Using Pharmacokinetics (PK) as a Tool During the Evaluation of Target Animal Safety (TAS)

Transcription

1 Using Pharmacokinetics (PK) as a Tool During the Evaluation of Target Animal Safety (TAS) Marilyn N. Martinez, Ph.D. Senior Research Scientist CVM-FDA Traditional paradigm for the target animal safety (margin of safety study): administer the dose and observe the response INPUT? EFFECTS What is the MARGIN OF SAFETY? By combining what is know about drug absorption, metabolism, distribution and elimination (ADME) from the non-pivotal information in the pharm/tox package, we can formulate appropriate risk questions to greatly improve our ability to design studies. 1

2 Time (hrs) And by taking samples during the pivotal TAS study we can greatly improve our ability to interpret study outcomes INPUT Opening the black box Prior Information + TAS PK DATA Data Interpretation Concentration (mcg/ml) We can now better define the MARGIN OF SAFETY EXAMPLES! Designing the Margin of Safety Our proposed product releases drug over a very long duration of time. It will be extremely difficult to do a chronic study at 3X duration. What should we do? Using prior PK data, a compressed study design can be developed that insures that the product safety will be adequately addressed and that the study can be designed to cover the duration of time needed to assess product safety. 2

3 Designing the Margin of Safety When should I monitor for effects? PK data will allow sponsors to correlate time after dosing to peak exposure, which can provide the information needed to determine if peak exposure is responsible for an acute adverse event. This will help guide the timing of clinical observations during the field study. Prior PK data will support protocol development with regard to the duration after dosing during which drug remains in the system and potentially influencing safety. Prior PK data is particularly important in protocol development when the formulation is an extended release product with multiphasic absorption characteristics. Designing the Margin of Safety The drug is orally administered to dogs or cats. Should the study be conducted under fed or fasted conditions? Prior information on food effects will enable drug sponsors to predict if prandial state influences the magnitude of drug exposure. If it does, the assessment can be made with regard to whether differences in systemic exposure (versus potential local gastrointestinal effects) warrants that the study be conducted under a specific prandial state (i.e., in fed versus fasted animals). Interpreting the Margin of Safety At 1x, 3x and 5x doses, no adverse events were observed. Since no animal will be given a 5X dose, this drug is very safe and there is a 5X margin of safety The data may confirm that there is doseproportional exposure and therefore that the drug is safe. OR The data may show that although exaggerated doses were given, far less than dose proportional increases were observed. In this case, the data may not adequately confirm that higher exposure (e.g., due to compromised elimination in diseased animals) will not lead to adverse effects. 3

4 Interpreting the Margin of Safety Several animals that vomited. What do I do now? Blood levels may confirm that there was negligible impact of the vomiting events on drug exposure. Therefore, all animals can be included in the analysis. OR The vomiting events were confirmed to reduce systemic drug exposure and therefore the animal(s) in question do not reflect concentrations of other animals in the dosing group. Interpreting the Margin of Safety Event occurs after repeated administration, but only in the higher dosing groups. Does this mean that the drug is unsafe? PK data may show that a greater than dose proportional accumulation occurred over time. This observation may limit the clinical relevance of the findings and help to establish drug safety. OR The data may suggest that the delay is attributable a physiological lag time associated with the adverse effect. This potential outcome would be evaluated during the field study and a determination made if we can label for it (e.g., monitoring by vet during use). OR The delay may reflect drug accumulation occurring over time, and therefore the possibility of similar adverse events during clinical use. Interpreting the Margin of Safety There were several animals that had some unexpected effects, even in the control group? What happened? How does that affect study interpretation? Drug contamination can occur from a variety of sources including aerosolized drug, licking, consumption of feces, etc. When this occurs, the distinction between dosing group and drug exposure can be blurred. Having PK data allows for an a determination as to whether or not contamination is likely to have occurred and if we can still interpret the data from the perspective of exposure-response relationships. 4

5 Hypothetical Examples: How might we use TAS PK data to help us interpret the results of a TAS study? Examples: Use of PK to help interpret the Adverse Effects (AEs) observed during the TAS study Two AEs were seen in the 5X dose group. Those subjects had higher blood levels than did the other subjects. Dose proportionality was observed. Assessments of this outcome should be based upon the severity of the AEs and the potential sources of variation in drug clearance (CL) to ascertain the likelihood of highly variable parent drug exposure in the general population. Examples: Use of PK to help interpret the AEs observed during the TAS study One AE was seen in the 5X dose group. That subject had lower drug concentrations than the other subjects in the 5X or 3X group. It also had concentrations lower than one of the 1X dose group subjects Reaction could be idiosyncratic. Or It might be unrelated to drug. Reaction could reflect toxic effect of a metabolite. Reaction, if at the injection site or in the gut, may reflect exaggerated local exposure unlikely to occur under field conditions. Or it could reflect host response to an implant or to an excipient. Assessments of this outcome should be based other information on the drug/product. 5

6 Examples: Use of PK to help interpret the AEs observed during the TAS study Adverse events were seen in one subject in the 3X group and one in the 5X dose group. However, animals with adverse events were not the subjects with the highest parent drug exposure. This could reflect either an inability to ascribe a predictable concentration-effect relationship across a population (i.e., the AE is a function of animal sensitivity). Or, it might reflect the presence of a toxic metabolite whereby those animals most efficient at generating that metabolite had the greatest likelihood for the AE. Or a reaction to the formulation. Or it might not be a drug related reaction. Is there anything in the literature about this (or a related) compound that might be useful in our interpretation? Examples: Use of PK to help interpret the AEs observed during the TAS study Adverse events were seen only in the 5X dose group. However, dose proportionality was not observed and much overlap was seen across the individual subjects and doses Furthermore, animals with AEs were not necessarily the subjects with the highest drug exposure. This suggests that there may be animals in the 1X dose group that may be at risk of experiencing the observed AE. Or it could indicate that adverse effects in 5X group may be associated with a nondrug related effect (e.g., reaction to an excipient). Examples: Use of PK to help interpret the AEs observed during the TAS study Adverse events were seen only in the 3X dose group, but the subjects experiencing the AE also had the highest systemic drug concentrations. This suggests that there is likely to be substantial variations in drug exposure under field conditions and that there is a risk of the observed AE occurring after a 1X dose. Or it could reflect a compromised Cl after chronic use due to drug toxicity (i.e., elevated concentrations are a consequence rather than a cause of the toxicity). 6

7 Examples: Use of PK to help interpret the AEs observed during the TAS study Adverse events were seen only in the 3X dose group. Subjects experiencing the AE were not the ones with the highest systemic drug concentrations, and it is highly likely that animals will have comparable drug exposure at a 1X dose under field conditions. Could the exposure-ae relationship be parabolic,rather than linear, in nature (i.e., AE decreases with dose due to feedback loops)? Based upon these results, we need to consider the possibility that the AE may not be readily correlated with a specific drug exposure but rather reflect the sensitivity of the individual subject to the drug (i.e., a within-subject exposure-response relationship). PK data is invaluable for evaluating changes in ADME during chronic dosing Concentration Concentration Concentrations after Dose 1 Time Samples taken after several months of drug administration Time 1X 3X 1X 3X In this example, the 1X and 3X profiles (after the first dose) are well distributed about the average, and drug concentrations after the 3X dose is 3-fold higher than that seen with a 1X dose. However, with chronic dosing, the predicted steady state profiles are markedly lower than the observed concentrations for the 1X and 3X groups. This could indicate enzyme inhibition (e.g., decreased first pass metabolism), or liver or kidney damage. We would need to explore changes in CL, Vd, etc. to better understand what occurred and its potential safety implications. Within the constraints of the size limits associated with the TAS study, PK assessments are invaluable for helping sponsors identify population safety factors This information can be incorporated into product labels that help the veterinarians use the product in a safe and effective manner. 7

8 Expanding the Population Inferrential Value of the TAS Study Data Does the subject represent the patient population? Yes No Influence of age (e.g., geriatric) Disease PK data from Studies in dossier Sources of ADME variability in a normal animal population Information from literature from target animal or other species (including human) Co-morbidity (e.g., renal failure, anorexia) Concomitant meds Influence on ADME and Drug Sensitivity POPULATION PREDICTION Summary PK can be used: To help formulate risk-based questions To support TAS study protocol development To facilitate the interpretation of the TAS study data To help generate population predictions from these data To support the development of label instructions that promote safe and effective drug use To support the interpretation of post-marketing adverse event reports Questions? Contact Information: Marilyn N. Martinez, Ph.D. Senior Research Scientist US FDA/CVM/ONADE/HFV-130 Phone #: marilyn.martinez@fda.hhs.gov 8