Inhaled drugs pharmacokinetics

Lipworth BJ (1996) Pharmacokinetics of inhaled drugs. Br J Clin Pharmacol 42 697-705. 

Eto, K., Y. Gomita, K. Furuno, K. Yao, M. Moriyama, and Y. Araki. Influences of cigarette smoke inhalation on pharmacokinetics of cimetidine in rats. DrugMetab Drug Interact 1991 9(2) 103-114. 

M. Hill, Effect of delivery mode on pharmacokinetics of inhaled drugs Experience with beclomethasone, Respiratory Drug Delivery VI. (R. Dalby, P. Byron, and S. J. Farr, eds.), Interpharm Press, Englewood, CO, 1998, p. 53. 

Witek, T. L, Jr. (2000), The fate of inhaled drugs The pharmacokinetics and pharmacodynamics of drugs administered by aerosol, Respir. Care, 45, 826-830. 

An excipient is defined as a material that is deliberately incorporated into the formulation to aid some physicochemical process, for example for a tablet, integrity, dissolution, bioavailability or taste excipients are typically chosen from among many compounds without pharmacological properties (e.g. lactose), although there are examples where pharmacokinetics change with the excipient used. There are specialized examples of excipients, for example propellants are excipients that assist in the delivery of inhaled drugs to the respiratory tract. For intravenous infusions or ophthalmic products, the excipients are usually pH buffers or... 

Most regulatory authorities will want reassurance that the pharmacokinetic (PK) properties of the marketed product closely resemble those in which the pivotal studies are carried out. This is not unreasonable if the PK properties differ, then so may dose size and frequency. Occasionally, a phase III study will be bridged to the marketed formulation by the demonstration, for example, that two different tablets have the same PK profile. However, the risk is that different formulations will not turn out to possess the same PK profile either new pivotal studies will have to be conducted with the new formulation or registration will be delayed until the new formulation is adapted so that it does match the phase III test material. For inhaled drugs, this is especially difficult. Time and money is often lost in both cases. It is a risky gamble to leave development of the final formulation until the end of a clinical development plan. 

Figure 1 Fate of inhaled drugs depositing in the airways. Aerosolized compounds delivered to the lumenal surface of central (i.e., tracheobronchial) and peripheral (i.e., alveolus) airways may be subject to different pharmacokinetic pressures. The sites of loss of a drug in passage from the airway lumen to the site of therapeutic action in the central airways (e.g., smooth muscle) and peripheral airways (e.g., blood in pulmonary circulation) are depicted in upper and lower diagrams, respectively. In the central airways, a drug may (1) interact with the mucus layer, (2) be removed by the mucociliary escalator, (3) have restricted access through the epithelium and be biotransformed or be complexed by epithelium-associated...

METHODS TO ASSESS PHARMACOKINETIC AND DYNAMIC PROPERTIES OF INHALATION DRUGS... 

Earlier we described how pharmacokinetic and dynamic properties of inhaled drugs are relevant for pulmonary selectivity. The assessment of pharmacokinetic and dynamic properties is consequently relevant for drug development and clinical practice. This section reviews some of the relevant techniques for assessing such properties. The available tools range from cell culture or isolated lung perfusion models to mucociliary clearance analysis, imaging techniques, and in vivo pharmacokinetic and dynamic analysis of the inhaled drug. 

Determinations of drug levels in the lung and comparison with plasma levels have been used for the pharmacokinetic assessment of inhalation drugs. In such a scenario, drug is typically delivered to the lung of animals or patients, who have... 

For a long time classical pharmacokinetic approaches could not be used, because the available analytical techniques were not sensitive enough to measure the low plasma levels in the picogram/mL range often observed after inhalation. However, with the availability of HPLC/MS techniques and their high sensitivity, pharmacokinetic analysis can now be performed for most inhalation drugs. 

Other Important Considerations for Pharmacokinetic Studies. When using systemic (plasma, serum, or urine) drug levels for the evaluation of inhalation drugs, one must take into consideration that these levels are made up of drug absorbed via the lung and the GI tract. Thus, these studies cannot be used a priori for characterization of the pulmonary fate of inhalation drugs (see Table 2). 

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... 

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. 

Adjei AL, Qiu Y, Gupta PK. Bioavailability and pharmacokinetics of inhaled drugs. In Hickey AJ, ed. Inhalation Aerosols. New York Marcel Dekker, 1996. 

Davies D. Pharmacokinetic studies with inhaled drugs. Eur J Respir Dis 1982 63 67-72. 

Lung deposition of inhaled drug can be determined by both scintigraphic and pharmacokinetic methods. 

Kielbasa W, Fung HL Pharmacokinetics of a model organic nitrite inhalant and its alcohol metabolite in rats. Drug Metab Dispos 28 386-391, 2000... 

Erichleb, M., Pharmacokinetics of gentamicin administered intratracheally or as an inhalation aerosol to guinea pigs, Drug Metab. Dispos. 1984, 12, 641-614. 

The ventilated and perfused human lung lobe was used as described by Linder and co-workers [74], A twofold difference in the appearance of drug and metabolites in the perfusate was found for the two formulations. Small fractions of the applied dose of BDP were immediately detectable in the perfusate and the amount of the major metabolite, beclomethasone-17-propionate (17-BMP), increased over the experimental period. These observations were similar to the clinical observations that BDP is detected rapidly in the plasma after inhalation and that the appearance of the active metabolite 17-BMP occurs rapidly. The kinetic differences between the formulations were explained on the basis of particle size effects with the conclusion that the discriminatory value of this system to examine the lung pharmacokinetics of inhaled medicines in the absence of systemic effects such as hepatic metabolism was apparent. 

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