96 Cm

Fig. 6.7. Multiple Dose Pharmacokinetics deemed to be bioequivalent. The bioequivalence study is the primary clinical study that a generic company has to conduct in order to get an approval when the drug patent expires. The above criteria and the two one-sided test procedure are the important means to prove that the generic formulation is bioequivalent to the innovator drug. Similar approach is also applied for drug-drug and drug-food effect studies.

Besides oral bioavailability, bioavailability can also be determined after administration via other extravascular routes, such as inhalation, transdermal, or subcutaneous injection.

Following single dose administration via extravascular route, the maximum concentration is defined as C , and the time to max'

reach maximal concentration is defined as T (Fig. 6.6). The max concentrations decrease in a first-order fashion, which implies that the decrease in concentration over time is dependent on the previous concentration. This type of reduction in drug concen tration brings up the concept of half-life, which is defined as the time taken for the concentration to fall by one-half. The halflife can be determined as ln 2/Xz, where Xz is the slope of the terminal disposition phase on log-transformed concentration data. The area under the plasma concentration versus time curve from 0 time up to the last measurable concentration is determined by the trapezoidal rule. The AUC extrapolated to infinity is calculated as Clast/Xz, where Clast is the last observed concentration.

Following multiple dose administrations, it takes about four half-lives to reach clinical steady-state (i.e., 93.75% of the true steady-state) (Fig. 6.7). If the drug behaves in linear kinetics, the area under the plasma concentration-time curve up to infinity after a single dose is equal to the area under the curve for a dosing interval at steady state (AUC0_m1 = AUC Tss). Accumulation after multiple drug dosing can be defined as the ratio of either AUC, Cmax, or Cmin at steady state for a dosing interval to the corresponding AUC, Cmax, or Cmin after single dose for the same time interval. The fluctuation is the ratio of the maximum concentration and minimum concentration at steady state.

Generally speaking, an ideal dose regimen should give both low fluctuation and low accumulation for the drug. Also, it is important to note that the time to steady state depends solely on the half-life of the drug, while the average steady-state concentration depends on the clearance of the drug and the dosing rate.

If the concentration of an NCE at any given time is proportional to the dose of the drug administered, then the PK of that drug is dose proportional (Fig. 6.8). Dose proportionality is necessary for linear kinetics, which implies that any concentration-time profile normalized for time and dose is superimposable. Nonlinear kinetics implies that concentration-time profiles are not superimposable due to either dose or time dependencies. The common

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