Pharmacology and Toxicology

Currently the FDA approves drugs based on a risk-benefit assessment; the agency considers that no prescription drug is free of risk. All prescription drugs carry some risks, and heath care professionals with prescriptive authority (physicians, nurses, and pharmacists) are the risk managers. Therefore health care professionals must have a clear understanding of the pharmacology and toxicology of biopharmaceuticals.

The pharmacology and toxicology of a drug candidate is summarized in the "Overview and General Introduction to Clinical Pharmacology" section of product labels. The FDA requires that a new drug application (NDA or BLA) must include an overall pharmacology and toxicology assessment [1,2]. While some of the pertinent issues for each medication vary, the summary information in product labels must include integrated knowledge about the pharmacology of the biopharmaceuti-cal (i.e., mechanisms of therapeutic action, possible side effects, and interaction with other drugs).

Dose-response profiles for wanted and unwanted effects are, for the most part, derived from clinical studies. This information is also summarized in product labels. However, acute and long-term safety studies at higher than usual doses cannot be carried out in humans. Therefore such studies are performed in appropriate animal models to estimate the upper limit of the human dose. Acute and long-term toxicology data are derived from at least two animal species receiving escalating doses of drug. Side-effect monitoring during long-term repetitive dosing may include changes in behavior, carcinogenic-ity, mutagenicity, and untoward reproductive effects. The use of multiple species also allows identification of interspecies differences in drug responses.

Animal studies also allow early elucidation of the time course of drug concentration in blood and tissues for establishing relationships between concentration and pharmacologic and toxicologic effects. The information provided from animal studies, particularly dose ranging and long-term toxicology studies, extends our ability to extrapolate safe and effective-dose ranges for human administration.

Animal data serve as the springboard to estimating a safe and effective range of doses for human therapeutic purposes. Initial doses in phase I studies are based on preclinical pharmacokinetic and safety data. First estimates of safe and effective drug concentrations in plasma in human studies are also based on animal data. The "Clinical Studies" section in the product label includes information derived from tolerance studies of the drug (phase I), pivotal human data demonstrating efficacy at a defined dose or dose range, and a description of untoward effects observed in healthy volunteers as well as in intended subjects (i.e., patients). Information relevant to patient population such as age, sex, and race is increasingly appreciated, but not all drug companies comply with FDA directives to provide such information. There is a growing public demand for safety and efficacy data on special populations, such as pediatric and elderly patients.

Obtaining unambiguous efficacy data in human clinical studies is almost always challenging and sometimes insurmountable. Establishing clinically relevant end points and demonstrating statistical significance between control and test groups can be difficult. For example, the difference in mortality in myocardial infarction patients treated with the thrombolytic agent alteplase and those receiving strep-tokinase is only 1% to 2%. Attempting to detect that difference with an acceptable level of confidence requires several thousand patients and many years. Despite these hurdles Genentech, the maker of alteplase, determined that the commercial impact of demonstrating a difference outweighed the risks of wasted resources in attempting to do so.

One of the issues unique to protein, peptide, and polymeric therapeutic products is that although they are purified, such products may contain infinitesimal amounts of cellular components and are rarely homogeneous. It is important to understand the effect of heterogeneity on pharmacology with regard to natural or engineered variations in peptide backbone and carbohydrate structures. Variations in glycosylation of protein pharmaceuticals may influence the rate of clearance of the protein (Figure 5.1). Some of the commonly used protein pharmaceuticals and the type of glycosyl group attached to each protein are listed in Table 5.1. An almost identical molecule such as interferon from two different manufacturers, even using the same recombinant host, is not likely to be identical. Often differences among the proteins produce subtle but detectable changes in biological function or disposition of the proteins that could introduce variation in therapeutic outcome.

Any significant changes in process or product formulation may also have significant impact on pharmacology, affecting therapeutic concentration range or window, bioavailability, or therapeutic

CO c

GM-CSF glycosylation

Figure 5.1. Effects of glycosylation on the plasma concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in rats at 30 minutes after administration. The native, fully glycosylated and sialated GM-CSF is represented by the cylinder. GM-CSF with 2, 1, and 0 N-linked gly-cosyl groups (at amino-acid positions aspargine27 and asparagines37) are represented by the rectangle, tapered cylinder, and pyramid. (Data source: Donahue et al. [17])

g Si

GM-CSF glycosylation

Figure 5.1. Effects of glycosylation on the plasma concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in rats at 30 minutes after administration. The native, fully glycosylated and sialated GM-CSF is represented by the cylinder. GM-CSF with 2, 1, and 0 N-linked gly-cosyl groups (at amino-acid positions aspargine27 and asparagines37) are represented by the rectangle, tapered cylinder, and pyramid. (Data source: Donahue et al. [17])

effects.As biopharmaceuticals near the end of their term of patent protection, generic manufacturers face the challenging task of developing methods to demonstrate bio-equivalence between the generic and original versions of the biopharmaceutical without resorting to very expensive clinical trials. Because there are no precedents for generic biopharmaceuticals, the FDA faces the daunting task of developing novel standards and guidelines.

0 0

Post a comment