Auc01

This approach is robust because it does not rely on any pharmacokinetic assumptions and allows the characterization of absorption processes among different drugs if IV data are available. For example, differences in the absorption profiles between fluticasone propionate and budesonide can easily be identified with this method, while differences in tmax were not able to readily provide this information. The mean residence time without availability of intravenous data should not be used to compare absorption profiles of different drug entities, because it is also determined by the systemic elimination of the drug. This approach is, however, suitable for evaluating the differences of different formulations of the same drug.

The "flip-flop" approach. Assuming that the absorption rate is much slower than the elimination rate, concentration-time profiles of an inhaled drug will show a terminal slope (slope of the semilogarithmic plot at late time points) that reflects ka rather than ke. This phenomenon is called "flip-flop" (Fig. 11). For drugs that are absorbed slowly from the lung, the terminal elimination phase after inhalation should be slower than after IV administration. Monitoring the occurrence of flip-flop has been used to prove or disapprove the distinct slow absorption of pulmonary drugs [88]. While the concept is correct for drugs that are absorbed much more slowly than they are eliminated, drugs with a small ke can

Figure 11 Effect of varying absorption rate constant (ka) on the concentration time plots for two hypothetical drugs with similar dose, bioavailability, clearance, and volume of distribution. Case 1 (smooth line): ka > ke; and Case 2 (broken line): ka < ke (flip-flop situation).

show similar terminal slopes after IV administration and inhalation, despite the fact that the drug is absorbed slowly from the lung. In this case, other PK parameters are more suitable for assessing the absorption properties. Deconvolution approaches. Concentration-time profiles have also been analyzed by deconvolution methods [89]. Application of deconvolution methods to inhalation drugs must consider the multicompartmental distribution processes observed for most inhalation drugs. This makes it necessary to use PK estimates after intravenous administration within the deconvolution process. Thus, deconvolution of concentration-time profiles are based on the comparison of data obtained after IV administration and inhalation. This allows the generation of an input function, which describes the systemic absorption process and will generate full absorption profiles similar to those obtained from the isolated perfused lung preparations. Because of the compartmental approach used in these deconvolution processes, this method gives information not readily available from the noncompartmental analysis. Using deconvolution, Brindley and coworkers [89] were able to identify that 50% of the pulmonary-deposited dose of fluticasone propionate (FP) is absorbed within 2 hours, while the rest is absorbed more slowly, with 90% being absorbed by 12hours. It is likely that differences in the absorption processes might reflect drug deposited in different regions of the lung (central or peripheral). Brindley and coworkers were able to show that, independent of the inhalation device, FP is multiexponential and that slow absorption into the systemic circulation provides a long pulmonary residence time [89]. Deconvolution of such data can be performed relatively easy with software such as PCDCON [90]. Similar approaches were able to show that after inhalation of fenoterol, parts of the delivered dose were absorbed relatively fast while the other fraction was absorbed more slowly [91]. This observation might be linked to differences in the absorption rate of a drug deposited into the lung vs. in the GI tract. In summary, deconvolution of inhalation data has the potential for analyzing the absorption processes in detail and with high resolution. It depends, however, on a somewhat complex data analysis.

Potential Role of Pharmacokinetics in Bioequivalence Studies. With more and more generic drugs entering the inhalation market, the industry [International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS)], professional organizations (e.g., Inhalation Technology Focus Group of the AAPS), and the FDA are currently trying to streamline bioequivalence testing. Potential methods to be considered include pure in vitro studies, imaging techniques, and pharmacokinetic and pharmacodynamic studies. Pharmacokinetics is the standard for establishing bioequivalence of orally administered products; however, pharmacokinetic studies did not play a major role in early discussions of bioequivalence studies for inhalation drugs because analytical tools were judged not sensitive enough to provide reliable information and so clinical studies were proposed. Today, with the availability of sensitive analytical techniques, pharmacokinetics studies are able to provide information relevant for bioequivalence testing. Table 3 indicates potential applications of pharmacokinetic approaches within bioequivalence evaluations.

For drugs with zero oral bioavailability, a number of parameters important for bioequivalence testing can be extracted from pharmacokinetic studies. Comparison between AUC0_^ estimates for innovator and generic products will provide direct information on the degree of pulmonary deposition because drug can enter the systemic circulation only through the lung. The resulting concentration-time profiles can be used to calculate the mean residence time, a parameter allowing conclusions on the absorption characteristics of the formulations.

Table 3 Questions Relevant for Bioequivalence Studies and Potential for Pharmacokinetic Approaches

Questions

Can PK be useful?

Factors determining the pulmonary effect

Factors determining the systemic exposure

• How much drug is absorbed through • the GI tract?

• Is the time profile of systemic • exposure similar?

Yesa (blocking of oral absorptionb might be necessary for drugs that are absorbed orally) No (only if absorption rates differ in central and peripheral areas of the lung)

Yesa (blocking of oral absorption might be necessary for drugs that are absorbed orally)

Yesb (study with and without blocking of oral absorption are necessary for drugs that are absorbed orally) Yesb (blocking of oral absorption might be necessary for drugs that are absorbed orally) Yes aOnly true for drugs lacking significant oral absorption.

bOr other methods to differentiate between pulmonary and oral components might have to be used (e.g., time delay between oral and pulmonary absorption).

The role of the pharmacokinetic assessment of generic drugs showing a distinct oral absorption component is limited, because plasma levels cannot clearly be related to the oral and pulmonary pathways. Information on the systemic exposure, however, can be obtained without any problems if pharmacokinetic methods exist that allow differentiation between pulmonary-absorbed and orally absorbed drug (see earlier section on the charcoal method and the link of early drug levels to pulmonary absorption). Under these conditions, estimates can be derived for how much drug enters the systemic circulation through pulmonary and GI absorption, and information on the pulmonary absorption kinetics can be obtained. It is, however, vital for such approaches that, for example, the charcoal-blocking procedure is fully validated and effective.

It seems that PK studies for bioequivalence testing represent a middle ground between in vitro studies and clinical studies assessing pharmacodynamic equivalency, because they provide relevant information without the need to perform clinical studies. However, clinical studies showing the equivalence between PK and PD studies should also be performed.

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