Just Accepted by Drug Development and Industrial Pharmacy

Pharmacokinetic properties and bioequivalence of oral-

ly inhaled salbutamol in healthy Chinese volunteers
Bo Jiang, Zourong Ruan, Jinliang Chen, Honggang Lou, Rong Shao, Fang Jin, Hua-
hao Shen

Doi: 10.3109/03639045.2016.1151027

Abstract
Context: Salbutamol is a short-acting β2-adrenergic receptor agonist that has been
used for many years for relief of bronchospasm. However, studies on the pharma‐
cokinetic profile of orally inhaled salbutamol doses used in clinical practice have not
yet been reported in Chinese subjects. Objective: The aim of this study was to com‐
pare the pharmacokinetics and evaluate the bioequivalence of two orally inhaled
salbutamol formulations.
Materials and methods: A single-dose randomized fasting two-period, two-treatment,
and two-sequence crossover open-label bioequivalence study was conducted in 24
healthy Chinese adult male volunteers, with a 1-week washout period between treatments. Plasma concentrations of sal‐
butamol were determined using liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic parameters,
including AUC0-0.33h, AUC0-24h, and Cmax were calculated and the 90% confidence intervals of the ratio (test/reference) phar‐
macokinetic parameters were obtained by analysis of variance on logarithmically transformed data.
Results: The mean (SD) pharmacokinetic parameters of the reference drug were AUC0-0.33h, 227.2 (89.9) pg·h/mL;
AUC0-24h, 2551.9 (1008.0) pg·h/mL; Cmax, 801.3 (307.3) pg/mL; and t1/2, 5.14(1.36) h. Those of the test drug were
AUC0-0.33h, 244.0 (104.4) pg·h/mL; AUC0-24h, 2664.4 (1081.8) pg·h/mL; Cmax, 873.7 (374.4) pg/mL, t1/2, 5.29 (1.23) h. The
median value for Tmax was 0.25 h for both formulations. The 90% confidence intervals for the AUC0-0.33h, AUC0-24h and
Cmax were in the range of 0.892 - 1.208, 0.876 - 1.195 and 0.911 - 1.203, respectively.
Conclusion: This single dose study found that the test and reference products met the regulatory criteria for bioequivalence
of China in healthy Chinese volunteers.

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the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to
any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently
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express understanding that the papers have not yet gone through the full quality control process prior to publication.
Pharmacokinetic properties and bioequivalence of orally inhaled

salbutamol in healthy Chinese volunteers

Bo Jiang1, Zourong Ruan1, Jinliang Chen1, Honggang Lou1, Rong Shao1, Fang Jin2, Huahao Shen1

1
Center of Clinical Pharmacology, 2nd Affiliated Hospital, School of Medicine, Zhejiang

University, Hangzhou 310009, China, 2Shanghai Fronthealth Pharmaceutical Technology Co., Ltd.,

Shanghai 201203, China

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Address for correspondence: Huahao Shen, MD, Center of Clinical Pharmacology, 2nd Affiliated

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Hospital, School of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, China.

Tel: +86-571-87783508. Fax: +86-571-87783969. E-mail: huahaoshen@zju.edu.cn

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Keywords
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β2-adrenergic receptor, inhalation administration, particle size profile, lung deposition, systemic

absorption
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Abstract

Context: Salbutamol is a short-acting β2-adrenergic receptor agonist that has been used for many

years for relief of bronchospasm. However, studies on the pharmacokinetic profile of orally

inhaled salbutamol doses used in clinical practice have not yet been reported in Chinese subjects.

Objective: The aim of this study was to compare the pharmacokinetics and evaluate the

bioequivalence of two orally inhaled salbutamol formulations.

Materials and methods: A single-dose randomized fasting two-period, two-treatment, and

two-sequence crossover open-label bioequivalence study was conducted in 24 healthy Chinese

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adult male volunteers, with a 1-week washout period between treatments. Plasma concentrations

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of salbutamol were determined using liquid chromatography coupled to tandem mass

spectrometry. Pharmacokinetic parameters, including AUC0-0.33h, AUC0-24h, and Cmax were

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calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic
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parameters were obtained by analysis of variance on logarithmically transformed data.

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Results: The mean (SD) pharmacokinetic parameters of the reference drug were AUC0-0.33h, 227.2

(89.9) pg·h/mL; AUC0-24h, 2551.9 (1008.0) pg·h/mL; Cmax, 801.3 (307.3) pg/mL; and t1/2,
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5.14(1.36) h. Those of the test drug were AUC0-0.33h, 244.0 (104.4) pg·h/mL; AUC0-24h, 2664.4

(1081.8) pg·h/mL; Cmax, 873.7 (374.4) pg/mL, t1/2, 5.29 (1.23) h. The median value for Tmax was
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0.25 h for both formulations. The 90% confidence intervals for the AUC0-0.33h, AUC0-24h and Cmax

were in the range of 0.892 - 1.208, 0.876 - 1.195 and 0.911 - 1.203, respectively.

Conclusion: This single dose study found that the test and reference products met the regulatory

criteria for bioequivalence of China in healthy Chinese volunteers.

Introduction

Salbutamol (INN) or albuterol (USAN) is a short-acting β2-adrenergic receptor agonist used for

the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary

disease1. Salbutamol is the first selective β2-receptor agonist to be marketed and it can be given

intravenously, orally, or by oral inhalation. Compared with intravenous and oral administration,

administration by oral inhalation required a smaller dosage and caused less systemic side effects

such as dry mouth, palpitations and fine tremor2. Although salbutamol aerosol was marketed for

many years, few pharmacokinetic studies were published because the minimal dosage meant that

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drug concentrations in plasma could not be detected using the equipment available at that time.

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Furthermore, the role of pharmacokinetics in establishing bioequivalence for orally inhaled drug

products (OIPs) had not yet been established for OIPs acting locally in the airways3-5. Recently,
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with the application of mass spectrometry (MS), a sufficiently sensitive bioanalytical assay was
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developed, and guidelines were issued by the European Medicines Association (EMA) and the US
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Food and Drug Administration (FDA), pharmacokinetic studies now play anincreasingly

important role in determining bioequivalence for OIPs 6-8.

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To protect the environment, chlorofluorocarbons (CFCs) were gradually prohibited in many

countries because of the need to protect the ozone layer from degradation. Thus CFCs used to
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generated medical aerosols by pressurized metered dose inhalers have become increasingly

restricted in terms of supply, and as a result, the pharmaceutical industry has transitioned to newer,

non ozone-depleting propellants, in particular hydrofluoroalkanes (HFAs)9. Salbutamol aerosol, a

generic product developed by Yangzhousanyao Pharmaceutical Co., Ltd. (Yangzhou, China), used

HFA-based pressurized metered dose inhalers (pMDIs) to replace CFC-containing inhalers, and
was required by the China Food and Drug Administration (CFDA) to prove bioequivalence with

the original product through a pharmacokinetic study.

The present paper describes a pharmacokinetic study to investigate the bioequivalence after a

single inhaled dose of a newly developed formulation of salbutamol (Yangzhousanyao

Pharmaceutical Co., Ltd., Yangzhou, China) and a marketed salbutamol aerosol (Ventolin®,

GlaxoSmithKline Pharmaceutical Co., Ltd., Suzhou, China) in healthy Chinese volunteers.

Materials and Methods

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Materials
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The test medication was salbutamol sulfate aerosol (lot no. 20111204, Yangzhousanyao
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Pharmaceutical Co., Ltd., Yangzhou, China) and the reference medication was Ventolin (lot no
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KR0330, GlaxoSmithKline Pharmaceutical Co., Ltd., Suzhou, China).

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Aerodynamic particle size analysis

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The in vitro impactor deposition profiles of both products were evaluated and compared by

Shanghai Fronthealth Pharmaceutical Technology Co., Ltd. Aerodynamic particle size distribution
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(APSD) of the two products was determined by Next Generation Impactor (NGI). Prior to

measurement, the NGI impactor plates were submerged in MilliQ water before placing in a

fume-hood to air-dry for 10 minutes. The sample was placed in the throat of the impactor under

study and tested for 5 s at 30 L/min. The sample was pierced using the actuator of the device

(pDMI) and the process was repeated for 10 times. After the last actuation, the device, throat and
all sample impactor stages were washed into separate volumetrics using MilliQ water, before

analysis by HPLC.

Subjects

Healthy Chinese male volunteers aged 20 to 40 years and with a body mass index between 19 and

24 kg/m2 were eligible for study participation. All volunteers were determined to be healthy by

physical examination, medical history, and on routine laboratory tests of blood chemistry,

hematology, urinalysis, 12-lead electrocardiogram (ECG), pulmonary function test, and drug

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screening performed within 3 weeks prior to the first administration of study drug. All volunteers

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were required to demonstrate correct metered dose inhaler technique with a placebo at screening.

Volunteers with known hypersensitivity to any biologic agent, reporting use of other drugs that
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might interfere with the study results within 14 days prior to the study, with any history of
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cardiovascular, hepatic, renal, hematogenous, or pulmonary disorders, or with a history of drug

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abuse were excluded from the study. Volunteers were instructed not to administer other

medications or drink alcohol and to avoid strenuous exertion throughout the study.
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The clinical study was carried out in accordance with the International Conference on

Harmonisation’s Good Clinical Practice Guideline10 and the principles of the World Medical
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Association’s Declaration of Helsinki11. The study was conducted at the Clinical Pharmacology

Center of the 2nd Affiliated Hospital (School of Medicine, Zhejiang University) between

December 2011 and July 2012 and according to a protocol approved by the Ethics Committee of

the 2nd Affiliated Hospital (School of Medicine, Zhejiang University). All eligible volunteers were

informed of the aim and risks of the study by the investigators, and provided written informed
consent before enrollment. All volunteers were compensated for their participation in the study.

All volunteers had the right to participation in the study, and had the right to terminate

participation in the clinical trial at any time without giving reasons.

Protocol

This study was a single-center, double-blind, randomized-sequence, 2-treatment and 2-way

crossover study to compare a generic formulation with a branded innovator formulation of

salbutamol aerosol in healthy Chinese male volunteers. The washout time between the two

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treatment periods was 7 days.

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Volunteers were admitted to the hospital on the day before the study. They were fasted for at

least 10 h prior to dosing. They then inhaled a single dose of 200 g salbutamol at approximately
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8:00 AM, which was provided in a pMDI delivering 100 g per actuation. Subjects remained
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fasting until 4 hours after dosing, when a standard lunch was provided. Water was available ad
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libitum.

Blood samples (2.0 mL) were collected into tubes containing ethylenediaminetetraacetic acid
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(EDTA) anticoagulant (BD, NJ, USA) at 0 hours (before administration) and at 0.083, 0.167, 0.25,

0.333, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after dosing. The baseline
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blood sample in each period was collected in a single aliquot, within 0.5 hours before

administration; post-dose samples were collected within 2 minutes of the scheduled times.

After collection, blood samples were centrifuged at 2095g for 10 minutes at 4 °C to separate

plasma. The plasma samples were stored at -70 °C until analyzed using liquid chromatography

coupled to tandem mass spectrometry.

 The tolerability of salbutamol was assessed in all volunteers by clinical observation and

spontaneous reporting of adverse events by investigators and volunteers. Clinical laboratory tests

(including hematology, blood chemistry, and urinalysis), 12-lead ECG, physical examinations, and

measurement of vital signs were performed at the end of the study. Adverse events (AEs) were

assessed for intensity, seriousness, and relationship to the study drug by the investigator.

Analytical procedures12

An API 4000 Quantum tandem mass spectrometer equipped with an electrospray ionization (ESI)

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source (Applied Biosystems, WI, USA) and an LC-20AD HPLC pump (Shimadzu, Japan).and an

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SIL-HTA autosampler (CTC Analytics, Switzerland) were used for LC-MS/MS analysis. Data

processing was carried out using the ANALYST data analysis program (Version 1.5.2) (Applied
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Biosystems, WI, USA).
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Liquid chromatographic separations were achieved using a Phenomenex Luna C18 column (100
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mm × 3.0 mm I.D., 3-μm particle size), which was protected by a guard column (4 × 3.0 mm I.D,

Phenomenex, CA, USA). The mobile phase was a mixture of 5 mM ammonium acetate containing
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1% ammonia and acetonitrile containing 0.1% formic acid (7:93) and was delivered at a flow rate

of 0.6 mL/min. Calibration curves were prepared in drug-free plasma. Appropriate volumes of
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working solutions and drug-free human plasma were added to each test tube to achieve final

concentrations of 11.7, 35.1, 93.6, 234, 585, 1170 and 2340 pg/mL. The quality control (QC)

samples included in each assay were prepared in the same way to achieve final concentrations of

23.4, 117, and 1872 pg/mL. Six calibration analyses were performed on 6 consecutive days, and

the QC values for each level were recorded. The regression equation for the salbutamol calibration
curves indicated good linearity. The intra-day accuracy was 96.2 - 99.1 % with precision of 0.7

-14.1 %. The inter-day accuracy was 93.8 - 101.6 % with precision of 1.0 - 4.6 %. The lower limit

of quantification for this method was 11.7 pg/mL.

Pharmacokinetic parameters and statistical analysis

Pharmacokinetic parameters were analyzed using Phoenix Build Software 6.3.0.395 (Certara L.P.,

CA, USA). The maximum concentration (Cmax) and time reach to Cmax (Tmax) were obtained

directly from the experimental data. The area under plasma concentration-time curve from time

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zero to the last quantifiable concentration (AUC0-tlast) was calculated using the linear/log

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trapezoidal method. The apparent elimination rate constant (λz) was estimated using linear least

squares regression analysis of the plasma concentration-time data obtained during the terminal
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log-linear phase. The terminal elimination half-life (t1/2) was calculated as 0.693/λz. The area under
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the plasma concentration-time curve extrapolated to infinity (AUC0-∞) was calculated as AUC0-∞=
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AUC0-tlast +Ct/λz, where Ct was the last detectable concentration. The relative bioavailability of the

test formulation was calculated as (AUC0-t[test]/AUC0-t[reference]) × 100% with AUC0-t calculated for
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the actual profile from 0 - 0.33 and 0 - 24 hours, respectively.

In accordance with Chinese Regulatory Guidelines13, a sample size ranging from 18 to 24

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volunteers was suggested for a pharmacokinetics and bioequivalence study. Twenty-four

volunteers were chosen for this study.

Schuirmann’s two 1-sided t test procedure was used to calculate the 90 % confidence interval

(CI) for the test: reference ratio of geometric mean Cmax and AUC. Tmax was tested parametrically

using the paired Wilcoxon test for significant differences between the two formulations. The
formulations were assumed to be bioequivalent if the 90 % CI for the mean point estimators (ratio

of test to reference) of geometric mean Cmax and AUC fell within the appropriate acceptance

ranges (80 - 125) % for Cmax, AUC0-0.33h, AUC0-24h and AUC0-∞. The same Phoenix Build Software

described previously, was used for inferential statistics; Excel 2007 (Microsoft Corp., Redmond,

WA, USA) was used to generate descriptive statistical data.

Results

Aerodynamic particle size analysis

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The mean fine particle dose (FPD) of the test and control formulation was 33.14 μg and 31.93 μg;

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and the mean fine particle fraction (FPF) of them was 32.41 ％ and 33.44 ％, respectively. The

mean mass median aerodynamic diameter (MMAD) of the test formulation was 2.54 μm, slightly
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less than Ventolin® (2.99 μm). There was no significant difference between the two formulations.
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The mean APSD from CUP 3 to Micro-orifice collector (MOC) was similar between the two
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formulations, and the similarity factor was 97.49%. The deposition profiles illustrated in Figure 1

indicate that the two formulations were near to identical.

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Subjects
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A total of 24 healthy adult male volunteers who met the inclusion and exclusion criteria as

described in the protocol were enrolled in the study and randomized to the treatment groups.

Demographic and baseline characteristics are shown in Table 1. Pulmonary function of the

subjects was also assessed in the screening visit. The mean forced vital capacity (FVC) and forced

expiratory volume in one second（FEV1） of the volunteers were indicative that the full drug dose
could be inhaled if they were well trained. All volunteers completed the study without drop-out.

Two of the 24 volunteers reported two AEs throughout the study. One had diarrheaand the other

had nausea. Symptoms resolved without medical treatment. Both of the AEs were judged as being

mild in severity and unrelated to study treatment by the investigator. No clinically significant

changes in vital signs, physical examination findings, ECG results, or laboratory findings occurred

in any of the study cohort.

Pharmacokinetics

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Figure 2 shows the mean plasma concentration-time curves of salbutamol after inhalation of a

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single dose of 200 g salbutamol in 24 healthy Chinese volunteers. Each point represents the

mean ± standard deviation.

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Table 2 represents the pharmacokinetic parameters for two formulations. The mean values for
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AUC0-0.33h with the reference and test drugs were 227.2 ± 89.9 pg·h/mL and 244.0 ± 104.4
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pg·h/mL respectively; mean AUC0-24h values were 2551.9 ± 1008.0 pg·h/mL and 2664.4 ± 1081.8

pg·h/mL respectively. The mean values for AUC0-∞ for the reference and test drugs were 2782.2 ±
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1094.1 pg·h/mL and 2900.6 ± 1081.8 pg·h/mL, respectively. The mean values for C max with the

reference and test drugs were 801.3 ± 307.3 pg/mL and 873.7 ± 374.4 pg/mL, respectively. The
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median value for Tmax was 0.25 hours for the two formulations, and t1/2 was 5.14 ± 1.36 hours for

the reference drug and 5.29 ±1.23 hours for the test drug.

Natural logarithm (ln) transformations of AUC0-t, AUC0-∞ and Cmax were performed prior to the

statistical analysis. As shown in Table 3, the parametric 90 % CIs for the geometric mean ratios of

the AUC0-0.33h, AUC0-24h, AUC0-∞ and Cmax were in the range of 0.892-1.208, 0.876-1.195,
0.889-1.197, 0.911-1.203, respectively, which indicated the two formulations met the

bioequivalence criterion.

Table 4 shows that the Tmax values of the test and reference formulations were 0.24 ± 0.10 and

0.23 ± 0.10 hours, respectively. No significant differences in Tmax were found between the test and

reference products.

Discussion

According to the sample size determination14, 10 volunteers, calculated from ln-AUC0-0.33h of

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the 24 volunteers in our study (intra-individual coefficient of variation = 11.6 %; μT/μR= 1.07), is

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adequate to attain a power of 80 % at a significance level of 0.05. Same result was obtained when

we calculated using DAS software 3.2.1 (China Pharmaceutical University, Nanjing, China). Thus,
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data from this study can be pooled and statistically analyzed. Despite the variability of each
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volunteer’s respiratory maneuvers, and the variable interaction of the aerosol cloud with the
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volunteers’ oral and airway anatomy, most studies have demonstrated surprisingly low

intra-individual variation (ranging from 6 to 16 %) given the variations in dose-to-dose drug

delivery from inhaler devices15-19. In this study, the intra-individual coefficient of variation of the
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AUC0-0.33h, AUC0-24h, AUC0-∞ and Cmax was around 9.4-11.6 %.

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To evaluate the bioequivalence of locally acting orally inhaled products (OIPs), the links

between pharmacokinetic data, in vitro fine particle mass (FPM) and clinical efficacy data are

currently a hot topic20-23. The EMA guideline advocates the use of pharmacokinetic studies to

determine BE, which suggests a stepwise approach, involves in vitro comparison, in vivo lung

deposition models (pharmacokinetics and scintigraphy), and pharmacodynamic / therapeutic effect

models. Adequate demonstration of the former precludes the need for further comparisons7.

However ， requirements in determination of BE in OIPs is according to the formulation

characteristics in FDA guideline8. The recommended approach for solution formulation is rely on

in vitro methods, and the suspension formulation is conduct in vivo studies in addition to in vivo

studies. Thus, pharmacokinetic data really have an important role to play in assessing

bioequivalence. In our study, the in vitro APSD data revealed no major differences between the

two pDMIs, and the pharmacokinetic data in vivo revealed the bioequivalence of the two

formulations, which indicated the in vitro and in vivo results were well matched.

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After inhalation from dry powder or metered-dose inhalers, only 10-50 % of the administered

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drug dose is delivered to the lung, and a substantial amount of the drug is swallowed and available

for oral absorption23-27. Therefore it was suggested that both pulmonary deposition and total
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systemic exposure should be assessed in bioequivalence studies between two inhaled products

6-7,28
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. The pulmonary deposition indicated the local effect of the drugs, which can be obtained
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from three different situations. First, it can be obtained directly from the area under the

concentration–time curve after inhalation in the case of drugs with negligible oral bioavailability.
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Second, the charcoal-block technique is used to block the absorption of the orally swallowed

fraction of the orally inhaled products29-32, which was not adopted in this study. Finally, different
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kinetics of drug absorption from the lung and the gastrointestinal tract can also be used to assess

the pulmonary absorption of inhaled drugs. It is reported that plasma sampling for up to 20

minutes and urine sampling for up to 30 minutes after inhalation of salbutamol reflects the

pulmonary-deposited fraction of the dose33-36. Total systemic exposure may be acceptable as a

surrogate of systemic safety, and can be calculated using the AUC obtained without charcoal22.
Results from this study showed that all of the parameters (AUC0-0.33h, AUC0-24h, and Cmax) met the

bioequivalence interval of 0.80 to 1.25, which indicated that the test formulation was

pharmacokinetically equivalent to the reference for both the pulmonary absorption and total

systemic exposure.

Du et al reported a pharmacokinetic study of salbutamol in a Chinese population after a single

inhaled dose of 1200 μg salbutamol33. Because an inhaled dose of 200 μg salbutamol is the actual

dose used in clinical practice today in China, data from that study can not reflect the real

pharmacokinetic feature of current treatments. The Tmax in our study was 0.25 hours, similar to

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values reported in the literature33.

Conclusions
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In this single dose study, the two salbutamol aerosol formulations provided in pMDIs delivering
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100 μg per actuation met the CFDA regulatory criteria for bioequivalence in healthy Chinese

volunteers. Both of the formulations were well tolerated.

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Declaration of Interest
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The authors report no declarations of interest. The authors alone are responsible for the content

and writing of this article.

The authors would like to thank the study sponsor (Yangzhousanyao Pharmaceutical Co., Ltd.,

Jiangsu, China). This research is also supported by the National Nature Science Foundation of

China (81400025).
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 Table 1. Demographic and baseline characteristics

Mean ± SD (range)
Age (years) 25.2 ± 2.2 (22~31)
Weight (kg) 64.8 ± 6.4 (52~75)
Height (cm) 172.0 ± 4.9 (165~182)
BMI (kg/cm2) 21.9 ± 1.7
FVC (L) 4.76 ± 0.65
FEV1 (L) 4.20 ± 0.55

Table 2. Pharmacokinetic parameters of salbutamol after a single orally inhalation administration

of two formulations.
Reference drug Test drug
Parameters
(n=24) (n=24)
AUC0-0.33h ( pg·h/mL) 227.2 ± 89.9 244.0 ± 104.4

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AUC0-24h (pg·h/mL) 2551.9 ± 1008.0 2664.4 ± 1081.8
AUC0-∞ (pg·h/mL) 2782.2 ± 1094.1 2900.6 ± 1081.8
Cmax ( pg/mL)
*
Tmax ( h)
t1/2 (h)
801.3 ± 307.3
0.25 [0.067~0.33]
5.14 ± 1.36
TE 873.7 ± 374.4
0.25 [0.067~0.33]
5.29 ± 1.23
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Values are presented as mean ± standard deviation.
AUC0-0.33h, area under the concentration-time curve from time 0 to 0.33 hours; AUC0-24h, area
under the concentration-time curve from time 0 to 24 hours; AUC0-∞, area under the
concentration-time curve with the last quantifiable concentration extrapolated based on the
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elimination rate constant; Cmax, maximum observed concentration; Tmax, time of maximum
observed concentration; t1/2, terminal half-life.
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*
Tmax is median (minimum, maximum).
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Table 3. Bioequivalence assessment for pharmacokinetic parameters for two salbutamol aerosol
formulations.
Parameters Geometric Mean Ratio 90%CI

AUC0-0.33h (pg·h/mL) 1.038 0.892～1.208

AUC0-24h (pg·h/mL) 1.023 0.876～1.195
AUC0-∞ (pg·h/mL) 1.032 0.889～1.197
Cmax (pg/mL) 1.047 0.911～1.203
AUC0-0.33 h, area under the concentration-time curve from time 0 to 0.33 hours; AUC0-24 h, area
under the concentration-time curve from time 0 to 24 hours; AUC0-∞, area under the
concentration-time curve with the last quantifiable concentration extrapolated based on the
elimination rate constant; Cmax, maximum observed concentration.

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Table 4. Summary statistics of the Tmax of test and reference formulation of single-dose inhaled
salbutamol 200 μg in healthy Chinese male volunteers (n=24).

Mean±SD
Test
0.24 ± 0.10
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Reference
0.23 ± 0.10
P value
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Max~Min 0.067 ~ 0.33 0.067 ~ 0.33 > 0.05
Median 0.25 0.25
Tmax, time of maximum observed concentration.
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