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When the oral and IV doses are different,
Therefore,
(1.35)
Similar Equations 1.32–1.35 apply for other extravascular routes also. If absorption from the site of administration is fast, the terminal slope of the semilogarithmic concentration‐time profile is defined by drug elimination rate. It is therefore parallel to the terminal slope of IV profile (see Figure 1.6b, c). It is then possible to extract the absorption rate constant and the elimination rate constant by the curve stripping method illustrated in Figure 1.6d. Alternatively, tmax may be calculated (tmax = ln(ka /kel )/(ka − kel )), assuming that contributions from processes other than absorption to tmax are negligible. In SC and topical administrations, drug absorption is slow, and the absorption rate constant, ka, is much slower than the kel (elimination constant) (Figure 1.6e). This is also referred to as flip‐flop kinetics. The PK profile in these routes is sometimes characterized by a lag time tlag . Flip‐flop kinetics and lag time can also occur when the oral route of administration is used, if gastric emptying is delayed for some reason (fed state, elderly, drug‐induced etc.).
The oral bioavailability of a drug is given by
where fabs is the fraction of dose absorbed, fgut is the fraction escaping gut extraction, and fhep is the fraction escaping hepatic extraction. If the IV PK profile is available, knowing the hepatic clearance, hepatic extraction, EH, can be calculated using Equation 1.26. fhep is related to EH by
(1.37a)
Figure 1.6. Oral pharmacokinetic profiles. (a) Maximum systemic concentration (Cmax ) and time at which Cmax is achieved (tmax ) following oral administration of a drug. (b) AUC for an orally administered drug that is nearly half of the AUC following IV administration of the same dose of that drug, indicating that the drug has about 50% oral bioavailability. (c) Area under the curve (AUC) for an orally administered drug that is nearly the same as the AUC following IV administration of the same dose of that drug, indicating that the drug has high oral bioavailability. (d) Curve stripping: Absorption rate constant ka is obtained from the residual slope of the straight line constructed by plotting the differences between the back‐extrapolated terminal slope and the observed curve in a semilogarithmic plot (illustrated with one of the four points plotted). (e) Flip‐flop kinetics with a lag time, tlag . Using the curve stripping method described in (d), the tlag and the ka can be obtained as shown.
Substituting for EH using Equation 1.28, and assuming systemic clearance (CLIV ) is driven by hepatic metabolism only,
(1.37b)
Knowing the F (Equation 1.34) and fhep, the gut bioavailability (fabs × fgut ) of a drug may be estimated using Equation 1.36. Often, the IV PK may not be available, especially for poorly soluble drugs requiring separate formulations. These are costly to develop and may not be stable. Estimation of oral PK parameters in the absence of IV PK is described in Box 1.1. In the absence of IV PK, fhep may be estimated by assuming complete drug absorption and neglecting gut metabolism, in which case the value of gut bioavailability becomes 1. In the absence of flip‐flop kinetics, the elimination rate and the half‐life may be obtained from the terminal slope of the oral PK profile. Obtaining clearance from fhep, the volume of distribution may be calculated. If gut metabolism cannot be neglected, then clearance can be calculated from the terminal half‐life, using a predicted volume of distribution.
1.2.6 Absorption from Solid Dosage Forms
An oral drug may be available in several dosage forms including the more common tablets and soft/hard gel capsules. A tablet comprises of the active pharmaceutical ingredient (API) and excipients compacted together and coated. Excipients include binders, flow‐aids, lubricants, preservatives, solubilizing, and flavoring agents. The release from these dosage forms and the dissolution of the drug may limit the rate of absorption.
The oral route is noninvasive and thus the most convenient route of drug administration. However, the bioavailability of many oral drugs is limited by drug solubility, dissolution, membrane permeability, or gut metabolism. Special formulations may therefore be needed to enhance drug exposure to the target tissue and control the exposure profile of a drug through the development of enabling and controlled‐release formulations respectively.
During drug development, the performance of different formulations, dosage forms, routes and different conditions of disease, fed/fasted states etc., may be compared even without IV PK, by determining the relative bioavailability, defined by Equation 1.38:
Assuming that the IV clearance (CLIV ) is same in both conditions, Equation 1.38 reduces to
(1.39)
To ensure equivalent performance of different batches of drug formulations, regulatory agencies require bioequivalence studies to be performed. To establish bioequivalence, the 90% confidence interval about the geometric mean test/reference ratios for both AUC and Cmax must fall within the bioequivalence range, which is 80–125%.
