How to set an health based exposure limit / Permitted Daily Exposure (PDE) for veterinary medicinal products

1. Establishing a Permitted Daily Exposure
for Veterinary Medicinal Products
3D-PharmXchange
19-Nov-2015

2. PDE
Veterinary Medicinal Products
EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012)
Current: Cleaning is a risk-reducing measure and carry-over limits for cleaning
validation studies are widely used in the pharmaceutical industry. A variety of
approaches are taken in order to establish these limits and often do not take
account of the available pharmacological and toxicological data.
New approach: Review and evaluation of pharmacological and toxicological data of
individual active pharmaceutical ingredients (API) enables determination of
science-based threshold levels

3. Product A
Subject: Unintended patient/person, target animal
PDE: Permitted Daily Exposure
“a dose that is unlikely to cause an adverse effect if an individual is exposed, by any
route, at or below this dose every day over a lifetime”
PDE
Veterinary Medicinal Products

4. Product A Product B
Cross-contamination
Drug product
Risk
- Target animals
- Patient population
- Consumers of food producing
animals
à To be implemented for all medicinal products in shared manufacturing facilities*
PDE
(permitted daily exposure)
Shared Facility Guideline
Medicinal products provide a benefit to the intended patient or target animal, however
as a cross contaminant, they provide no benefit to the patient or target animal and may
even pose a risk
* Often excluding therapeutic macromolecules and peptides
RiskAssessment
PDE
Veterinary Medicinal Products

5. Dose/day
PDE = ------------------------------ = XXX mg/kg/day
F1 * F2 * F3 * F4 * F5
PDE (permitted daily exposures)Veterinary PDE
Ø It is possible to use the PDE approach to
establish different limits for different target
species, however, due to the impracticability
of it and considering a pragmatic approach,
PDEs should be derived assuming human
exposure.
Ø In case of food producing animals, neither
the target animal nor the consumer should
be exposed to residual active substance
levels exceeding the PDE
PDE
Veterinary Medicinal Products

6. F is 1 – 12 (ICH Q3C)
F1 = A factor to account for extrapolation between species
• Factor 1 – 12, based on body surface conversion
• Not all species assessed
F2 = A factor of 10 to account for variability between individuals
• Option to use 15 for sensitive patient subpopulations
F3 = A variable factor to account for toxicity studies of short-term
exposure
• Factor 1, 2, 5, 10
• Life-long (rodent/non-rodent) versus study duration: acute,
chronic, organogenesis (reprotoxicity)
F4 = A factor that may be applied in cases of severe toxicity
• Factor 1, 5, 10
• Potential subjective assessment of ‘severe’ in studies other
than those described in the guideline (i.e. reprotoxicity)
F5 = A variable factor that may be applied if the no-observed-effect-
level ‘NOEL’ was not established
• Factor 1-10
• E.g. NOEL(1)/NOAEL(1-5), LOEL(5-10)/LOAEL(10)
PDE: F factoren
Dose/day
PDE = ------------------------------ = XXX mg/kg/day
F1 * F2 * F3 * F4 * F5
PDE (permitted daily exposures)
PDE
Veterinary Medicinal Products

7. Non-clinical
Safety pharmacology, Repeated dose toxicity,
Genotoxicity, Carcinogenicity, Reprotoxicity
Sensitization
Clinical
Pharmacological effects
Dosing regimen
Adverse Events - severity / incidence
Critical effects / PDE selection
Information necessary
PDE: documenten
Dose/day
PDE = ------------------------------ = XXX mg/kg/day
F1 * F2 * F3 * F4 * F5
PDE (permitted daily exposures)
PDE
Veterinary Medicinal Products

8. Non-clinical
Safety pharmacology, Repeated dose toxicity,
Genotoxicity, Carcinogenicity, Reprotoxicity
Sensitization
Clinical
Pharmacological effects
Dosing regimen
Adverse Events - severity / incidence
Critical effects / PDE selection
• Which data?
o Internal/external public literature
o US product label/EU SPC
o Use of old (non-GLP) data?
“The conservative approach in the EU may reflect the central
position of the SPC in risk management of new pharmaceuticals.
A typical feature of the US PI was the detailed description of the
efficacy and safety result of the pivotal clinical trials”
Nieminen et al, 2005
Information necessary
PDE
Veterinary Medicinal Products

9. Non-clinical
Safety pharmacology, Repeated dose toxicity,
Genotoxicity, Carcinogenicity, Reprotoxicity
Sensitization
Clinical
Pharmacological effects
Dosing regimen
Adverse Events - severity / incidence
Critical effects / PDE selection
o Which (repeated dose) studies to include?
o Are the non-clinical findings biologically relevant? How do
you assess significance of non-clinical versus clinical
findings?
o Threshold of toxicological concern (TTC): 1.5 μg/day for
substances which pose a chemical risk for potential
genotoxicity
Note:
à Staged TTC (less than lifetime (LLT)) is possible depending
on dosing frequency/duration
à For veterinary medicines the TTC can be indicated per kg
weight (e.g. for a 50 kg animal the TTC of 1.5 μg/day would
be 0.03 μg/kg/day)
PDE: documenten
Information necessary
PDE
Veterinary Medicinal Products

10. Non-clinical
Safety pharmacology, Repeated dose toxicity,
Genotoxicity, Carcinogenicity, Reprotoxicity
Sensitization
Clinical
Pharmacological effects
Dosing regimen
Adverse Events - severity / incidence
Critical effects / PDE selection
o How do you determine the lowest dose?
Ø Difference in dose/kg or per dose/patient
Ø E.g. surface area for dermal application (FTU-finger
tip unit)
o Multiple dosing regimens and routes of exposure possible
for one drug
Ø Consider accumulation
Ø Extrapolation: dermal/oral/inhalation/parenteral
(bioavailability % / assumed absorption [100%]) x PDE
PDE: documenten
Information necessary
PDE
Veterinary Medicinal Products

11. Non-clinical
Safety pharmacology, Repeated dose toxicity,
Genotoxicity, Carcinogenicity, Reprotoxicity
Sensitization
Clinical
Pharmacological effects
Dosing regimen
Adverse Events - severity / incidence
Critical effects / PDE selection
o Target population (unintended exposure patient)
o Sensitive human subpopulations:
Ø Liver/kidney failure
Ø Pediatrics/Geriatrics
Ø Sex (hormones)
o Selection of critical effect
Ø Serious Adverse Event (consider incidence)
Ø ‘Common’ Adverse Event : target organ system (e.g.
gastrointestinal tract, CNS etc.)
Information necessary
PDE
Veterinary Medicinal Products

12. Non-clinical
Safety pharmacology, Repeated dose toxicity,
Genotoxicity, Carcinogenicity, Reprotoxicity
Sensitization
Clinical
Pharmacological effects
Dosing regimen
Adverse Events - severity / incidence
Critical effects / PDE selection
o Report all pivotal human and animal critical effects
o Include justification for F factors
o Select
Ø the lowest/most conservative PDE
Ø or the most appropriate, i.e. most sensitive (and
relevant) indicator of an adverse effect
Information necessary
PDE
Veterinary Medicinal Products

13. Dose/day
PDE = ------------------------------ = XXX mg/kg/day
F1 * F2 * F3 * F4 * F5
PDE (permitted daily exposures)
Lowest dose
Species extrapolation Intraspecies correction
(sensitive subpopulation)
Completeness data
(duration/type of study)
TTC
Accumulation
Reprotox
SAE/common AE
Incidence
NO(A)EL/LO(A)EL
+ bioavailability
extrapolation
PDE: samenvattend
PDE
Veterinary Medicinal Products