Validation Studies for Modification of Sequencing Guidelines
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The Animal Feed Division has recently made updates to the Medicated Sequencing Guide. The Drug Ranking Model (Model) served as the basis for these changes and will be the basis for additional changes in the future. Manufacturing facilities must follow the Canadian Food Inspection Agency (CFIA) Medicated Sequencing Guide to be considered in regulatory compliance. Changes to the guide may be requested by facilities but to allow for evaluation and decision-making, those requests must provide all the data necessary to populate the Model. The purpose of this document is to identify the data that would be necessary. (For a brief synopsis of the Model please see Appendix 1).
The facility requesting changes must provide pharmacokinetic parameters of oral bioavailability and terminal half-life data sufficient to estimate the accumulation of drugs in edible tissues (meat) of livestock as well as information from feeding trials needed to evaluate transfer factors relating drug feed concentrations to residues in eggs and milk.
These terms are discussed below:
Oral Bioavailability (Meat)
Oral bioavailability is a measurement of the extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action following oral administration. This value takes into account incomplete absorption and first-pass metabolism of a drug. Classically, oral bioavailability is determined by comparing plasma exposure (i.e., Area Under the Curve) after intravenous and oral administration. If information for this value is not available, a default assumption of 100% was used in the development of the model. For a better understanding of bioavailability please refer to Toutain and Bousquet-Melou (2004a)
Terminal Half-Life (Meat)
In the case of the exposure model, the terminal half-life is the time required for one half the drug present at pseudo-equilibrium in edible tissues to be eliminated following oral administration. These data may be determined from appropriately conducted drug residue depletion studies with the drug by the oral route in the species of interest and measuring the depletion of the marker residue in edible tissues upon cessation of drug treatment and at appropriate intervals thereafter. The half-life of the drug in each tissue is then determined from the residue depletion data with the terminal half-life for the model being selected as that of the slowest depleting edible tissue. There is no default assumption for this portion of the model and as such the absence of this parameter for a drug - livestock species combination prevents the application of the model. For a better understanding of terminal half-life please refer to Toutain and Bousquet-Melou (2004b)
Transfer Factors (Eggs or Milk)
Transfer Factors for eggs and milk are obtained from the slope of the feed drug concentration versus egg or milk drug concentration curve from feeding trials that report these concentrations. Estimates of the concentration of residues of drugs in eggs and milk are then estimated in the Model by direct linear extrapolation. However, the continuum of animal husbandry needs to be recognized within the context of feed and food safety whereby laying hens and dairy cattle can become part of the human food chain when egg or milk production becomes questionable. That is to say, Transfer Factors for eggs or milk in the absence of terminal half-life parameter for laying hens or dairy cattle, respectively, can not be considered. For a better understanding of transfer factors please refer to Leeman et al. (2007).
Complete studies demonstrating these parameters and/or peer reviewed journal articles may be submitted to the Animal Feed Division (Attention David Johnson) to fill data gaps. It should be noted that a literature review has been conducted to identify available data from the public domain including peer reviewed literature, government documents (e.g., United States Food and Drug Administration (FDA) Centre of Veterinary Medicine (CVM) Freedom of Information (FOI) Summaries, information from the Joint World Health Organization/Food and Agriculture Ogranization (WHO/FAO) Expert Committee on Food Additives (JECFA), European Agency for the Evaluation of Medicinal Products (EMEA), European Food Safety Authority (EFSA), Food Standards Australia New Zealand (FSANZ), etc.) and CFIA will be working with the Canadian Animal Health Institute (CAHI) in order to attempt to fill data gaps. A list of literature that has been reviewed can be provided upon request.
Please also note that it is the CFIA Animal Feed Division's hope that in the future other Model parameters, specifically drug carryover rate and previous batch concentration, may be utilized directly by Feed Manufacturers when assessing their sequencing activities. Please see Appendix 1 which provides a brief synopsis of the Model including how all of the above mentioned parameters are used.
For additional information please contact David Johnson of the Animal Feed Division 613-221-4610.
- Leeman W.R., Van Den Berg K.J. and Houben G.F. (2007). "Transfer of chemicals from feed to animal products: The use of transfer factors in risk assessment."
- Food Additives and Contaminants 24(1): 1-13.
- Toutain P.L. and Bousquet-Melou A. (2004a). "Bioavailability and its assessment."
- Journal of Veterinary Pharmacology and Therapeutics 27(6): 455-66.
- Toutain P.L. and Bousquet-Melou A. (2004b). "Plasma terminal half-life."
- Journal of Veterinary Pharmacology and Therapeutics 27(6): 427-39.
Drug Ranking Model
The Drug Ranking Model uses a science-based approach for estimating potential human exposure to drugs through consumption of edible products of livestock exposed to from carryover residues of drugs in feeds (Carryover Scenario) and comparing this exposure to approved use (Approved Use Scenario) exposure within the same model. Within the context of the model, an unacceptable risk is determined when estimated human drug exposure via carryover residues exceeds exposure via approved use.
The Drug Ranking Model
A brief synopsis of the Drug Ranking Model is provided. The Model can be broken into three discrete portions: 1.) Livestock Exposure, 2.) Drug Accumulation, and 3.) Human Exposure.
1) Livestock Exposure
Livestock exposure is estimated for Approved Use and Carryover Scenarios. The approved use scenario uses the maximum use rate in feeds for livestock as defined in the Compendium of Medicating Ingredient Brochures (CMIB). The carryover scenario assumes a conservative 20% carryover rate with a previous batch concentration of the highest approved use rate as per the CMIB into feeds. Feed intake for each scenario is fixed for a given species and class of livestock. It is also assumed that exposure to carryover occurs on a daily basis.
The outcome of Livestock Exposure portion of the model is a daily drug intake amount.
2) Drug Accumulation
For both Approved Use and Carryover Scenarios, the outcome of Drug Accumulation portion of the model is the amount of drug having accumulated in edible products as described for Meat and Eggs/Milk below.
In order for a drug to accumulate in tissues it needs to gain access to tissue where accumulation can occur. Oral bioavailability is the measurement of the extent of a therapeutically active drug that reaches the systemic circulation and is available to at the site of action (i.e., to accumulate) following oral administration. This measurement takes into account incomplete absorption and first-pass metabolism and is conservatively assumed to be 100% if no data are available.
Next, the amount of bioavailability drug will accumulate in an animal until dosing stops (i.e., withdrawal occurs) since the new dose is added to the unmetabolized or unexcreted portions remaining from previous exposures. The Drug Accumulation portion of the model assumes non-saturable first-order kinetics and a daily dosing interval. This results in the accumulation of the drug being directly proportional to the terminal half-life of the drug in the livestock species being considered.
For the Approved Use Scenario drugs with withdrawal times, a withdrawal factor was determined based on the mandatory withdrawal period and the terminal half-life of the drug in the livestock species being considered. No withdrawal interval is determined for the Carryover Scenario since the use is unintentional and no withdrawal time is applied.
For meat, accumulated drug residues are assumed to be distributed throughout the edible mass of the carcass.
Estimates of the concentration of residues of drugs in eggs and milk are determined from direct comparison of studies reporting the feed concentration of a drug and the resulting maximum resulting residue in either eggs or milk. This ratio (i.e., slope of the feed vs. egg or milk concentration curve) is then applied to estimate the concentration of drug residues in these edible products from drug concentrations in feeds used to determine livestock exposure for both Approved Use and Carryover scenarios.
3) Human Exposure
Human exposure from residues via meat, milk and eggs for the Approved Use and Carryover scenarios are determined by assuming human intake of drug residues from the consumption of 500 grams of meat or eggs and 1.5 litres of milk. The highest drug intake estimated from the Approved Use scenario, be it from meat, milk, or eggs, is then used to compare residue intake estimates from the Carryover scenario. An unacceptable risk is determined when estimated human drug exposure via carryover residues exceeds exposure via approved use.
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