Pharmacokinetic studies for proving bioequivalence of orally inhaled drug productsâ€”critical issues and concepts

Thakkar, Karan; Mhatre, Suyog; Jadhav, Manish; Goswami, Sailendra; Shah, Rajen D.

doi:10.3389/fphar.2015.00117

Cited by 8 publications

(6 citation statements)

References 31 publications

(33 reference statements)

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“…In addition, the issue, whether PK studies represent the most sensitive marker of BE, is currently under extensive discussion . Thus, some critical points have been identified regarding the proof of BE in case of orally inhaled drug products (Thakkar et al, 2015). The BE results for the FLP and SAL data utilized in this analysis are listed in Table 3.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…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

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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.

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“…This randomized, evaluator-blinded, active-controlled, single dose, two-arm crossover PK study in healthy subjects was conducted at a single site located in the United States. Because doses administered through inhalation may be too small for detection in plasma concentration, (4) a high dose of five times the normal dose (i.e., 10 inhalations) was used to ensure adequate measurements of plasma concentrations for PK analysis. To thoroughly explore the PK profile of Epi-HFA, a stable isotope deuterium-labeled epinephrine was used to differentiate the administered exogenous epinephrine (epinephrine-d3) from the endogenous epinephrine (epinephrine-h3).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Study of Epinephrine Hydrofluoroalkane (Primatene MIST) Metered-Dose Inhaler

Kerwin

Marrs²,

Luo³

et al. 2020

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: Primatene Ò MIST CFC, an epinephrine metered-dose inhaler (MDI), was discontinued from the market owing to environmental concerns from its use of chlorofluorocarbon (CFC) propellant. As a result, a new epinephrine MDI was developed using hydrofluoroalkane (HFA) propellant. This article reports the pharmacokinetic (PK) profile of the newly Food and Drug Administration-approved epinephrine HFA MDI. Methods: A randomized, evaluator-blinded, active-controlled, single-dose, two-arm crossover study was conducted to evaluate the PK profile of epinephrine HFA (Primatene Ò MIST) and epinephrine CFC (Primatene Ò MIST CFC) in 23 healthy volunteers to characterize the epinephrine absorption extent and rate. The study was performed at a high dose of five times the normal dose to obtain measurable plasma epinephrine levels. Plasma epinephrine levels were measured and safety was assessed by adverse events (AEs), vital signs, clinical laboratory tests, and physical examinations. Results: Epinephrine HFA demonstrated a greater systemic drug exposure (greater area under the curve) than that of epinephrine CFC (*37% higher). The C max occurred at *2 minutes and was significantly higher in the epinephrine HFA group (0.18 ng/mL) compared with the CFC version (0.046 ng/mL) at normal dose. Within 20 minutes, both groups demonstrated comparable plasma epinephrine levels. No clinically significant adverse effects were found to be associated with epinephrine HFA, even after an ultrahigh dose (i.e., 10 inhalations). Conclusions: The systemic exposure of epinephrine HFA was found to be higher for the first 20 minutes, and then comparable with epinephrine CFC. Minimal AEs were found in this study despite the very high 1250-2200 lg inhaled doses (i.e., 10 inhalations) used for PK characterization.

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Pharmacokinetic studies for proving bioequivalence of orally inhaled drug productsâ€”critical issues and concepts

Cited by 8 publications

References 31 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

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

Pharmacokinetic Study of Epinephrine Hydrofluoroalkane (Primatene MIST) Metered-Dose Inhaler

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