Pharmacology in Zoo Animals
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Pharmacology in Zoo Animals
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
� Animal Groups in Zoological Medicine
– Free living wildlife
Introduction
� Animal Groups in Zoological Medicine
– Captive wildlife
Introduction
�Why I became interested
in this subject …
– Clinical need for drug doses
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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
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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
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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
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Problems with Drug Extrapolations
Interspecies Differences
Problems with Drug Extrapolations
Toxic effects of drugs
Problems with Drug Extrapolations
Neonatal metabolism
Problems with Drug Extrapolations
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
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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
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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
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“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
Practical Considerations
� Starting the Study
– Preliminary questions
� Is it needed?
� Is it available?
� Is the drug safe?
�Will it be effective?
Practical Considerations
� Starting the Study
– Design of the study
� Consult
– Pharmacologist
– Statistician
– Animal management
– IACUC
Practical Considerations
� Formulations and Drug Availability
Practical Considerations
� Formulations and Drug Availability
� Number of Available Animals
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Practical Considerations
� Formulations and Drug Availability
� Number of Available Animals
� Animal Related Challenges
Practical Considerations
� Formulations and Drug Availability
� Number of Available Animals
� Animal Related Challenges
– Dosing the Animals
Practical Considerations
� Formulations and Drug Availability
� Number of Available Animals
� Animal Related Challenges
– Dosing the Animals
– Sample Collection
Practical Considerations
� Formulations and Drug Availability
� Number of Available Animals
� Animal Related Challenges
� 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
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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
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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
� What is interesting about zoological pharmacology?
– “Practical science”
Conclusions
� What is interesting about zoological pharmacology?
– “Practical science”
– New applications for existing drugs
Conclusions
� What is interesting about zoological pharmacology?
– “Practical science”
– New applications for existing drugs
– Determines new drug dosages
Questions ?