Animal & Veterinary
APPLYING PHARMACOKINETICS IN VETERINARY PHARMACEUTICALS REGULATION
by Marilyn N. Martinez, Ph.D.
FDA Veterinarian Newsletter January/February 1998 Volume XIII, No I
Pharmacokinetics is the study and characterization of the time course of drug concentrations within the body. These concentrations are a function of drug absorption, distribution, metabolism, and excretion (ADME). In turn, each of these variables is a function of a drug's physico-chemical properties and patient physiology. Thus, pharmacokinetics is a science that integrates mathematics, biochemistry, physiology, and pharmacology.
Clinical pharmacokinetics deals with the application of pharmacokinetic principles to the safe and effective therapeutic management of patients. It examines the relationship between pharmacokinetic processes and the intensity and time course of a clinical response. With the advent of clinical pharmacokinetics, practitioners have acquired a tool for individualizing dosage regimens to accommodate interpatient variability in dose/systemic drug concentration/drug response. For an excellent review on this subject, readers may consult an article by Peck, et al., in Pharm. Res., 1992;9:826-833.
Within the Center for Veterinary Medicine (CVM), pharmacokinetic study data have been submitted to meet a broad range of objectives. These include:
- Support of applications for new chemical entities or chemical entities in a new animal species: These studies tend to provide information on volume of distribution, drug clearance, extent of drug bioavailability, and estimates of the terminal elimination half life. Elimination half life can be used to predict the magnitude of drug accumulation with multiple dosing, the time needed to reach steady state, and the time needed to reduce blood concentrations to some target concentration. These studies may also include information on the predictability of drug concentrations across a wide range of dosages (that is, the demonstration of linear pharmacokinetics). It may also examine the relationship between dose, the drug concentration/time profile, and a therapeutic (pharmacodynamic) variable.
- Supplemental applications for new indications or expansion of label claims: These applications are generally considered from a perspective of relative bioavailability. Relative bioavailability investigations are used to compare the blood concentration/time profiles generated by a "test" versus a "reference" treatment. In relative bioavailability (bridging) studies, the sponsor is the holder of the NADA and therefore has right of access to the clinical safety and efficacy information. Therefore, the approval criteria can be based upon information within the NADA.
- Dose selection for clinical confirmation trials: For some compounds (for example, fluoroquinolones and beta lactams), the correlation between drug concentration and efficacy (the pharmacokinetic/pharmacodynamic relationship) has been well described (refer to: Antimicrobial Therapy in Veterinary Medicine, Prescott, J.F. and Baggot, J.D., eds., Iowa State University Press, 1993). Alternatively, some classes of compounds (for example, anti-inflammatory drugs and corticosteroids) have complex pharmacodynamic processes that may obscure existing kinetic/dynamic relationships. In other cases, serum concentrations may poorly reflect the tissue concentration of highly lipophilic compounds (for example, azilide and macrolide antibiotics).
- Expansion of an approved dose range: In this situation, the fundamental question is whether or not blood concentrations can be predicted on the basis of an administered dose. When this is not the case, the drug is considered to exhibit dose-dependent (nonlinear) pharmacokinetics. Nonlinear pharmacokinetics can occur as a result of saturable protein binding or dose-dependent absorption or elimination processes.
- To support applications for new drug combinations: These applications are generally considered from a perspective of relative bioavailability.
- To support applications for new salt forms, revised formulations or new routes of administration: These kinds of studies are traditionally reviewed from the perspective of relative bioavailability.
- To support the approval of generic new animal drug applications (ANADA's): Sponsors who submit an ANADA do not have right of access to the original safety and efficacy data. Therefore, strict approval criteria are used to confirm product comparability in terms of the rate and extent of drug absorption. CVM's 1996 Bioequivalence Guidance (which is available from the FDA Veterinarian) provides a detailed description of the criteria used when assessing the approvability of an ANADA.
For the most part, the fundamental study objectives of CVM pharmacokinetic studies parallel those encountered by the Agency's human drug counterpart. Accordingly, many of the tenets governing the evaluation of these pharmacokinetic studies are comparable across FDA Centers. However, the very nature of veterinary medical practice necessitates differences between the types of pharmacokinetic studies submitted in support of veterinary versus human drug applications. Some of the unique aspects of veterinary pharmacokinetic submissions include:
- Drug delivery for ruminant versus monogastric species. Extrapolation of oral drug bioavailability among monogastric species is complicated by potential differences in drug intestinal permeability, GI pH and the activity of intestinal mucosal and hepatic enzymes. Clearance may also vary due to interspecies differences in protein binding, drug metabolism and renal function. However, the complexities associated with interspecies extrapolations are significantly magnified when comparing the oral bioavailability of products across ruminants versus monogastric species. An administered dose can be greatly diluted by ruminal fluids and drug absorption impaired by its adsorption onto fermenting materials. Moreover, the pH variations and fluid movements across the rumen may cause further discrepancies in the rate and extent of drug absorption in ruminating versus monogastric species.
- The pharmacokinetics of drugs administered to poikilotherm species. Through these applications, CVM encounters several problems that are unique to veterinary medicine. Firstly, "inert'' ingredients included in the formulation of products for use in poultry or mammalian species may prove highly toxic to aquatic species. Secondly, from a pharmacokinetic perspective, not only can kinetics vary with water salinity and temperature, but also with the method of drug sampling (for example, cannulated fish versus free swimming fish). Furthermore, when assessing drug ADME in aquatic species, one must consider the possibility that the drug will partition from the fish into the surrounding fluids, yielding inappropriately large estimates of volume of distribution. Thus, a broad spectrum of issues and sources of potential data bias must be considered when analyzing drug pharmacokinetics in aquatic animals.
- The pharmacokinetic or bioequivalence assessments of drugs administered ad lib in food and water to groups of animals rather than to individual patients: Since we never know the exact dose and intake rate for the individual animal, bioavailability assessments must be based on animal blocks (pens). This becomes particularly complex when only one blood sample can be obtained per animal (e.g., studies in chicks and turkey poults). In addition, the dose regimen must allow for potentially poor food or water consumption in sick animals. Thus, as part of the drug review process, decisions must be made regarding the need for a loading dose (such as a 2X dose in the drinking water or intravenous drug administration).
- Human food safety. While human pharmacokinetic issues focus on drug concentrations within the therapeutic and toxic range, veterinary medicine must also attend to terminal drug concentrations that can affect human food safety. For some drugs, the use of a highly sensitive assay may reveal the presence of a deep, slowly depleting tissue compartment or a component of the administered dose that slowly trickles into the systemic circulation. While these latter issues are rarely of any clinical relevance, they may be critical to human food safety. When the relationship between blood and tissue drug concentrations are well understood, CVM may use pharmacokinetic data to determine if a new dosage regimen (or other supplemental application) requires the submission of additional human food safety information.
The incorporation of pharmacokinetic principles into the regulation and labeling of veterinary pharmaceuticals affords a tremendous improvement in animal health care. It can be used to guide the practitioner in choosing the most effective and economic dosage regimen. In this age of the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), pharmacokinetics allows CVM to develop alternative approaches to drug regulation and, through an understanding of the kinetics of dose-ranged products, enables CVM to provide practitioners with the guidance needed to assure a safe and abundant food supply.