIs. The variabilities from different sources should be considered, and more mechanistic studies should be carried out to help better understand the differences among species and breeds (Martinez, Court, Fink‐Gremmels, & Mealey, ; Martinez, Gehring, Mochel, Pade, & Pelligand, ). As the depletion studies were carried out by different labs and with different commercial brands of PPG, the experimental and random variances may be larger than the physiological variability considered in the population PBPK model.…”

Section: Discussionmentioning

confidence: 99%

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

Mainquist-Whigham

Karriker

et al. 2019

Vet Pharm & Therapeutics

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Penicillin G is widely used in food‐producing animals at extralabel doses and is one of the most frequently identified violative drug residues in animal‐derived food products. In this study, the plasma pharmacokinetics and tissue residue depletion of penicillin G in heavy sows after repeated intramuscular administrations at label (6.5 mg/kg) and 5 × label (32.5 mg/kg) doses were determined. Plasma, urine, and environmental samples were tested as potential antemortem markers for penicillin G residues. The collected new data and other available data from the literature were used to develop a population physiologically based pharmacokinetic (PBPK) model for penicillin G in heavy sows. The results showed that antemortem testing of urine provided potential correlation with tissue residue levels. Based on the United States Department of Agriculture Food Safety and Inspection Service action limit of 25 ng/g, the model estimated a withdrawal interval of 38 days for penicillin G in heavy sows after 3 repeated intramuscular injections at 5 × label dose. This study improves our understanding of penicillin G pharmacokinetics and tissue residue depletion in heavy sows and provides a tool to predict proper withdrawal intervals after extralabel use of penicillin G in heavy sows, thereby helping safety assessment of sow‐derived meat products.

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“…129 Other sources of variability A large number of pharmaceutical, physiological, pathological and pharmacological factors have been described as having an impact on the PK and clinical outcomes of antimicrobial use, particularly in mammals. [130][131][132][133] However, there are a growing number of examples of factors influencing PK and clinical outcome in poultry, with representative examples presented below. It should be recognised that most of the examples on sources of PK variation have been reported in studies of antimicrobial agents not registered for use in birds in Australia (all registered antimicrobial agents are set out in Appendix 2).…”

Section: Water Sanitisersmentioning

confidence: 99%

Antimicrobial prescribing guidelines for poultry

Gray¹,

Jenner²,

Norris³

et al. 2021

Aust Veterinary J

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Forewordantimicrobial prescribing guidelines for poultry Antimicrobials are essential to modern medicine for treating a range of infections in humans and animals. Importantly, antimicrobial resistance (AMR) is a growing global threat that presents a serious risk to human and animal health. Inappropriate and/or unrestrained use of antimicrobials in humans and animals exerts a strong selection pressure on microbial populations to evolve resistant traits. As a result, antimicrobials have become less effective over time leading to treatment complications and failures, and increased healthcare costs for people and animals. Resistant organisms spread between people, animals and the environment. Globalisation and international travel facilitates this spread between countries.Here in Australia, the veterinary profession and food-producing animal industries have a long history of addressing AMR. Their previous and ongoing worka result of partnerships across the animal sectorhas resulted in demonstrated low levels of AMR in our food-producing animals. Over the past 5 years, the veterinary profession has consolidated its partnership with industry and government by helping to successfully implement Australia's First National Antimicrobial Resistance Strategy 2015-19. With the recent release of Australia's National Antimicrobial Resistance Strategy -2020 and Beyond (2020 AMR Strategy), the veterinary profession will continue to play a critical role in how we minimise AMR.One of the seven key objectives of the 2020 AMR Strategy relates to appropriate antimicrobial usage and antimicrobial stewardship practices. Resistance to antimicrobials occurs naturally in microorganisms, but it is significantly amplified by antimicrobial overuse, growth promotion use, and poor husbandry and management.The antimicrobial prescribing guidelines for poultry directly addresses the fourth objective of the 2020 AMR Strategy, and in particular, Priority Area for Action 4.1, that seeks to 'ensure that coordinated, evidence-based antimicrobial prescribing guidelines and best-practice supports are developed and made easily available, and encourage their use by prescribers'. These guidelines for Australian poultry veterinarians are sure to be a ready resource. They have been developed specifically for the Australian poultry industry and contain best-practice prescribing information to help clinical veterinarians in their day-to-day use of antimicrobials. The guidelines encourage veterinarians to first pause and consider the need to use antimicrobials in that circumstance: Are there effective non-antimicrobial alternatives? Prevention and control of infections through strict on-farm biosecurity is a recognised approach to minimising disease entry and the need to use antimicrobials. Vaccination may also be available to control several important poultry diseases. If antimicrobial use is indicated, have you considered the five rights: right drug, right time, right dose, right duration and right route? Using a lower rating or narrow-spectrum antimicrobial i...

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

Cited by 10 publications

References 40 publications

High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

Antimicrobial prescribing guidelines for poultry

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