Dosage Forms And Veterinary Feed Directives

Dosage Forms And Veterinary Feed Directives

Geof Smith and Jim E. Riviere

One of the primary differences between human and veterinary pharmacology is the wide range of dosage forms available to the veterinarian that occurs as a direct consequence of significant differences in the way drugs are administered to animals and humans. These differences are a consequence of obvious dissimilarity in anatomy and physiology, but also are a direct consequence of variations in behavior, husbandry practices, and inability to verbally communicate with animal versus human patients. In addition, some animals are raised for food production and thus drug delivery strategies that result in injection-site residues may not be acceptable solely due to possible human consumption of the delivery device or its residues. Different dosage forms are employed for four main reasons: ease of administration and thus compliance, controlled rate of drug delivery, ability to minimize meat or milk withholding times, and husbandry constraints in treating populations of animals in a production environment. The focus of this chapter is to introduce the reader to the wide variety of dosage forms encountered in veterinary medicine. Specifics on most of these formulations can be found in the individual therapeutic chapters or the introductory chapters on pharmacokinetics and drug absorption, distribution, metabolism, and excretion.

Pharmacokinetic Considerations and Controlled-Drug Delivery

By far, the dosage form has the greatest influence on the rate and extent of absorption of drugs. The physiology behind these factors is discussed in Chapter 2, their resulting effects on a drug’s plasma concentration-time profile are presented in Chapter 3, and pharmaceutical aspects in Chapter 5. The development and impact of these formulations has been extensively reviewed elsewhere (Hardee and Baggot, 1998; Baggot, 2002; Martinez et al., 2002). When the absorption characteristics of a drug’s formulation become rate limiting, and flip-flop pharmacokinetics becomes operative, the shape of the drug’s concentration–time profile, and thus pharmacological effect, is in control of the formulation and not the animal’s ability to clear the drug. In addition, innovations in drug delivery allow existing drugs to be more effectively used and provide extension of the commercial life of the product for a manufacturer.

The classic example of the effect of formulation is seen with the plasma concentration–time profiles of potassium, procaine, and benzathine penicillin G (Figure 59.1). The formulation strategy is to complex the active drug (e.g., penicillin G) with a moiety that delays its release to the surrounding capillary beds by modulating the drug’s solubility. A pharmaceutics text should be consulted for the chemistry of these processes. The result is that the rate of release of the compound from the dosing formulation becomes slower than that of the drug’s elimination, making it rate limiting.

Graph shows time in hours from 0 to 30 versus lnCp from 0.01 to 10 with plots for iv K plus pen G, im K plus pen G, im (procaine pen G), and im (benzathine pen G).

Figure 59.1 Effects of formulation and route of administration on the plasma concentration versus time profiles of penicillin G.

The potential problems with these strategies are twofold. If one considers antimicrobial therapy for bacteria with very high therapeutic thresholds (e.g., minimum inhibitory concentrations, MICs), the prolonged-release formulations may never provide effective therapeutic drug concentrations. Second, such so-called “depot” preparations in food animals may result in persistent drug concentrations in tissues, thereby prolonging the withdrawal time. Drug depots at injection sites may persist much longer than effective blood concentrations and may be easily detected at slaughter. One must exhibit care to differentiate drug tissue concentrations at injection sites from those achieved after absorption and systemic distribution (Sanquer et al., 2006).

This scenario also nicely illustrates the reason that knowledge of both the extent and rate of drug absorption are needed to adequately describe the absorption of a drug and underscores why determination of drug bioequivalence (e.g., dosage form interchangeability) requires assessing both metrics related to rate (peak, time to peak) and extent (AUC) of drug absorption. The importance of these factors was also discussed in Chapter 3 under dosage regimen construction.

Approved dosages are very dependent upon the formulation of the drug utilized, a factor that must be considered when using any drug in a veterinary patient. This approach has recently been taken advantage of to develop other once-daily dosing of drugs such as antibiotics in veterinary species, the increased dosing interval being due either to the use of drugs with inherently long half-lives or depot release characteristics. These formulations stress the necessity of knowing the dosage form used when conducting any pharmacokinetic analysis as it may modulate the rate-controlling factor in drug disposition. In many cases, this can be detected only from intravenous pharmacokinetic experiments.

The development of depot preparations has received a great deal of attention by pharmaceutical industries. Some contraceptives in humans achieve monthly dosing intervals through injection in the subcutaneous tissue of insoluble tablets, which results in very slow drug release; the best example is the use of levonorgestrel implanted capsules (Norplant®). Similar strategies have been employed in veterinary medicine for the administration of growth promotants. These include estradiol formulated in rubber implants (Compudose®), progesterone and estradiol pellets (Synovex®), and zeranol (Ralgro®). Newer approaches include use of biodegradable gels that may be injected as a liquid through a syringe; these gels form a slowly degrading solid once in the tissue. Temperature-sensitive thermogels can also be used to control release of drug once in the body at physiological temperatures. A great deal of new technology is being developed for such formulations that promises more sophisticated dosage forms in the future. These approaches are fully discussed in Chapter 5.

Oral drug dosage forms achieve control of release through modulation of the surface area of dissolving drug particles, through the size of particles that alter their gastrointestinal transit time, or through the use of multiple layers in the formulation that control the rate and extent of drug release and dissolution. The simplest example is to coat a drug to prevent its dissolution in the acid environment of the stomach. These formulations are specifically designed for specific species, due to differences in gastrointestinal content and motility, as well as issues that include palatability. Capsules can be designed that initially release a bolus of readily soluble drug that functions as a loading dose into the animal. This is then followed by slower release of drug that maintains effective levels. For some compounds, only local delivery is needed to the gastrointestinal tract (e.g., certain antiparasitics), and the formulation can be designed for such activity. One recent example of this is the anthelmintic eprinomectin, which has been released in an extended therapy formulation (LongRange®

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Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Dosage Forms And Veterinary Feed Directives
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