Interpretation of absorption rate data for inhaled fluticasone propionate obtained in compartmental pharmacokinetic modeling

Krishnaswami, Sriram; Hochhaus, Günther; Barth, Jeffrey T.; Derendorf, H

doi:10.5414/cpp43117

Cited by 16 publications

(19 citation statements)

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“…Another point that requires special attention is the fact that due to slow dissolution of FLP in the lungs and the non-existence of intravenous data, there is a difficulty to distinguish whether this situation is flip-flop or not. This issue of potential misassignment of the inhaled fluticasone propionate PK parameters was highlighted in the study of Krishnaswami and colleagues who investigated the pharmacokinetics of FLP after single-and multiple-dose administration in 14 healthy volunteers (Krishnaswami et al, 2005). Based on these findings, there can be a mismatching of the absorption with the disposition parameters.…”

Section: Accepted Manuscriptmentioning

confidence: 95%

“…In these articles a discrimination between a central and a peripheral lung region presenting different absorption rates was discussed. However, the development of more complex models and the incorporation of multiple absorption processes through the lung require the use of rich data from both intravenous and inhaled administrations (Bartels et al, 2013;Krishnaswami et al, 2005;Mobey and Hochhaus, 2001). The characterization of the PK models used in this analysis was based solely on data after inhalation which restricted any differentiation between parallel absorption processes.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

See 1 more Smart Citation

Population pharmacokinetics of fluticasone propionate/salmeterol using two different dry powder inhalers

Soulele

Macheras

Silvestro³

et al. 2015

European Journal of Pharmaceutical Sciences

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Section: Accepted Manuscriptmentioning

confidence: 95%

Section: Accepted Manuscriptmentioning

confidence: 99%

Population pharmacokinetics of fluticasone propionate/salmeterol using two different dry powder inhalers

Soulele

Macheras

Silvestro³

et al. 2015

European Journal of Pharmaceutical Sciences

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“…Without the availability of IV data (which is frequently not-publicly-available), it is impossible to determine the actual systemic clearance and volume of distribution parameter value (i.e., both can only be determined as apparent parameters, i.e., as a function of the systemic bioavailability). Moreover, drawing conclusions based on inhalation data alone about absorption or dissolution characteristics of the inhaled drug, i.e., the occurrence of the often mentioned flip-flop kinetics after drug inhalation (42,66,92) is not feasible. These identifiability issues are also relevant for orally administered solid dosage forms.…”

Section: Empirical (Data-derived) Pk Modelingmentioning

confidence: 99%

“…Thus, data after IV and oral administration as well as inhalation is highly desirable to allow determination of all PK parameters and specifying the pulmonary drug absorption appropriately. The challenge of flip-flop kinetics after drug inhalation has been discussed in more detail in (66).…”

Section: Empirical (Data-derived) Pk Modelingmentioning

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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“…Mathematical (pharmacometric) modelling can be applied to draw conclusions about the pulmonary fate of inhaled olodaterol in the target patient population by evaluating PK data from multiple clinical trials following different routes of administration (IV, inhalation, oral) [5,6,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Model‐based evaluation of pulmonary pharmacokinetics in asthmatic and COPD patients after oral olodaterol inhalation

Borghardt

Weber

Staab

et al. 2016

Brit J Clinical Pharma

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AIMSOlodaterol is an orally inhaled β 2 -agonist for treatment of chronic obstructive pulmonary disease (COPD). The aims of this population pharmacokinetic (PK) analysis were: (1) to investigate systemic PK and thereby make inferences about pulmonary PK in asthmatic patients, COPD patients and healthy volunteers, and (2) to assess whether differences in pulmonary efficacy might be expected based on pulmonary PK characteristics. METHODSPlasma and urine data after olodaterol inhalation were available from six clinical trials comprising 710 patients and healthy volunteers (single and multiple dosing). To investigate the relevance of covariates, full fixed-effect modelling was applied based on a previously developed healthy volunteer systemic disposition model. RESULTSA pulmonary model with three parallel absorption processes best described PK after inhalation in patients. The pulmonary bioavailable fraction (PBIO) was 48.7% (46.1-51.3%, 95% confidence interval) in asthma, and 53.6% (51.1-56.2%) in COPD. In asthma 87.2% (85.4-88.8%) of PBIO was slowly absorbed with an absorption half-life of 18.5 h (16.3-21.4 h), whereas in COPD 80.1% (78.0-82.2%) was absorbed with a half-life of 37.8 h (31.1-47.8 h). In healthy volunteers absorption was faster, with a half-life of 18.5 h (16.3-21.4 h) of the slowest absorbed process, which characterized 74.6% (69.1-80.2%) of PBIO. CONCLUSIONSThe modelling approach successfully described data after olodaterol inhalation in patients and healthy volunteers. Slow pulmonary absorption was demonstrated both in asthma and COPD. Absorption characteristics after olodaterol inhalation indicated even more beneficial lung targeting in patients compared to healthy volunteers. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• A long pulmonary residence time was demonstrated in healthy volunteers that might contribute to the long-lasting pulmonary efficacy of olodaterol inhaled with the Respimat® device. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2016) 82 739-753 739

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Interpretation of absorption rate data for inhaled fluticasone propionate obtained in compartmental pharmacokinetic modeling

Cited by 16 publications

References 0 publications

Population pharmacokinetics of fluticasone propionate/salmeterol using two different dry powder inhalers

Population pharmacokinetics of fluticasone propionate/salmeterol using two different dry powder inhalers

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Model‐based evaluation of pulmonary pharmacokinetics in asthmatic and COPD patients after oral olodaterol inhalation

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