R03: Drugs for obstructive airway diseases

The dose splits before you model anything. Part deposits in the lung and is absorbed without first pass; the swallowed fraction goes to the gut and is subject to it [1,2]. Plasma concentration is the sum of two inputs with different rates and bioavailabilities [3,4] (see absorption).

Plasma is a poor surrogate for local effect. It tracks systemic safety, adrenal suppression for corticosteroids and tremor for beta-2 agonists, far better than it tracks bronchodilation [5,6]. Modern inhaled corticosteroids are designed to widen that gap through near-complete first-pass removal of the swallowed fraction [5,7].

Isolating the lung dose. A charcoal block prevents gut absorption and is the established way to measure the pulmonary portion [8,9]. It is redundant for corticosteroids whose swallowed fraction is already non-bioavailable.

Endpoint. FEV1, strongly baseline-dependent, so models use change from baseline with an explicit placebo component [10,11], plus a circadian term when spirometry is serial. Bronchodilator dose-response on FEV1 saturates early and is noisy [12], which is why methacholine challenge is used to separate closely spaced doses [13].

Corticosteroid effect is not concentration-driven. It builds over repeated dosing, so the model needs a time-course component rather than a direct link [14,15]. The registrational endpoint is often exacerbation rate, an over-dispersed count [16,17].

Mechanistic extrapolation. Lung PBPK is established here, predicting regional deposition, dissolution and local versus systemic exposure for inhaled drugs whose plasma levels cannot report airway concentration, and supporting inhaled bioequivalence [18,19].

Device variability. The device is a major source of exposure variability that oral and intravenous drugs do not have [7]. The same molecule from different devices can differ roughly two-fold in pulmonary bioavailability [20], and airway obstruction itself alters deposition, so the most obstructed patients may receive the least drug [21,22].