Pharmacokinetic/Pharmacodynamic Aspects of Aerosol Therapy using Glucocorticoids as a Model

Hochhaus, Günther; Möllmann, H; Derendorf, Hartmut; Gonzalez‐Rothi, Ricardo J.

doi:10.1002/j.1552-4604.1997.tb04262.x

Cited by 99 publications

(49 citation statements)

References 29 publications

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“…Higher oral and IV doses, however, would result in higher plasma concentrations associated with a higher probability of systemic adverse drug reactions (8,9), since drug deposited in the lung is typically not instantaneously absorbed to systemic circulation. Hence, for drugs without instantaneous pulmonary absorption, oral drug inhalation typically results in a favorable benefit/(systemic) risk ratio (10).…”

Section: The Lung As Target For Drug Administrationmentioning

confidence: 99%

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

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Abstract. During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

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Section: The Lung As Target For Drug Administrationmentioning

confidence: 99%

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

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“…This model has been previously used to assess and identify PK and PD parameters relevant for pulmonary selectivity (Hochhaus et al, 1997). Two hypothetical glucocorticoids, differing only in tissue and plasma protein binding, were compared at the same pulmonary dose.…”

Section: Compoundmentioning

confidence: 99%

“…Free concentrations were determined after intravenous administration of the drugs to rats, and the receptor occupancies in the lung were related to the free tissue drug concentrations. In addition, a previously used PK/PD model was used to simulate differences in protein binding on pulmonary selectivity and targeting after inhalation of drugs that differ in protein binding (Hochhaus et al, 1997).…”

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confidence: 99%

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Budesonide and Ciclesonide: Effect of Tissue Binding on Pulmonary Receptor Binding

Wu¹,

Blomgren²,

Ekholm³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Newer inhaled glucocorticoids often show low systemic side effects because of their high protein binding. This study was interested in evaluating the effects of increased plasma protein and tissue binding on pulmonary receptor occupancy. Rats received des-ciclesonide (des-CIC; the active metabolite of the prodrug ciclesonide) and budesonide (BUD; a drug with lower protein binding but similar receptor affinity) as constant rate infusion over 6 h (intravenous bolus of 30 g/kg, followed by 10 g/h/kg over 6 h). Total and free glucocorticoid concentration in plasma and tissues, as well as the number of occupied lung glucocorticoid receptors, was determined. A pharmacokinetic/pharmacodynamic (PK/PD) model investigated the effects of varying plasma and tissue binding on pulmonary and systemic receptor occupancy after inhalation. After constant rate infusion, the total drug concentration in tissues and plasma was comparable for both drugs, whereas the free concentration of des-CIC in all the tissues and plasma was one fifth to one seventh that of BUD. This translated into lower receptor occupancy in the lung for des-CIC (49 ؎ 11%) than for BUD (94 ؎ 8%). The PK/PD model predicted lower receptor occupancy in the lung and the systemic tissues when a drug with pronounced binding was inhaled. Glucocorticoids with higher plasma and tissue binding might show not only lower systemic side effects but also reduced efficacy in the lung when given in a similar microgram dose.

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“…9, 14. To describe the interaction between the lungs and the systemic circulation, it is important to allow for a back‐flow of drug from the blood to the lungs.…”

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confidence: 99%

A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

Boger

Wigström

2018

CPT Pharmacom & Syst Pharma

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The heterogeneous nature of the lungs and the range of processes affecting pulmonary drug disposition make prediction of inhaled drugs challenging. These predictions are critical, as the local exposure cannot be measured and current inhalation physiologically based pharmacokinetic (PBPK) models do not capture all necessary features. Utilizing partial differential equations, we present an inhalation PBPK model to describe the heterogeneity in both lung physiology and particle size. The model mechanistically describes important processes, such as deposition, mucociliary clearance, and dissolution. In addition, simplifications are introduced to reduce computational cost without loss of accuracy. Three case studies exemplify how the model can enhance our understanding of pulmonary drug disposition. Specific findings include that most small airways can be targeted by inhalation, and overdosing may eradicate the advantage of inhalation. The presented model can guide the design of inhaled molecules, formulations, as well as clinical trials, providing opportunities to explore regional targeting.

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Pharmacokinetic/Pharmacodynamic Aspects of Aerosol Therapy using Glucocorticoids as a Model

Cited by 99 publications

References 29 publications

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Budesonide and Ciclesonide: Effect of Tissue Binding on Pulmonary Receptor Binding

A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

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