Pharmacokinetics And Bioavailability

[Monica Okane]

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This guidance discusses what types of information you, the applicant, should submit in your new drug application (NDA) or abbreviated new drug application (ANDA) for a liposome drug product reviewed by the Center for Drug Evaluation and Research (CDER). The discussion addresses the following topics for liposome drug products: (A) chemistry, manufacturing, and controls (CMC); (B) human pharmacokinetics and bioavailability or, in the case of an ANDA, bioequivalence; and (C) labeling in NDAs and ANDAs.

Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s). More accurately, bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug's intended targets have unimpeded access.[1][2][3]

For most purposes, bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site.[4] However, one should understand that this definition excludes drugs that do not require access to systemic circulation for function (eg, certain topical drugs). The bioavailability of these drugs is measured by different parameters discussed elsewhere.[2]

Bioavailability is an integral part of the pharmacokinetics paradigm. Pharmacokinetics is the study of drug movement through the body and is often represented by the acronym ABCD which stands for administration, bioavailability, clearance, and distribution. Administration refers to the route and dosing of a drug. Clearance is the active form of a drug being removed from the systemic circulation. Distribution measures how widely a drug can travel to fluid compartments of the body; this definition assumes distribution follows absorption if taken orally.[5]

The route of administration (ROA) and the drug dose can significantly impact both the rate and extent of bioavailability. The dose of a drug is indirectly proportional to its bioavailability (Equation 5). A drug with relatively low bioavailability requires a larger dose to reach the minimum effective concentration threshold. The various routes of administration each contain a unique capability to facilitate a certain plasma drug concentration for a certain length of time. In many cases, altering the route of administration calls for an alteration of the dosage. For example, an oral drug requires passage through the gastrointestinal (GI) system, subjecting it to intestinal absorption and hepatic first-pass metabolism.[4] On the contrary, an intravenous (IV) drug is assumed to be immediately delivered to the systemic circulation because it is not subject to absorption or first-pass metabolism to determine adequate dosage.

Drug clearance can be thought of as the metabolic and excretory factors on the rate and extent an active drug leaves the systemic circulation. Clearance is measured by the drug elimination rate divided by the plasma drug concentration. The drug elimination rate is classically categorized into a binary system. A drug is eliminated either by first-order or zero-order kinetics. In zero-order kinetics, a constant amount of a drug is eliminated over time regardless of plasma concentration. However, zero-order kinetics implies absorption and elimination can become saturated, potentially leading to toxicity. In first-order kinetics, a constant fraction of the drug is eliminated over time via the intrinsic half-life of the drug.

Further, first-order drug elimination is exponentially proportional to plasma concentration (unlike zero-order kinetics). This implies that drug elimination will exponentially increase when the drug has a higher plasma concentration. Therefore, providers should know which category of elimination the drugs they prescribe follow, as this will affect drug clearance and bioavailability. For drugs following first-order kinetics, accumulation can occur if doses are delivered too frequently. This could result in unintended supratherapeutic consequences and side effects.[6]

Together, bioavailability and clearance can be used to determine the steady-state concentration of a drug.[5] Steady-state concentration is the time frame in which the concentration of a drug in the plasma is constant. This occurs when the rate of a drug reaching systemic circulation is equal to the rate a drug is removed from systemic circulation.[6] Thus, disparities in factors affecting the respective medications' bioavailability are important to consider when assessing therapeutic efficacy. Factors that alter drug clearance will reliably alter bioavailability and steady-state concentration. Such is the case in renal diseases that inhibit the kidneys' ability to eliminate drugs in the urine. Any degree of failure to eliminate a drug may augment its bioavailability by maintaining a larger drug plasma concentration than would normally be expected over time.

In contrast with bioavailability which measures the rate and extent an active drug reaches the plasma of systemic circulation, distribution is a measure of the rate and extent a drug is delivered to the various compartments of the body; total body water, intracellular volume, extracellular volume, plasma volume, and blood volume. Drugs capable of venturing into multiple fluid compartments are considered in a multi-compartment distribution model. Drugs that are thought to immediately distribute to their target domains, and do not normally distribute to peripheral compartments, are considered part of the single-compartment model. In the single-compartment model, any reduction in plasma drug concentration is assumed to have resulted from drug elimination.[7]

The multi-compartment model is useful for tracking drug flow throughout the fluid compartments. In both models, distribution is referred to as the volume of distribution (Vd) since volume is a convenient metric to compartmentalize the distribution of solutes, including drugs. The volume of distribution can be an important indicator of changes in bioavailability. The volume of distribution can be determined instantaneously by the proportion of the total amount of a drug in the body compared to the plasma concentration of the drug at a given time.[7] (Equation 1):

Extrapolating from the equation, a drug with a larger Vd will have a larger distribution outside the central compartment (plasma systemic circulation). One must consider how the relative breadth of a drug's volume of distribution might affect the drug's potential bioavailability. To illustrate, a drug that readily flows across multiple compartments may not be ideal if the intention is to maximize the plasma drug concentration.

Foundational to how bioavailability is classically defined is that an intravenously administered active drug delivered directly into systemic circulation yields a bioavailability of 100%. The bioavailability (F) of a medication delivered via other routes of administration can be determined by the mass of the drug delivered to the plasma divided by the total mass of the drug administered (Equation 2):

In pharmacologic contexts, an area under the curve graph (AUC) plots the plasma concentration of a drug on the y-axis versus the time following drug administration on the x-axis (example shown in Figure 1).[8] The area under the curve is directly proportional to drug absorption. Recall that the bioavailability of any drug delivered intravenously is theoretically 100%, or 1. This allows for convenient calculation of the bioavailability of drugs not delivered intravenously. By dividing the area under the curve of a medication delivered orally, for example, by the area under the curve for the same dose of that same drug delivered intravenously, one may successfully calculate the bioavailability of the oral medication.[9]

Bioavailability can be derived from an area under the curve (AUC) graph (Equation 3), which can be observed in the associated Figure 1.[4] For clinical purposes, a conceptual understanding of an AUC graph is crucial.

Thus, bioavailability is measured on a continuous range from 0 to 1 but can be represented as a percentage.[4] As a memory device, "F" can be thought of as a "fraction" because bioavailability is a non-IV drug's AUC divided into its IV version.

Limitations of current theoretical models of bioavailability do exist. Calculating bioavailability using AUC data assumes a constant drug clearance and a uniformly distributed concentration of the drug once it reaches the plasma. In all other cases, AUC data is unreliable.[10]

Oral drugs, unlike drugs with other ROAs (eg, IV medications), must undergo intestinal absorption and hepatic first-pass metabolism.[4] Many structural and physiological gastrointestinal (GI) alterations, such as GI surgery or chronic inflammatory intestinal conditions, affect this absorption, typically by reducing bioavailability.[11] Genetic polymorphisms of intestinal transporters that facilitate absorption (eg, P-glycoprotein 1) also affect drug bioavailability.[12] Verapamil, a calcium channel blocker that inhibits P-glycoprotein, has been shown to augment the plasma concentration of immunosuppressive drugs that utilize P-glycoprotein in their elimination, such as cyclosporine and tacrolimus, increasing the risk for toxicity.[13]

Following drug absorption into the intestines, drugs are delivered to the liver via the portal system. The liver is the site of first-pass metabolism. The bioavailability of a drug will be reduced proportionally to the fraction of the initial dose converted to inactive metabolites by liver enzymes.[14] Notably, hepatic cytochrome P450 metabolism can significantly alter drug bioavailability.[15]

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