or without blocking

aOr other methods able to differentiate between absorption through the lung and GI tract.

aOr other methods able to differentiate between absorption through the lung and GI tract.

For drugs that show significant oral bioavailability (e.g., salbutamol [75]), terbutaline sulfate [76], budesonide [77]), different approaches, such as the charcoal-block technique, or the knowledge of differences in the pulmonary and GI absorption lag times can be utilized to determine the pulmonary fate of the inhaled drug.

The rationale for the charcoal-block design is that for a number of drugs, oral absorption of swallowed drug can be blocked by coadministered charcoal. Typically, using this technique, the subject ingests charcoal slurry both at the time of drug administration and 1 and 2 hours after drug administration. Thus, accurate delineation of pulmonary absorption can be achieved because the absorption of the orally swallowed fraction of the inhaled product is blocked by charcoal. Comparison of drug levels with and without charcoal administration allows one to assess the degree of orally absorbed drug [77]. Such approaches have been described for terbutaline [76], triamcinolone acetonide [78], budesonide [77], and other glucocorticoids [79]. It is, however, vital for this approach to ensure the efficacy of the charcoal treatment by assessing the charcoal block after oral administration of drug [77].

Another approach for drugs with significant oral bioavailability is based on the finding that the absorption rates from the lung and the GI tract differ for a number of drugs, with the pulmonary absorption being much faster. Thus, drug reaching the systemic circulation rapidly after the inhalation represents drug absorbed from the lung. Such differences in the absorption lag times from the lung and the GI tract have been utilized to determine the pulmonary deposition of salbutamol [80]. Hindle et al. showed that under these conditions one does not need to collect blood samples but that the collection of urine is sufficient. Furthermore, negligible amounts of unchanged salbutamol were excreted in the urine within the first 30min when given orally [80]. In contrast, salbutamol can be detected in the urine within the first half hour when given as inhalation, indicating that the pulmonary absorption is faster. This method was validated in clinical trials, indicating that 30-min urinary excretion of salbutamol following a variety of inhalation maneuvers reflects the pulmonary-absorbed fraction of the dose [81]. Monitoring the urine levels over long time periods can then be used as a marker for the total systemic drug exposure. The time lag between the oral and pulmonary absorption has been utilized for other drugs, such as nedocromil [82], sodium cromoglycate [83], and gentamicin [84]. One needs, however, to consider that this approach is drug specific and cannot be applied to all classes of drugs and that the time resolution is limited when urine is collected, especially if only done once.

It is clear that pharmacokinetic studies in humans provide significant information for inhalation drugs. Relevant key parameters obtained from PK studies include the pulmonary deposition efficiency, parameters assessing the pulmonary absorption, and the overall degree of systemic exposure (Table 2). Some approaches suitable for assessing these and other pharmacokinetic properties are discussed next.

Pharmacokinetics After Oral and Intravenous Administration. For proper characterization of an inhalation drug, information on the systemic pharmacokinetic properties needs to be provided. One of the major challenges for such studies is to provide a suitable formulation for injection, especially because new drug candidates are often very lipophilic. The resulting parameters of such studies (systemic clearance, volume of distribution, half-life, mean residence time) can then easily be extracted from concentration-time profiles after IV administration and subsequent standard pharmacokinetic analysis by noncompartmental approaches. In addition, a detailed compartmental analysis based on concentration-time profiles will be useful in evaluating the systemic distribution processes in sufficient detail. This will be especially important if deconvolution procedures (see later) are included for the assessment of the pulmonary absorption profiles.

In addition to intravenous studies, estimates of the oral bioavailability of the drug need to be provided. For glucocorticoid studies, often very large doses of steroid have to be given to be able to obtain measurable drug levels. The percent oral bioavailability can then easily be obtained by comparing the dose-adjusted area under the concentration-time profiles after oral and IV administration:


An elegant way of obtaining information on IV and oral dosing at the same time (with the advantage of reducing the variability of such estimation by deleting the interassay variability) is to use unlabeled drug for one form of administration and to dose at the same time a deuteriated form of the drug for the other form of administration [85].

Degree of Systemic Availability. The overall degree of drug absorbed into the systemic circulation is a parameter quantifying the systemic exposure after inhalation. Systemic drug exposure (systemic availability) can easily be determined using noncompartmental approaches by comparing the area under the plasma concentration-time profile, extrapolated to infinity (AUC«), observed after intravenous administration of the drug (AUCIV) with that after inhalation (AUCinh). To calculate these parameters, standard techniques for the determination of the AUC« (trapezoidal rule and extrapolation to infinity) can be used. Correlation of the AUC« obtained after inhalation with that after IV administration allows calculation of the systemic availability after inhalation.

The following equation provides such a correlation if doses after IV administration (DIV) and inhalation (Dinh) differ:

Systemic availability (%) = AUCinh X D|V x 100 ' '' ' AUCiv X Dinh

For drugs with zero oral bioavailability this method also provides a direct estimate of the pulmonary deposition efficiency of the device. For drugs with distinct oral bioavailability, this method, combined with charcoal-block, enables calculation of both pulmonary and oral availabilities [86].

This method can also provide important information on the degree of systemic exposure for the assessment of bioequivalence, by comparing the AUC« for innovator and generic products, using the following equation for the relative systemic availability:

Relative systemic availability (%) = A,UCgenenc X 100


Area-under-the-curve determinations allow one to estimate the degree of accumulation of drug during therapy by comparing the AUC during one dosing interval obtained after the first dose and at steady state.

Urine data, as previously described, might also be used for the assessment of the degree of systemic absorption through the lung (early urine data) and the total systemic exposure (total urine excretion). Resolution of such data will, however, depend on the correct cutoff time points defining pulmonary and oral absorption. For total systemic exposure, the amount of drug found in the urine after a single inhalation (Amountinh) and the amount found after a single IV injection (AmountIV) found in the urine (during a time period encompassing the total elimination of drug) allows the determination of the percentage of systemic exposure after inhalation. This percentage for an inhalation dose of Dinh and an injection dose DIV can be calculated by the following equation:

Amountinh X DIV

Relative systemic exposure (%) =-X 100

AmountIV X Dinh

Cmax• Cmax (maximum observed concentration) is also a parameter being affected by dose reaching the systemic circulation, absorption, and distribution kinetics. Since it is affected by a number of parameters, the interpretation of results depends on the nature of the study performed. For example, the differences in Cmax between two devices delivering a solution-based drug with negligible oral bioavailability might indicate differences in the respirable fraction between the two devices. In other studies (that evaluate immediate-release and sustained-release preparations but similar deposition efficiencies), differences in Cmax might indicate differences in the absorption profile. Thus, additional information (deposition efficiency, delivered dose) might be necessary to evaluate the results correctly.

Pharmacokinetic Tools to Characterize Absorption Kinetics. The sustained character of lung absorption is important for the degree of pulmonary selectivity. It is therefore important to evaluate lung absorption with pharmacokinetic tools. Several tools have been used to provide this information, including the time to reach the maximum plasma concentration (tmax), the mean absorption time (MAT), flip—flop, and deconvolution. These approaches are described next.

tMax- The time to reach maximum concentrations (tmax) has been used to evaluate how fast the drug is absorbed. This is done under the assumption that the slower the absorption from the lung, the longer will be tmax. The following equation, derived for a drug whose systemic distribution can be described by a one-compartment body model, shows that tmax depends not only on the absorption rate (ka) but also on the elimination rate (ke):

Thus, for a given drug, a formulation with a slower absorption rate should show an increased tmax value. Because of the relatively fast absorption often seen after inhalation, sampling at early time points has to be frequent, in order to obtain reliable estimates of tmax. However, one cannot necessarily use tmax to determine whether two different drug entities are being absorbed with different rates because tmax is determined not only by ka but also by ke (which is likely to be different for two different drugs). In this case, knowledge of ke (obtained after IV administration) and tmax can be used to calculate ka. It is even more complicated for drugs with multicompartmental distribution properties. In these cases, tmax is determined by the absorption process and k10 (elimination rate of systemically available drug) and by rate constants governing the distribution among all systemic compartments. Also in these cases, an early tmax might not always indicate a fast absorption and a later tmax might not indicate a slow absorption process if two drugs differ in their systemic compartmental distribution pattern (differences in the rate constants among systemic compartments) [87]. Thus, the use of tmax to characterize the absorption pattern must be carefully considered. Mean absorption time (mat). A much more robust parameter than tmax seems to be the estimation of the mean absorption time (MAT). This parameter can easily be obtained by noncompartmental analysis by estimating the mean residence time after inhalation (MRTinh) and comparing it with the mean residence time after IV administration (MRTIV):


The MRT is calculated from AUC0-1 and the area under the first momentum curve (AUMC0-1):

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