1 argentina 17 phamacology of megavertibrates.ppt -...

Pharmacology in Zoo Animals

ISAZA, 2017 1


Ramiro Isaza, DVM, MS, MPH, DACZM, DECZM

Professor, Zoological MedicineCollege of Veterinary Medicine

University Florida

Introduction

� How do I pick a dose ?

Introduction

� Animal Groups in Zoological Medicine

– Pets

Introduction


– Free living wildlife

Introduction


– Captive wildlife

Introduction

�Why I became interested

in this subject …

– Clinical need for drug doses


ISAZA, 2017 2

LECTURE OUTLINE

� Selecting a drug

�Metabolic scaling

� Basic pharmacology

Selecting Drugs for Use in Zoological Medicine

� Formularies

– Anecdotal

– Empirical

– Pharmacokinetic

Short Cut … Lack of Scientific Data

� Limited number of published studies in non-domestic species

� No “approved” drugs

� First usage of a drug in a new species

� “Follow the leader”

Selecting a Dose Choosing a Drug

� Efficacy


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Choosing a Drug

� Efficacy

� Route

� Toxicity

� Cost

Principles of Zoological Pharmacology

� “One Medicine”

Principles of Zoological Pharmacology

� One Medicine = One Pharmacology?

Dog dose = Elephant dose

7 mg/kg 7 mg/kg

METABOLIC SCALING

METABOLIC SCALING Central Concept


ISAZA, 2017 4

Biological Parameters

� Water intake 105 (Kg) 0.88

� Urine output 44 (Kg) 0.82

� Kidney weight 0.0212 (Kg) 0.85

� Liver weight 0.082 (Kg) 0.87

� Creatinine clearance 4.2 (Kg) 0.82

Physiological Rates

� Heart beat duration 1.19 (Kg) 0.27

� Breath duration 4.7 (Kg) 0.28

� Glucose turnover 0.179 (Kg) 0.25

� Mammal life span 11.8 (Kg) 0.20

Basic allometric formula: k(W)x

W = weight in kilograms

x = 0.75

k = Species specific constant

70 for placental mammals

49 for marsupials

78 for non-passerine birds

129 for passerine birds

10 for reptiles

Metabolism vs Body Size Metabolic Scaling

Metabolic Scaling in the Real World

� Accepted in oncology � Used in anesthesiology

Metabolic Scaling in the Real World


ISAZA, 2017 5

DRUG DOSE EXTRAPOLATIONS

� Used in pharmaceutical industry

Example Dose Extrapolation

� Dog dose for Cefazolin

is 10 mg/kg

�What is the mouse dose?

Calculations

� 70 (20 0.75 ) = 662 Kcal for the dog

� 70 (0.02 0.75) = 3.7 Kcal for the mouse

� 200 mg/662 x 3.7 = 1.12 mg

� So..The scaled dose for the mouse is

1.12 mg/0.02 kg = 55.9 mg/kg

All extrapolations are guesses

Drug Dose Extrapolations

One Medicine = One Pharmacology ?

� Many drugs do not scale well

� Extrapolation of doses can cause problems

Problems with Metabolic Scaling


ISAZA, 2017 6

Problems with Drug Extrapolations

Interspecies Differences


Toxic effects of drugs


Neonatal metabolism


Bottom-line

� Scaled drug dosages are guesses

� Often very inaccurate

� Use with extreme caution

However…….

Metabolically scaled drug dosages may represent the best estimate when the true dose is unknown.

E-Mail Case


ISAZA, 2017 7

Example Case Example Case

Elephant dose = 0.6 mg/Kg

My Opinion Pharmacokinetic Studies

WHY RUN A PK STUDY?

� I want to determine a “proper dose”

� I want to publish a study

What Type of Study ?

� Pharmaceutics

� Pharmacodynamics

� Pharmacokinetics

� (Toxicology)

� Implants

� Transdermal delivery systems

� Portable/implantable pumps

Pharmaceutics

“New Dosage Forms”


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Pharmacodynamics

� Anthelminticstudies

� Anesthesia studies

� Case reports using drugs

“What the drug does to the body”

Pharmacokinetics

“What the body does to the drug over time”

Pharmacokinetic Parameters

� Models and parameters that are designed to estimate clinically useful information from data that describes drug concentration over time.

T ½CmaxVdAUC

Parmacokinetic Basics

ADME

� Absorption

� Distribution

� Metabolism

� Excretion

ADME

� Absorption – movement of drug into general/systemic circulation


ISAZA, 2017 9

ADME

� Absorption

� Distribution – reversible movement from blood to tissues (establishment of a equilibrium)

ADME

� Absorption

� Distribution

� Metabolism – chemical conversion/change of drug to inactive and/or active compounds

Metabolism

� The goal of metabolism is to make a drug MORE polar/H2O soluble

MetabolismSpecies Differences

ADME

� Absorption

� Distribution

� Metabolism

� Excretion – elimination of drug from body via renal, biliary, pulmonary, and/or dermal processes

� Urine

� Bile

� Feces

� Sweat

� Saliva

� Milk

� Expired Air

Excretion


ISAZA, 2017 10

“What the body does to the drug over time”

Pharmacokinetics

� Uses ADME to predict a dose T ½

CmaxVdAUC

� How do I pick a dose for a megavertebrate?– Run a pharmacokinetic study…

Practical Considerations


� Starting the Study

– Preliminary questions

� Is it needed?

� Is it available?

� Is the drug safe?

�Will it be effective?


� Starting the Study

– Design of the study

� Consult

– Pharmacologist

– Statistician

– Animal management

– IACUC


� Formulations and Drug Availability



� Number of Available Animals


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� Animal Related Challenges





– Dosing the Animals





– Dosing the Animals

– Sample Collection





� Analytical Issues

Example Study FAMCICLOVIR PHARMACOKINETICS IN YOUNG ASIAN ELEPHANTS

Ramiro Isaza

Robert P. Hunter

Laura K. Richman

Richard J. Montali

Dennis L. Schmitt

David E. Koch

William A. Lindsay


ISAZA, 2017 12

Famciclovir

� Elephant Endotheliotropic Herpesvirus (EEHV)

Region Abortus Neonate ≤ 10 yrs old > 10 yrs old Survivors

North America 0 0 16 3 2/19

Europe 2 1 6 2 1/11

Asia 0 0 2 0 0

Montali - 2003

Famciclovir

� All “young” Asian Elephants are at risk!

Famciclovir

� Human Dose = 7 mg/kg PO every 8 hours

� Empirical elephant dose of 5 – 8 mg/kg PO Q8hr

� Unknown juvenile elephant pharmacokinetics

Purpose of the study

� Determine PK of Famciclovir

� Compare PK of Oral vs. Rectal

� Recommend a clinically relevant elephant dosage

� Asian Elephants less than 10 years old

� Three treatment groups consisting of 4 elephants in each group (5 mg/kg PO, 5 mg/kg Rectal, 15 mg/kg Rectal)

� Serial blood samples at: 0, 0.17, 0.33, 0.67, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, & 24 hrs

� Analysis for both famciclovir and penciclovir using

validated LC / MS methods

Methods


ISAZA, 2017 13

Penciclovir Pharmacokinetics

� Rapid absorption by all routes tested

(RO > PO)

� T1/2 about 2 hours

� Recommended dose 8-15 mg/kg every

8 hours

Conclusions

� What is interesting about zoological pharmacology?

Conclusions


– “Practical science”

Conclusions



– New applications for existing drugs

Conclusions



– New applications for existing drugs

– Determines new drug dosages

Questions ?

1 argentina 17 phamacology of megavertibrates.ppt -...

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