Methods for Assessing Pulmonary Targeting

Beta Switch Program

The Beta Switch Weight Loss Program

Get Instant Access

Inhalation therapy has been introduced into the clinics to ensure pulmonary effects with reduced systemic side effects. Animal and human studies for assessing pulmonary targeting are summarized next. Table 4 summarizes approaches for assessing pulmonary targeting.

Assessment of Pulmonary Targeting in Animal Models. Animal models are important tools in assessing the pharmacodynamic performance of antiasthma drugs. Pulmonary models have been developed for rat and mice, which allow the assessment of anti-inflammatory properties of a drug after antigen challenge. Alternatively, pulmonary eosinophilia can be induced by nonallergic modes,

Table 4 Methods to Quantify Pulmonary Targeting

Assessment of pulmonary targeting in animal models

• Sephadex-based models (eventually in conjunction with thymus weight)

• Receptor occupancy (or other pharmacodynamic markers) in lung and systemic circulation

Assessment of pulmonary targeting in humans

• Comparison of pulmonary effects after inhalation and systemic administration of doses inducing similar systemic effects

• Comparison of pulmonary effects after inhalation of different drugs at doses achieving identical systemic effects

• PK/PD-based approaches in humans e.g., by administering sephadex [92-94]. This results in an increase in lung weight. The topical activity of inhaled glucocorticoids has been tested in such models by administering the glucocorticoid into the left lung lobe of rats, followed by administration of sephadex to the whole lung. Observing the differential effects of the glucocorticoid on left and right lobe weight can assess targeting. Targeting is observed when the effects on the left lobe are more pronounced than the effects on the right lobe, which will be exposed only to systemic glucocorticoid concentrations [95]. Alternatively, systemic effects of glucocorticoids have been assessed by monitoring the effects on thymus weight and comparing those with the local effects in the sephadex assay with the drug administered to the whole lung [95].

Other targeting models in rats or mice are based on the ex vivo monitoring of receptor occupancy after intratracheal administration of the drug, described here for glucocorticoids. Such models are based on the finding that the glucocorticoid receptors are similar in different tissues, resulting in identical receptor occupancy-time profiles when free levels in different tissues are identical, e.g., after systemic administration of a drug. Pulmonary targeting after intratracheal administration can then be assessed by comparing the receptor occupancy in the lung to a systemic organ such as the liver or kidney. A more pronounced receptor occupancy in the lung after intratracheal administration would then indicate pulmonary targeting. Similar approaches could be designed for cell membrane receptors, for example, for the beta-adrenergic receptors, using ex vivo receptor-binding approaches developed for other membrane receptors [96].

Assessment ofPulmonary Targeting in Humans. The direct assessment of pulmonary targeting in humans is not trivial. Quite often it is reduced to separately monitoring pharmacodynamic effects in the lung and systemic circulation. Comparing these properties with other drugs or dosing regimens often allows some conclusion on pulmonary selectivity. Because of the importance of assessing systemic and pulmonary effects, the following sections will first review approaches to assessing pulmonary and systemic effects and then discuss clinical approaches to quantifying targeting.

NONCOMPARTMENTAL ANALYSIS TO ASSESS SYSTEMIC EFFECTS IN HUMANS. The degree of systemic side effects can easily be measured for most inhalation drugs. This includes, for example, the change in plasma potassium levels [97,98] and increase in heart rate for beta-2-adrenergic drugs. Other parameters, such as lymphocyte numbers, the suppression of 24-hour urine cortisol [70,99] and 24-hour serum cortisol levels [100] (a more sensitive parameter) have been used for inhaled glucocorticoids.

In addition, linear growth measurements by stadiometry or knemometry, long-term bone density measurements, and the monitoring of bone markers have been used (for review see Refs. 101 and 102). As shown in Fig. 12 for the Cortisol suppression by inhaled steroids, comparison between baseline and treatment-time profiles permits the calculation of the degree of suppression:

„ „ . 100(A.UCBaseline 2 AUCxreatment) % Suppression =-———-

AUCBaseline

Pk/pd-based modeLs to assess systemic effects in humans. While "noncompartmental" approaches are purely descriptive, PK/PD models for the evaluation of systemic side effects have been developed for a number of drug classes, including beta-2-adrenergic drugs (effects on potassium [97]), increase in heart rate [91], and glucocorticoids (cortisol suppression [103]), as well as effects on lymphocytes and granulocytes [104]. These approaches have the advantage of being useful in clinical trial simulations, thereby helping to streamline drug development. In general, plasma levels after inhalation are linked through

Figure 12 Illustration of the quantification of 24-hour cortisol suppression during multiple dosing of an inhaled steroid given b.i.d. The difference between placebo, or baseline (dashed line), and active treatment (solid line) can be used to calculate the degree of cortisol suppression. (Generated using an Excel spreadsheet developed by S. Krishnaswami et al., Ref. 114.)

Figure 12 Illustration of the quantification of 24-hour cortisol suppression during multiple dosing of an inhaled steroid given b.i.d. The difference between placebo, or baseline (dashed line), and active treatment (solid line) can be used to calculate the degree of cortisol suppression. (Generated using an Excel spreadsheet developed by S. Krishnaswami et al., Ref. 114.)

a PK/PD approach with the pharmacodynamic effects either directly (through an Emax model) or, in the case of hysteresis between plasma concentrations and effect, through a so-called effect-compartment model (e.g., drug concentration in a hypothetical effect compartment is linked to the effect) or through an indirect-response model (e.g., drug modulates the synthesis rate of a hormone).

For other models, such as indirect-response [105] and effect-compartment models [106], it is necessary to model more complex effect-time relationships.

For example, such simple PK/PD models as described in Fig. 13 have been used to describe the effects of beta-2-adrenergic drugs on the heart rate, but models incorporating an effect-compartment [106] or indirect-response model [105] are necessary for other drug actions, such as the effects of glucocorticoids on lymphocytes and endogenous cortisol suppression (for review see Ref. 107).

Major advantages of such models are that they enable the identification of dosing regimens with given characteristics. They also enable the identification of equivalent doses of two different drugs or the prediction of how changes in doses and delivery devices will affect the systemic side effects. Assessment of puLmonary effects in humans. In order to fully characterize an inhalation drug, knowledge of the topical-to-systemic-effect ratio is desirable. Thus, in addition to systemic side effects, pharmacodynamic assessments of the pulmonary effects need to be generated. Various lung function tests, including forced expiratory volume in one sec (FEVj), peak expiratory flow rate (PEFR), forced vital capacity (FVC), mid-expiratory flow rate (MEFR), and use of airway hyperresponsiveness, have been used to measure the degree of pulmonary effects in asthmatics using the spirometer or body plethysmography. Besides these, biomarkers of local effects, such as the reduction in certain cytokines, and modulation of nitric oxide [108,109] can be useful. In addition, the use of more traditional clinical parameters, such as diary scores, the need of rescue medication, treatment failures, progression of disease, and other routinely measure clinical parameters, are useful.

Figure 13 Simple PK/PD model linking plasma concentration directly to the effect.

For beta-2-adrenergic drugs, pulmonary effects, such as the reduction in FEVj, are "hard parameters" that have been used for the assessment of pulmonary bioequivalence. As an example, detailed information has been given by the Endocrinology, Metabolism and Allergy Unit Bureau of Pharmaceutical Assessment Therapeutic Products Programme Health Canada (http://www.hcsc. gc.ca/hpb-dgps/therapeut/zfiles/english/guides/mdi/mdiatt_e.html) to use lung function parameters (FEV1) for establishing equivalence or relative potency and safety of a second-entry short-acting beta-2-agonist metered-dose inhaler in asthmatic patients with defined severity.

For glucocorticoids, monitoring the pulmonary effects is made difficult because the time profile of glucocorticoid effects takes days or weeks to detect, and consequently time resolution of the pulmonary effects is low. Suitable surrogate markers of the pulmonary effects have not yet been fully described. This makes studies to quantify the pulmonary effects challenging, because dose-effect relationships obtained by using clinical outcome parameters are often very flat, and differences among different inhaled steroids are not easy to establish. Some data seem to suggest that pulmonary effects after exercise-induced asthma or stimulation with adenosine phosphate [110,111] is more sensitive, and dose-response curves are easier to obtain [112]. Typical results of such studies include the assessment of the comparative efficacy of different doses of the same drug or clinically relevant doses of different inhalation drugs.

Pk/pd-based modeLs to assess puLmonary effects in humans. Currently, direct PK/PD methods for pulmonary effects have not been established, because the assessment of free drug concentration in the lung is very difficult, especially in humans.

Using systemic and puLmonary effects to assess puLmonary targeting in humans. Using markers for both systemic and pulmonary effects, attempts have been made to quantify or demonstrate pulmonary targeting. In one possible clinical design, pulmonary effects observed after systemic administration of the drug and after inhalation are compared. In this case (and without the availability of a robust PK/PD model), doses after systemic administration and inhalation have to be selected in such a way that systemic drug levels and systemic side effects are equivalent after both forms of administration. Pulmonary effects are then quantified after oral administration and inhalation. If pulmonary targeting is observed after inhalation, one would expect similar systemic effects after oral absorption but more pronounced systemic effects after inhalation (Fig. 14).

Toogood and coworkers used such an approach for the assessment of budesonide [113]. Patients were pretreated with beclomethasone dipropionate and then randomized to oral or inhaled budesonide, at doses expected to yield similar systemic budesonide levels. At these doses, the time to relapse

Figure 14 Clinical differences in pulmonary targeting. Doses of inhaled drugs are identified that will produce equipotent systemic effects. The drug with the higher degree of pulmonary effects will show more pronounced targeting. In a similar design, the same drug could be given orally and through inhalation. More pronounced pulmonary effects after inhalation snow targeting.

Figure 14 Clinical differences in pulmonary targeting. Doses of inhaled drugs are identified that will produce equipotent systemic effects. The drug with the higher degree of pulmonary effects will show more pronounced targeting. In a similar design, the same drug could be given orally and through inhalation. More pronounced pulmonary effects after inhalation snow targeting.

(the primary pulmonary outcome parameter) was longer for inhaled budesonide than after oral budesonide or placebo. This clinical approach showed, for the first time, targeting of an inhaled steroid. Such noncompartmental approaches for pulmonary targeting can be easily demonstrated for beta-2-adrenergic drugs, which show much steeper dose-response curves.

Pharmacokinetic/Pharmacodynamic modeling approaches might also be useful in demonstrating pulmonary targeting after inhalation. Such approaches have the advantage that one does not depend on the realization of similar systemic drug levels after systemic and pulmonary drug administration or on the difficulties to find such equivalent doses. A PK/PD-based approach to quantify the degree of pulmonary targeting was described for the beta-2-adrenergic drug fenoterol. Fenoterol was given systemically and after inhalation. The pharmacokinetic and pharmacodynamic (heart rate, change in FEVj) data obtained after intravenous drug administration allowed the establishment of a robust PK/PD model with high predictive power for both systemic side effects and pulmonary effects. Figure 15 shows a discrepancy between PK/PD-derived predicted and clinically measured pulmonary effects. The differences between the PK/PD-based predicted pulmonary effects and the actual clinical responses (composite of systemic and local effects) allow the quantification of the degree of pulmonary targeting, because these effects must be induced by the higher pulmonary drug concentrations.

Figure 15 Effects of inhaled fenoterol (400 mg) on the heart rate (HR, open circles) and on reduction in pulmonary resistance (closed circles). Although the plasma levels of fenoterol are a good descriptor for systemic effects (HR), plasma levels cannot be used to predict effects on the pulmonary resistance. The area between the closed circles and the lower smooth line represents pulmonary selectivity.

Figure 15 Effects of inhaled fenoterol (400 mg) on the heart rate (HR, open circles) and on reduction in pulmonary resistance (closed circles). Although the plasma levels of fenoterol are a good descriptor for systemic effects (HR), plasma levels cannot be used to predict effects on the pulmonary resistance. The area between the closed circles and the lower smooth line represents pulmonary selectivity.

Was this article helpful?

0 0
Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

Get My Free Ebook


Post a comment