Drugs That Are Also Endogenous Substances

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Bioequivalence studies of endogenous drug substances need special considerations. This is because for these substances there are measurable baseline concentrations in biological fluids, either because the product is manufactured in the body, such as levothyroxine or ursodiol, or is available from dietary sources, such as potassium chloride [14]. As previously stated, bioequivalence studies are conducted to compare formulation performance. With most drug products, the only source of the drug appearing in the blood is from the dosage form. With endogenous substances, there are two or more sources causing the substance to appear in blood. Adding complexity are feedback processes with substances like hormones, circadian rhythms, and influxes from the diet. Figure 4 shows that, following dosing with an endogenous substance, both release from the dosage form and body production contribute to blood levels.

Thus, in most cases, the FDA recommends baseline correction for endogenous substances. Measurement of the endogenous baseline depends on the characteristics of the endogenous substance. Often, a baseline is determined from one to three measurements taken before the drug products are given. Less often, sampling at regular intervals throughout the day for at least two days prior to dosing is performed. The baseline sampling should take place at several intervals to account for fluctuations due to circadian rhythms. Corrections should be subject- and period-specific. One important consideration in comparing generic and reference products is to give an adequate dose, because the plasma concentrations have to be high enough so that the substance can be accuratelyandreliablydeterminedbytheassay, after baseline correction. The objective is to discern any differences between a generic and reference product, without failing products that are almost identical.

Potassium chloride presents a special case. Serum measurements cannot be used for bioequivalence studies of potassium chloride products. Because homeostatic mechanisms maintain potassium concentrations in biological fluids within a narrow range, serum concentrations change minimally in response to a bolus dose. As shown in Fig. 5, the baseline is very high relative to any changes occurring after dosing. In fact, in pharmacokinetic studies of postassium chloride tablets, following an 80 mEq dose, serum potassium increases only about 5% relative to baseline [14]. Since virtually

FIGURE 4 Two or more sources contribute to blood levels of a drug that is already present in the body as an endogenous substance. The drug that appears in the blood and throughout the body arises from body production in addition to release from the dosage form. With some endogenous substances, especially hormones, there can be a feedback process such that production and storage of the compound changes as blood or body concentrations change. When determining bioequivalence of formulations of these types of drugs, it may be necessary to use a baseline correction to account for the amount in blood that did not come from the formulation.

FIGURE 4 Two or more sources contribute to blood levels of a drug that is already present in the body as an endogenous substance. The drug that appears in the blood and throughout the body arises from body production in addition to release from the dosage form. With some endogenous substances, especially hormones, there can be a feedback process such that production and storage of the compound changes as blood or body concentrations change. When determining bioequivalence of formulations of these types of drugs, it may be necessary to use a baseline correction to account for the amount in blood that did not come from the formulation.

all of ingested potassium is excreted in urine, measuring urine output of potassium is an accurate means of comparing the potassium released from generic vs. reference formulations. The FDA recommends that, for potassium chloride bioequivalence studies, subjects ingest a standardized potassium diet for an equilibration period of several days before sampling takes place [10]. This practice helps achieve a relatively stable baseline before dosing starts.

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