The most commonly used method to determine the rate of absorption is by reporting the time (tmax) to reach the (observed) peak plasma concentration (Cmax) of drug after dose intake. The observed Cmax of the administered drug characterizes the peak exposure after dose intake. Other methods to determine the rate of absorption may be employed, which may be more meaningful for the comprehension of the absorption processes of the drug, since tmax and Cmax are governed by both absorption and elimination processes. Examples of other methods are deconvolution or calculations of the absorption rate constant (ka), and can also be utilized [18].

The extent or completeness of absorption of intact drug or the active moiety is usually expressed by the area under the plasma concentration-time curve, AUC, as a quantitation of exposure. Comparative bioavailability is expressed as a fraction (or percent) of the administered dose, where another pharmaceutical formulation or route of administration serves as reference. Comparative bioavailability (F) is calculated as:

Dosereference AUCj test


AUQeierence where AUC denotes the area under the plasma concentration-time curve, and dose adjustments are performed if unequal doses of the test and reference drugs are administered. Alternative biological fluids, e.g., whole blood or urine, can also be used for the determination of bioavailability. Absolute bioavailability (F) is determined after administration of an intravenous reference dose, where the intravenously administered dose is assumed to be 100% bioavailable. Relative bioavailability (Frei) is determined when the reference dose is administered extravascularly, e.g., as an oral solution or a suspension. Early indications of a lower Frei than expected may call for additional modifications of the drug substance where ultra micronization or other measures may increase the in vivo absorption of the drug.

In certain cases, absorption is the slowest, rate-limiting step in the disposition of a drug. Differences in terminal t1/2 of the drug after different routes of administration may indicate rate-limiting absorption processes [1]. Again, an intravenous reference dose is one of the most straightforward ways to determine the basic pharmacokinetic properties of the drug or formulation, since the intravenous route of administration circumvents all absorption processes.

Relative or absolute bioavailability of the dosage form should to be established. In early stages of drug development, the oral tablet formulations are usually of immediate release (IR) character, and an oral solution, or suspension, are used as the reference if an intravenous formulation is not available. This study can be valuable as a point of reference, if subsequent modifications and optimizations are made to the dosage form during further drug development. It is possible to link formulation changes by bioavailability studies between formulations, and in vitro dissolution comparisons may also preclude in vivo studies if only minor modifications are made. However, major changes between clinical trial formulations and/or the formulation intended for commercial use may warrant bioequivalence studies (see related chapters in the Biopharmaceutics section).

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