Pharmacokinetics of Fluticasone Propionate Inhaled via the Diskhaler?? and Diskus?? Powder Devices in Healthy Volunteers

Mackie, Alison E.; McDowall, Jo E.; Falcoz, Christine; Ventresca, Pietro; Bye, Alan; Daley‐Yates, Peter T.

doi:10.2165/00003088-200039001-00004

Cited by 44 publications

(46 citation statements)

References 3 publications

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“…11,12) The present results support and confirm those previous studies, as the estimated amount of drug deposited in stage 2 was 10.1 mg at a flow rate of 60 l/min, adequate for obtaining a good effect from a Diskhaler and similar to the 12% reported previously. Moreover, the amount of drug deposited in stage 2 at a flow rate of 60 l/min was 10.1 mg and slightly increased to 11.3 mg at 90 l/min.…”

Section: Discussionsupporting

confidence: 92%

Analysis of Relationship between Peak Inspiratory Flow Rate and Amount of Drug Delivered to Lungs Following Inhalation of Fluticasone Propionate with a Diskhaler

Yokoyama

Yamamura

Ozeki

et al. 2007

Biological & Pharmaceutical Bulletin

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A fluticasone propionate dry powder inhaler with a Diskhaler (FP-DH), developed for inhalation of corticosteroids, is widely used for the treatment of asthma. A dry powder inhaler (DPI) is a breath controlled drug delivery system, in which a turbulent airstream is created by exploiting the patient's own inspiratory flow rate and is required to aerosolize particles for inhalation at a satisfactory peak inspiratory flow rate, which can achieve sufficient diffusion of the drug into the lungs. Therefore, it is considered that the inspiratory flow rate of the patient has a significant influence on the effects of drugs administered by an FP-DH.It was reported that 28 of 233 patients who inhaled corticosteroids for asthma could not achieve the optimal flow rate of 60 l/min, of whom 5 were treated for exacerbation of symptoms.1) Thus, it is very important to clarify the relationship between inspiratory flow rate and amount of drug delivered into the lungs when using a DPI. Although several in vitro studies have shown the delivery of drugs into the lungs at unvaried or slightly varied high flow rates, there is no known examination of the detailed relationship of these factors. [2][3][4][5][6] In the present study, we investigated the relationship between inspiratory flow rate and amount of drug delivered into the lungs by quantification of FP after inhalation with an FP-DH equipped with a twin impinger at various inspiratory flow rates. MATERIALS AND METHODS Materials A Flutide® 100 Rotadisk ® (GlaxoSmithKline K.K., Lot No. 355) was used as the FP-DH in the present study. A blister contains a mixture of 100 mg of microfine FP blended with lactose to a total weight of 25 mg. Geometric particle size of FP was Ϲ5 mm ( 90%м of particles), 7) aerodynamic particle size of FP was 3.3 mm, 8) and geometric particle size of lactose was 60-90 mm.7) To investigate the amount of drug inhaled, we used an inhalation simulator ( Fig. 1), which consisted of a flow recorder placed in a plastic air-tight box that covered the FP-DH equipped with a twin impinger and a vacuum pump. The FP-DH was kept at angle of 90°to the inlet of the impinger. The flow rate was recorded using a Vitalograph ® 2120 Handheld Storage spirometer (Vitalograph Ltd.), and data was transferred to a computer and analyzed using Vitalograph ® Spirotrac ® IV software. The relative amounts of the drug distributed inside a plastic box (a), and the device (b), throat (c), stage 1 (upper impinger) (d), and stage 2 (lower impinger) (e) were determined by measuring the amounts of drugs in those areas. The experiments were performed at 20°C with 30% relative humidity. The flow rates ranged from 18.7 to 77.3 l/min for 2 s. A Diskhaler is a dry powder type of inhaler that utilizes a breath controlled drug delivery system. The inspiratory flow rate of the patient would have a significant influence on the effects of drugs administered by a Diskhaler. Thus, we investigated the relationship between inspiratory flow rate and amount of drug delivered into the lungs when using a flutica...

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Section: Discussionsupporting

confidence: 92%

Analysis of Relationship between Peak Inspiratory Flow Rate and Amount of Drug Delivered to Lungs Following Inhalation of Fluticasone Propionate with a Diskhaler

Yokoyama

Yamamura

Ozeki

et al. 2007

Biological & Pharmaceutical Bulletin

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“…As the terminal elimination phase is entered at a late stage, around 8±16 h after administration (Figure 1), it is dif®cult to make proper estimates of the terminal elimination half-life if plasma is sampled during a time period that is too short. This is a likely explanation as to why shorter half-lives, ranging from 3.1 to 8.3 h for intravenous administrations, were found in previous studies [1,6,18,19]. In those studies, the estimates were made from plasma concentrations obtained only up to 24 h, at most, after administration.…”

Section: Discussionmentioning

confidence: 92%

“…If so, the terminal half-life would be longer after inhalation than after intravenous administration. There are studies indicating a shorter half-life after intravenous administration (7±8 h) [5] than after inhalation (10±12 h) [6], but determination of the terminal halflife may have been inaccurate in the intravenous studies due to plasma concentrations going below the lower limit of quanti®cation (LOQ). An improved bioassay with a lower LOQ, in combination with high intravenous doses and longer sampling time, would enable a more correct estimation of the terminal phase of the plasma concentration curve.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Thorsson

Edsbäcker

Källén

et al. 2001

Brit J Clinical Pharma

156

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Aims To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids. Methods Twenty-one subjects (13 healthy and 8 mild asthmatic patients) received uticasone propionate via a chloro¯uorocarbon-propelled pressurized metered-dose inhaler (pMDI) (healthy subjects only) and Diskus 1 and budesonide via Turbuhaler 1 , 1000 mg twice daily for 7 days. Intravenous doses (200 mg) of both compounds were used as references. Plasma concentrations of¯uticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC-MS-MS). Plasma concentrations of cortisol were determined by LC-MS every second hour for 24 h at baseline, and following each treatment. Results The volume of distribution was found to be larger and the elimination half-life and mean absorption time longer for¯uticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was signi®cantly higher than that of uticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% con®dence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of¯uticasone via pMDI was signi®cantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2-fold [1.7, 2.9] higher than that of¯uticasone pMDI and 3.4-fold [2.8, 4.0] higher than that of uticasone Diskus. In addition, the lung deposition of¯uticasone via pMDI was 1.5-fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was signi®cantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for¯uticasone pMDI, which was signi®cantly lower (ratio 0.32 [0.24, 0.42]) than that for¯uticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ signi®cantly between treatments with¯uticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]). Conclusions Budesonide and¯uticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for uticasone. Despite a signi®cantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of¯uticasone via pMDI and similar to that of¯uticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of¯uticasone and budesonide.

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“…This can be illustrated by performing similar calculations for another inhaled steroid with similar in vitro potency [2] (i.e.¯uticasone propionate (FP)). The systemic bioavailability of FP in healthy subjects delivered via the Diskus TM (GlaxoWellcome, Research Triangle Park, NC, USA) is y17% [3]. However, this result is based on data from a study where FP plasma levels were measured following a 1,000 mg dose, with an assay limit of detection of 25 pg .…”

Section: To the Editorsmentioning

confidence: 99%

Systemic bioavailability of inhaled steroids: the importance of appropriate and comparable methodology

Derendorf¹,

Daley‐Yates²,

Pierre³

et al. 2001

Eur Respir J

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Pharmacokinetics of Fluticasone Propionate Inhaled via the Diskhaler?? and Diskus?? Powder Devices in Healthy Volunteers

Cited by 44 publications

References 3 publications

Analysis of Relationship between Peak Inspiratory Flow Rate and Amount of Drug Delivered to Lungs Following Inhalation of Fluticasone Propionate with a Diskhaler

Analysis of Relationship between Peak Inspiratory Flow Rate and Amount of Drug Delivered to Lungs Following Inhalation of Fluticasone Propionate with a Diskhaler

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Systemic bioavailability of inhaled steroids: the importance of appropriate and comparable methodology

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Pharmacokinetics of Fluticasone Propionate Inhaled via the Diskhaler?? and Diskus?? Powder Devices in Healthy Volunteers

Cited by 44 publications

References 3 publications

Analysis of Relationship between Peak Inspiratory Flow Rate and Amount of Drug Delivered to Lungs Following Inhalation of Fluticasone Propionate with a Diskhaler

Analysis of Relationship between Peak Inspiratory Flow Rate and Amount of Drug Delivered to Lungs Following Inhalation of Fluticasone Propionate with a Diskhaler

Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®

Systemic bioavailability of inhaled steroids: the importance of appropriate and comparable methodology

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Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®