Bioequivalence of Inhaled Formoterol Fumarate Assessed from Pharmacodynamic, Safety and Urinary Pharmacokinetic Data

Marzo, A; Monti, N.; Tettamanti, R; Crivelli, Fabrizio; Bo, Lorenzo Dal; Mazzucchelli, Paolo; Meoli, Andrea; Pezzuto, Donatella; Corsico, Angelo Guido

doi:10.1055/s-0031-1300249

Cited by 6 publications

(6 citation statements)

References 2 publications

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“…After repeated inhaled doses, concentrations up to 15 ng.mL ‐1 and 25.6 ng.mL ‐1 were described. The cumulative percentage of the dose recovered in urine up to 24 h ranged from 10.7 to 17.9% (mean 14.7%), in agreement with data of previous studies …”

Section: Resultssupporting

confidence: 91%

“…The cumulative percentage of the dose recovered in urine up to 24 h ranged from 10.7 to 17.9% (mean 14.7%), in agreement with data of previous studies. [12,13,15,18] It is worth to notice that 8 h after administration, only residual concentrations of formoterol were detected in urine ( Table 2), indicating that no accumulation of the compound occurs. In agreement with our results, concentrations of formoterol the third day after repeated inhaled doses did not significantly differ with concentrations obtained the first day of administration.…”

Section: Resultsmentioning

confidence: 93%

“…[6] The definition of a threshold concentration requires the performance of different administration studies in healthy subjects to assess the urinary levels of the compound after administration of allowed doses. [7][8][9][10] In spite of the high number of pharmacokinetic studies of formoterol in healthy subjects [11][12][13][14] or patients with asthma or COPD, [15] few data on urinary concentrations of formoterol after inhaled administrations are available in the literature to support the threshold value defined by WADA. [16][17][18][19] The objective of this work was to evaluate the threshold concentration of formoterol recently defined by WADA by studying urinary concentrations of the compound in healthy volunteers after inhalation of the maximum allowed dose and in samples from athletes with declared inhaled administration.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the urinary threshold concentration of formoterol in sports drug testing

Ventura

Damasceno

Ramirez

et al. 2013

Drug Testing and Analysis

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The use of formoterol in sports is allowed by inhalation at the maximum recommended therapeutic dose. Recently, a threshold concentration of 30 ng.mL(-1) was defined by the World Anti-Doping Agency (WADA) to distinguish between therapeutic and forbidden use of formoterol. The objective of this work was to evaluate that threshold concentration. Concentrations of formoterol were measured in urine samples collected after administration of 18 µg of inhaled formoterol to five healthy volunteers, and in samples collected in routine doping tests belonging to athletes having declared inhaled formoterol use. Formoterol was detected up to 8 h after administration in all volunteers with concentrations up to 19.6 ng.mL(-1) . From 28 routine samples, 27 had less than 10 ng.mL(-1) of formoterol and only in one of the samples the concentration was 25 ng.mL(-1) . Therefore, administration of formoterol by inhalation at the maximum dose allowed by WADA will not produce false positive results using a threshold concentration of 30 ng.mL(-1) , and the experience up to now in routine doping tests indicates that the probability of obtaining urines with concentrations greater than 30 ng.mL(-1) is close to nil. For this reason, sports authorities should re-evaluate the need of a threshold concentration for formoterol and its practical usefulness.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Evaluation of the urinary threshold concentration of formoterol in sports drug testing

Ventura

Damasceno

Ramirez

et al. 2013

Drug Testing and Analysis

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“…In order to describe the time course of con-centrations after topical application, an LC-MS-MS method was set up and validated, operating in the dynamic range of 1-100 ng/ml in plasma and subcutaneous tissues [9]. Similar situations occurred inter alia with topical application of lidocaine (dynamic range 200-30,000 pg/ml), nimesulide (dynamic range 500-80,000 pg/ml), inhaled budesonide (dynamic range 25-100 pg/ml), and formoterol (dynamic range 200-15,000 pg/ml, matrix urine) [10,11] (Table 2).…”

Section: Plasma Concentrations After Topical Application Of Drugsmentioning

confidence: 95%

Tandem Mass Spectrometry (LC-MS-MS): a Predominant Role in Bioassays for Pharmacokinetic Studies

Marzo¹,

Bo²

2011

Arzneimittelforschung

Self Cite

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Plasma concentrations of drugs and drug metabolites in bioavailability studies are routinely bioassayed with high performance liquid chromatography (HPLC), gas chromatography (GC), and liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) methods. In the 1980s and 1990s, HPLC had achieved a relevant role compared to GC and other techniques in pharmacokinetic bioassays. However, in the last few years the LC-MS-MS technique, known as tandem mass spectrometry, has attained a predominant role over all other techniques. This is because it requires a less amount of matrix, possesses better specificity and sensitivity, and requires a shorter operating time. In the experience of the authors, LC-MS-MS in fact requires on average 3-4 fold shorter time to complete a bioequivalence study when performed by one operator than does HPLC. The higher cost of the apparatus and technical assistance of LC-MS-MS are fully compensated by the shorter operating time. Part or most of the HPLC apparatuses have been or are being replaced by LC-MS-MS systems in laboratories operating in clinical and pre-clinical pharmacokinetics and, to a large extent, in those involved in assessing permeability in screening procedures of new chemical entities. This paper analyses the growing development of the LC-MS-MS technique and compares four couples of methods validated with HPLC or GC versus LC-MS-MS, giving analytical details of the two approaches.

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“…For its quantitation, several non-mass spectrometric methods have been described in the frame of pharmacokinetic experiments (Nadarassan et al, 2007;Butter et al, 1996;Rosenborg et al, 1999). Quantitative detection methods applying mass spectrometric detection are limited to a GC-MS method (Kamimura et al, 1982), a UPLC-MS (Sardela et al, 2012), and two LC-MS/MS methods Marzo et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Forced degradation of mometasone furoate and development of two RP-HPLC methods for its determination with formoterol fumarate or salicylic acid

El‐Bagary

Fouad

El-Shal

et al. 2016

Arabian Journal of Chemistry

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Two simple, selective and precise stability-indicating reversed-phase liquid chromatographic methods were developed and validated for the determination of mometasone furoate in two binary mixtures, with formoterol fumarate (Mixture 1) and salicylic acid (Mixture 2). Also, a forced degradation study of mometasone furoate was carried out including acid and alkali hydrolysis, oxidation, thermal and photo-degradation. For mixture 1, the method was based on isocratic elution using a mobile phase consisting of (Acetonitrile: 3 mM Sodium lauryl sulfate) (60:40, v/v) at a flow rate of 1 ml min À1 . Quantitation was achieved applying dual wavelength detection where mometasone furoate and its degradation products were detected at 247 nm and formoterol fumarate and its degradation product were detected at 214 nm at 30°C. For mixture 2 and for the forced degradation study, separation was based on isocratic elution of mometasone furoate, its degradation products and salicylic acid on a reversed phase C8 column using a mobile phase consisting of acetonitrile:water:methanol:glacial acetic acid (60:30:10:0.1, v/v) at a flow rate of 2 mL min À1 . Quantitation was achieved with UV detection at 240 nm. In addition, products from alkaline forced degradation of mometasone furoate were verified by LC-MS. Linearity, accuracy and precision were found to be acceptable over the concentration range of 10-800 lg mL À1 and 5-60 lg mL À1 for mometasone furoate and formoterol fumarate, respectively and over the concentration range of 5-320 lg mL À1 and 20-1280 lg mL À1 for mometasone furoate and salicylic acid,

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Bioequivalence of Inhaled Formoterol Fumarate Assessed from Pharmacodynamic, Safety and Urinary Pharmacokinetic Data

Cited by 6 publications

References 2 publications

Evaluation of the urinary threshold concentration of formoterol in sports drug testing

Evaluation of the urinary threshold concentration of formoterol in sports drug testing

Tandem Mass Spectrometry (LC-MS-MS): a Predominant Role in Bioassays for Pharmacokinetic Studies

Forced degradation of mometasone furoate and development of two RP-HPLC methods for its determination with formoterol fumarate or salicylic acid

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