Pharmacokinetics of Orally Inhaled Drug Products

Hochhaus, Günther; Horhota, Stephen T.; Hendeles, Leslie; Suárez, Sandra; Rebello, Juliet

doi:10.1208/s12248-015-9736-6

Cited by 36 publications

(27 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The EMA currently suggests a stepwise evaluation of in vitro and in vivo pharmacokinetic and pharmacodynamics studies, while the US-FDA endorses an 'aggregate weight of evidence' approach for establishing the bioequivalence of inhalation drugs (Apiou-Sbirlea et al, 2013;Lu et al, 2015). Even though the performance of a bioequivalence study is not always considered sufficient to establish therapeutic equivalence between two locally acting orally inhaled drugs (Lu et al, 2015), and certain critical issues when conducting such studies exist (Thakkar, Mhatre, Jadhav, Goswami, & Shah, 2015), PK studies are still considered the most sensitive methodology in detecting differences between two inhalation drug products (Hochhaus, Horhota, Hendeles, Suarez, & Rebello, 2015).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Soulele

Macheras

Karalis

2017

Biopharm & Drug Disp

View full text Add to dashboard Cite

Salmeterol (SAL) is a long-acting β2-adrenergic agonist, which is widely used in the therapy of asthma. The aim of this study was to investigate the pharmacokinetics (PK) of inhaled salmeterol in asthma patients using two different dry powder inhalers. This analysis was based on data from 45 subjects who participated in a two-sequence, four-period crossover bioequivalence (BE) study after single administration of the test (T) and reference (R) products. In order to mimic more closely the real treatment conditions, activated charcoal was not co-administered. Plasma concentration-time (C-t) data were initially analysed using classic non-compartmental PK approaches, while the main objective of the study was to apply population PK modeling. The relative fraction of the dose absorbed via the lungs (R ) was set as a parameter in the structural model. The plasma C-t profiles of salmeterol showed a biphasic time course indicating a parallel pulmonary and gastrointestinal (GI) absorption. A two-compartment disposition model with first order absorption from the GI and very rapid absorption from lungs (like an i.v. bolus) was found to describe successfully the C-t profiles of salmeterol. The estimated R value was 13% suggesting a high gut deposition of inhaled salmeterol. Women were found to exert less capability to eliminate salmeterol than men, while body weight (in allometric form) was found to be an important covariate on the peripheral volume of distribution.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Soulele

Macheras

Karalis

2017

Biopharm & Drug Disp

View full text Add to dashboard Cite

show abstract

“…The efficacy of inhaled COPD treatments is associated with the presence of the drug in the lungs [12]; however, absorption into the systemic circulation may elicit additional pharmacologic effects that could influence the safety and tolerability profile of the drug. [13] Previous studies have found that the pharmacokinetic (PK) profiles of BGF MDI and GFF MDI were comparable between Western and Japanese healthy adults.…”

Section: Introductionmentioning

confidence: 97%

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study

Chen

Yu³

et al. 2019

Clinical Therapeutics

View full text Add to dashboard Cite

Purpose: The objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixeddose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing.Methods: This Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18e45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 mg, BGF MDI 160/14.4/10 mg, or GFF MDI 14.4/10 mg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC 0e12 , C max , and T max . Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values.Findings: Ninety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC 0e12 and C max were increased dose proportionally from BGF MDI 160/14.4/10 mg to BGF MDI 320/14.4/10 mg, respectively (single dose: AUC 0e12 , 811.8 vs 1748 h $ pg/mL; C max , 224.3 vs 459.3 pg/mL; repeated dosing: AUC 0e12 , 1250 vs 2510 h $ pg/mL; C max , 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC 0e12 and C max were similar across all treatments (single dose: AUC 0e12 , 27.20e29.40 h $ pg/mL; C max , 4.884e5.674 pg/mL; repeated dosing: AUC 0e12 , 69.49e77.08 h $ pg/mL; C max , 11.30e13.12 pg/mL) and formoterol (single dose: AUC 0e12 , 46.49e53.58 h $ pg/mL; C max 9.651e10.62 pg/mL; repeated dosing: AUC 0e12 , 81.94e85.32 h $ pg/mL; C max, 16.13e17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%e56.3%). There were no new or unexpected findings on tolerability.Implications: Overall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267. (Clin Ther. 2019;41:897e909)

show abstract

“…However, when plotted in Figure , these k a values of FP were found to be far lower than the value predicted from MW and K D ‐dependent diffusion. This suggested that the lung absorption of fluticasone propionate was unusually slow (a half‐life of ~3.5 h) and thus rate‐limited by a mechanism other than lung membrane diffusion, such as dissolution due to poor aqueous solubility (~0.1 μg/ml), as has been attributed elsewhere (Hochhaus, Horhota, Hendeles, Suarez, & Rebello, ; Sakagami & Arora‐Lakhani, ). In contrast, the k nad values were different in the MDI and DPI delivery, and the DPI delivery resulted in a greater k nad value (faster non‐absorptive disposition) than the MDI delivery (Table ).…”

Section: Resultsmentioning

confidence: 70%

“…In contrast, the k nad values were different in the MDI and DPI delivery, and the DPI delivery resulted in a greater k nad value (faster non‐absorptive disposition) than the MDI delivery (Table ). Like CPFX, the non‐absorptive disposition of FP in the lung was primarily due to mucociliary clearance (Hochhaus et al, ; Sakagami & Arora‐Lakhani, ). If so, this greater k nad value for the DPI would make sense, given that its 12% of the in vitro DTL in a size < 2 μm, compared with 33% for MDI (Table ), predicted a shallower lung regional deposition and faster mucociliary clearance.…”

Section: Resultsmentioning

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

View full text Add to dashboard Cite

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

show abstract

Pharmacokinetics of Orally Inhaled Drug Products

Cited by 36 publications

References 8 publications

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study

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

Contact Info

Product

Resources

About