Translational Model to Predict Pulmonary Pharmacokinetics and Efficacy in Man for Inhaled Bronchodilators

Hendrickx, Ramon; Bergström, Eva Lamm; Janzén, David; Fridén, Markus; Eriksson, Ulf G.; Grime, Ken; Ferguson, Douglas

doi:10.1002/psp4.12270

Cited by 29 publications

(26 citation statements)

References 34 publications

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“…With the results (Table ) from the lung delivery and disposition model (Figure C and Figure ), it should be clear that the F A value was an underestimate due to a loss of the inhaler's delivery efficiency (F deliv = 0.22); and the k A and k abs values were overestimates due to the rate constant of lung non‐absorptive disposition (k nad = 0.48 h −1 ). Mathematically, the following relationships were found among these parameters:

F_{A} = F_{deliv} \times F_{abs}

k_{A} = k_{abs} = k_{a} + k_{nad}

By now, many different modeling approaches have been attempted for accurately interpreting and predicting the PK profiles of inhaled drugs and products in humans (Bäckman et al, ; Borghardt et al, ; Byron, ; Hendrickx et al, ; Jones & Harrison, ; Weber & Hochhaus, ). Among them, with an advent of computation software, such as Gastroplus™, PK‐SIM™ and SimCyp Simulator™, PBPK modeling has recently gained a great interest for use in various stages of inhaled drug and product development (Bäckman et al, ; Borghardt et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Several approaches have been attempted in order to clarify and predict the kinetic behavior of inhaled drugs in humans, including compartment model‐based simulation (Byron, ; Weber & Hochhaus, ), the scaled use of animal data (Hendrickx et al, ; Jones & Harrison, ), and multiplex physiologically based PK (PBPK) modeling (Bäckman et al, ; Borghardt et al, ). However, to yield accurate and convincing outcomes, many variables and complexities uniquely inherent to inhaled aerosol delivery, deposition, and drug disposition must properly be taken into consideration (Bäckman et al, ; Hastedt et al, ; Sakagami & Gumbleton, ).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model

Raut

Dhapare

Venitz

et al. 2019

Biopharm & Drug Disp

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The kinetic clarification of lung disposition for inhaled drugs in humans via pharmacokinetic (PK) modeling aids in their development and regulation for systemic and local delivery, but remains challenging due to its multiplex nature. This study exercised our lung delivery and disposition kinetic model to derive the kinetic descriptors for the lung disposition of four drugs [calcitonin, tobramycin, ciprofloxacin and fluticasone propionate (FP)] inhaled via different inhalers from the published PK profile data.With the drug dose delivered to the lung (DTL) estimated from the corresponding γ-scintigraphy or in vivo predictive cascade impactor data, the model-based curvefitting and statistical moment analyses derived the rate constants of lung absorption (k a ) and non-absorptive disposition (k nad ). The k a values differed substantially between the drugs (0.05-1.00 h −1 ), but conformed to the lung partition-based membrane diffusion except for FP, and were inhaler/delivery/deposition-independent.The k nad values also varied widely (0.03-2.32 h −1 ), yet appeared to be explained by the presence or absence of non-absorptive disposition in the lung via mucociliary clearance, local tissue degradation, binding/sequestration and/or phagocytosis, and to be sensitive to differences in lung deposition. For FP, its k a value of 0.2 h −1 was unusually low, suggesting solubility/dissolution-limited slow lung absorption, but was comparable between two inhaler products. Thus, the difference in the PK profile was attributed to differences in the DTL and the k nad value, the latter likely originating from different aerosol sizes and regional deposition in the lung. Overall, this empirical, rather simpler model-based analysis provided a quantitative kinetic understanding of lung absorption and non-absorptive disposition for four inhaled drugs from PK profiles in humans. K E Y W O R D Scurve-fitting, inhaled drug, modeling, pharmacokinetics (PK), statistical moment analysis

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F_{A} = F_{deliv} \times F_{abs}

k_{A} = k_{abs} = k_{a} + k_{nad}

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model

Raut

Dhapare

Venitz

et al. 2019

Biopharm & Drug Disp

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“…Similarly, micro-kinetic models suggest that the retention of β-agonists is due to the interaction with the phospholipid membrane to produce a depot for maintenance of local efficacious drug concentrations around the target receptor (Sykes et al., 2014 ). The multiphasic lung profile of β-agonist bronchodilators ( Figure 1(c) ) has recently been characterized with a pharmacokinetic model structure with both a shallow (rapidly equilibrating) and deep (slowly equilibrating) lung compartment (Hendrickx et al., 2017 ) where the release of drug from the unidentified deep compartment provides the lung retention. In contrast, Borghardt et al.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the regional localization of inhaled salmeterol retention in the lung

et al. 2018

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Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d3-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.

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“…Here, E denotes the effect associated with a given C u,bronchi , E max represents the maximum attainable effect (here 100%), and the EC 50,free represents the unbound concentration needed to achieve half-maximal effect. To exemplify the impact for the example of SAL, the EC 50 for SAL was taken from Hendrickx et al [8], who measured the inhibition of methacholine-induced bronchoconstriction and found an EC 50 of 36 nM (total lung concentration). This value was scaled to unbound concentrations using the fraction unbound in plasma (f u,plasma ) and the estimated K p in bronchi (K p,B ):…”

Section: Modelling and Simulationmentioning

confidence: 99%

“…The local pulmonary tissue PK and therefore the local tissue retention is determined by two aspects, first the tissue affinity and second the local perfusion. Due to experimental difficulties, investigations of pulmonary tissue retention have been mostly qualitative in nature [6,7] or were based on empirical estimation of tissue distribution or absorption rate constants [8,9]. A more mechanistic quantitative determination of pulmonary disposition kinetics remains challenging for various reasons: First, after inhalation the variability in the PK is typically much higher compared to other routes of administration, so that a larger data set is required to infer on the pulmonary tissue retention.…”

Section: Introductionmentioning

confidence: 99%

Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention—A Combined In Vivo/In Silico Approach Based on Four Model Drugs

et al. 2020

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Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (Kp) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in Kp between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local Kp, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases.

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Translational Model to Predict Pulmonary Pharmacokinetics and Efficacy in Man for Inhaled Bronchodilators

Cited by 29 publications

References 34 publications

Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model

Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model

Uncovering the regional localization of inhaled salmeterol retention in the lung

Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention—A Combined In Vivo/In Silico Approach Based on Four Model Drugs

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