XENOBIOTICA

2019, VOL. 49, NO. 4, 457–462

https://doi.org/10.1080/00498254.2018.1465210

RESEARCH ARTICLE

Pharmacokinetics and bioequivalence of two strontium ranelate formulations

after single oral administration in healthy Chinese subjects
Dan Zhang, Aihua Du, Xiaolin Wang, Lina Zhang, Man Yang, Jingyi Ma, Ming Deng and Huichen Liu
Department of Clinical Pharmacology, Aerospace Center Hospital, Beijing, P.R. China

ABSTRACT ARTICLE HISTORY

Received 7 March 2018
1. Pharmacokinetics of exogenous strontium (Sr) and bioequivalence of a new oral formulation Revised 10 April 2018
Accepted 11 April 2018
of strontium ranelate compared with the brand-name drug in healthy Chinese subjects
was evaluated. KEYWORDS
2. A balanced, randomized, single-dose, two-treatment parallel study was conducted in 36 Pharmacokinetics; bioequi-
valence; strontium ranelate;
healthy Chinese subjects. Subjects were randomly allocated into two groups of 18 to receive granules; suspension;
a single oral dose of test formulation and reference formulation under a fasting state, Chinese subjects;
respectively. Blood samples were collected at 19 designated time points up to 240-h post- parallel study
dose. Serum concentrations of Sr were quantified by ICP-MS.
3. A total of 36 subjects were enrolled and completed the study. Nine mild adverse events in
6 subjects were reported. The Cmax, AUC0–72 h, AUC0–t, and AUC0–1 of test and reference for-
mulations shown as mean ± SD were 6.97 ± 1.78 and 6.78 ± 1.80 mg/mL, 199 ± 51 and
187 ± 38 mgh/mL, 303 ± 89 and 278 ± 54 mgh/mL, and 337 ± 109 and 305 ± 60 mgh/mL,
respectively.
4. Two formulations were bioequivalent, and both were generally well tolerated.

Introduction reported (Donneau & Reginster, 2014; Jonville-B era et al.,

V
R 2009; Kinyo  et al., 2011; Yu et al., 2015). European Medicines
The brand-name drug Osseor (strontium ranelate for sus-
pension) has been imported and used in China for a decade.
Strontium ranelate is mainly used for preventing fractures in
post-menopausal women and men with severe osteoporosis,
and patients cannot be treated with other medicines
approved for osteoporosis (EMA, 2016). It is composed of
two atoms of stable nonradioactive strontium (Sr) and an
organic moiety ranelic acid (Reginster et al., 2003). Its chem-
ical structure is shown in Figure 1. In human, the absorption,
distribution and binding to plasma proteins of ranelic acid
are very low, the accumulation and metabolism of ranelic
acid are not found, and the excretion mainly in the form of
unchanged drug of absorbed ranelic acid occurs rapidly via
the kidney (EMA, 2016; Reginster et al., 2003). The absolute
bioavailability of Sr is about 25% after an oral dose of 2 g
strontium ranelate, which is reduced by about 60–70% when
strontium ranelate is taken with calcium (Ca) or food. Bone
tissue has a high affinity for Sr, while the binding of Sr to
human plasma proteins is low, so most of the absorbed Sr is
deposited in the bones. Sr is not metabolized, its excretion
occurs via the kidneys and the gastrointestinal tract, and its
half-life is approximately 60 h (EMA, 2016).
Recently, cutaneous and cardiovascular toxicities associ-
ated with the treatment of strontium ranelate have been
Agency (EMA) recommends that Osseor could be given mar-
keting authorization but with further restrictions (EMA, 2014).
Under normal conditions, the Sr/Ca ratio in human bones is
between 1:1000 and 1:2000 roughly in the same range as in
the human serum, Ca is substituted in a small extent by Sr,
and Sr is more readily dissociated from bone than Ca
(Cabrera et al., 1999; Pilmane et al., 2017; Pors Nielsen, 2004).
Overdosing of Sr interferes the gastrointestinal tract absorp-
tion, the bone metabolism, and the renal excretion of Ca,
and induces hypocalcemia, so it have a deleterious effect on
bone mineralization and even have other adverse effects on
the body (Pilmane et al., 2017). Thus, strontium ranelate may
not be a wide therapeutic index drug as we expected when
it was firstly authorized to marketing, especially for patients
with cardiovascular diseases, and possibly for patients with
severe renal impairment. Fully considering the patient’s med-
ical history, renal function, and dosage, or assessing the phar-
macokinetic properties of Sr in patients may be very
important for the clinical use of strontium ranelate. Besides
the factors of patients, the consistencies of the drug quality
between different batches of the same manufacturer, and
between different products of the different manufacturers
also have direct influence on the pharmacokinetic properties

CONTACT Huichen Liu huichenliu@163.com Department of Clinical Pharmacology, Aerospace Center Hospital, 15 Yuquan Road, Haidian District, Beijing
100049, P.R. China
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
458 D. ZHANG ET AL.
Figure 1. Chemical structure of strontium ranelate.
of Sr. Therefore, it’s necessary to establish a scientific and
reasonable strategy for the pre-marketing bioequivalence
evaluation and the post-marketing consistency evaluation of
strontium ranelate oral formulations.
A new oral formulation, strontium ranelate granules, has
been developed in China. To ensure consistency of the drug
quality between this new formulation and the brand-name
drug, it’s necessary to assess the pharmacokinetic properties
of this new formulation and evaluate the bioequivalence in
comparison with the brand-name drug in healthy Chinese
subjects. The present study established a scientific and rea-
sonable strategy to study the pharmacokinetics of exogenous
Sr, assessed the pharmacokinetics of Sr in Chinese after sin-
gle oral administration by sensitively and accurately quantify-
ing exogenous Sr from the drug in human serum with a full
consideration of subtracting endogenous Sr, and evaluated
the bioequivalence of two oral formulations with reasonable
study design based on a pilot study (Zhang et al., 2015).
Materials and methods
Study design and subjects
The study protocol and informed consent document of the
formal bioequivalence study in healthy Chinese subjects after
single oral administration of two strontium ranelate formula-
tions were approved by the Ethics Committee of Aerospace
Center Hospital (Beijing, China). The study was conducted in
accordance with the Declaration of Helsinki, Good Clinical
Practice guidelines, and the law and regulations of the
People’s Republic of China.
A balanced, randomized, single-dose, two-treatment paral-
lel study was designed in view of the results of the pilot bio-
equivalence study. Subject enrollment was planned for up to
36 healthy Chinese male subjects with the sample size of 18
which determined from the minimum sample size calculated
by nQuery Advisor 7.0 (Statistical Solutions Ltd., Cork, Ireland)
based on the test significance level (a) of 0.05, the bioequiva-
lence limit of 0.8000–1.2500, the power (1-b) of 0.8000, the
intra-subject CV determined from the pilot bioequivalence
study, and expected geometric mean ratio (GMR) (test formu-
lation/reference formulation) to assume the two formulations
equivalent (US FDA, 2002).
The aims and risks of the study were fully explained to all
subjects who then gave written informed consent, and were
involved in the study after a series of screening examinations
including inquiry, physical examination, laboratory tests, and
some special examinations. All enrolled subjects confirmed
that they had not donated blood or participated in other
drug clinical trials within 3 months prior to dosing, and were
required to abstain from other medications, alcohol, tobacco,
caffeinated products and products rich in Sr from 48 h before
dosing until completion of the study.
Drug administration and sample collection
Strontium ranelate granules (test formulation, 2 g strontium
ranelate per packet, Lot No. 12081601 with the content of
strontium ranelate 98.8%) and strontium ranelate for suspen-
sion (OsseorV, reference formulation, 2 g strontium ranelate
R
per packet, Lot No. 906285 with the content of strontium
ranelate 98.0%) used in the study were produced by Beijing
Haiyan Pharmaceutical Co., Ltd. of Yangtze River
Pharmaceutical Group (Beijing, China) and Les Laboratoires
Servier Industrie (Gidy, France), respectively. All subjects
maintained in a fasting state from at least 10 h before dosing
until 4 h after dosing, and were randomly allocated into two
groups of 18 to receive a single oral dose of test and refer-
ence formulations, respectively. Test and reference formula-
tions containing 2 g strontium ranelate, which was the
clinical recommended daily dose, were administered to the
subjects after dissolved and suspended in 200 mL water,
respectively. Venous blood samples (3 mL) were collected by
venepuncture into red Hemogard Cap VacutainerV (Becton,
R
Dickinson and Company, Franklin Lakes, NJ, USA) before and
0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 144, 192,
and 240 h after dosing. After standing at ambient tempera-
ture for at least 30 min, serum was separated by centrifuga-
tion (3500  g for 7 min at ambient temperature) and stored
immediately at 80  C until analysis.
Safety evaluation
Physical examination, vital signs, clinical laboratory tests, 12-
lead ECG, and chest X-ray were conducted on all subjects
during screening and at study termination. Vital signs were
also performed at the day before, 1 h before, and 1, 3, 24,
and 72 h after dose. The clinic staff monitored throughout
the study for adverse events (AEs) and graded the AEs as
mild, moderate, or severe based on direct observation and
interview with subjects, and the results of the various exami-
nations. The investigator judged the relationship of AEs to
the study treatment as certain, probable, possible, unlikely,
none, or unassessable.
Bioanalysis
Strontium ranelate (purity 98.0%, Lot No. 18-SSR-98-1) was
purchased from Toronto Research Chemicals Inc. (North York,
Canada). The internal standard (IS) stock solution of germa-
nium (Ge, 1000 lg/mL, unique No. 12506) was purchased

from National Center of Analysis and Testing for Nonferrous
Metals and Electronic Materials (Beijing, China). Nitric acid
(HNO3, extra-pure BV-III grade, 70.0 ± 1.0%, Lot No. 120318)
purchased from Beijing Institute of Chemical Regent (Beijing,
China) and distilled water purchased from Guangzhou
Watson’s Food & Beverage Co., Ltd. (Guangzhou, China) were
used without further purification.
Serum concentrations of Sr were quantified using our previ-
ously published inductively coupled plasma-mass spectrometric
(ICP-MS) method (Zhang et al., 2015). In brief, serum sample
(50 lL) was added with IS working solution (5.00 mg/mL, 50 lL)
and 0.1% HNO3 (1400 lL) to directly dilute the serum sample,
then the mixture was vortex-mixed for 1 min and introduced
directly into the plasma by pneumatic nebulization for ICP-MS
analysis. ICP-MS analysis was performed using collision cell tech-
nology (CCT) mode. Elements measured for calculations were
88
Sr and 72Ge, and CCT gas was hydrogen-helium (7:93, v/v).
Alternate matrix method by using distilled water as an alternate
analyte-free matrix for the preparation of calibration standards
was used to avoid the influence of endogenous Sr in blank
(drug free) serum on the quantification. No compound in blank
water sample and no other endogenous substance in blank
serum sample interfered the determination of analyte and IS.
But the corresponding blank value of the endogenous analyte
should be subtracted from each serum sample for the determin-
ation of exogenous analyte. Under the conditions of the
method, there was no carry-over effect or influence of endogen-
ous substances on the ionization of analyte or IS. The method
was linear in the concentration range of 0.0300–15.0 lg/mL
with intra- and inter-batch relative SD (RSD) less than 8.0% and
relative error (RE) within ±3.0%. The lower limit of quantitation
(LLOQ) of the method was 0.0300 lg/mL. Sr was stable in solu-
tion and in serum under various storage conditions.
All serum samples of the study were analyzed using the
validated method. The concentration of exogenous Sr at
each sampling time after dosing was determined as the
measured concentration of Sr in serum at corresponding
sampling time subtracting the concentration of endogenous
Sr, which was the measured concentration before dosing. All
the measured concentrations in serum samples collected
before dosing were higher than LLOQ, and the mean value
shown as mean ± SD was 0.0545 ± 0.0074 lg/mL.
Pharmacokinetics assessments
Non-compartmental method was used for the main pharma-
cokinetic parameters calculating by WinNonlin 6.3 (Pharsight
Corporation, St. Louis, MO, USA). Cmax, the maximum serum
concentration, and Tmax, the time to reach Cmax, were both
determined from the observed serum concentrations of
exogenous Sr. AUC0–72 h and AUC0–t were the area under
the serum concentration-time curve (AUC) from 0 to 72 h
Table 1. Demographic characteristics of subjects (data are shown as mean ± SD [range]).
Age (years)
All subjects (n ¼ 36) 25 ± 3 (2030)
Subjects in the group receiving test formulation (n ¼ 18) 25 ± 3 (2130)
Subjects in the group receiving reference formulation (n ¼ 18) 25 ± 3 (2030)
XENOBIOTICA 459
post-dose and from 0 to the last quantifiable data point
obtained by the linear trapezoidal rule, respectively. AUC0–1
was the AUC from 0 to infinity by adding AUC0–t with the
quotient of last measurable serum concentration (Ct) and the
terminal elimination rate constant (kz). The elimination half-
life (t1/2) was calculated as 0.693 divided by kz, which was
determined by linear least squares regression of the terminal
portion of the log-transformed serum concentration-time
curve. The apparent clearance (CL) and the apparent volume
of distribution (Vd) were calculated as dose/AUC0–1 and
dose/AUC0–1/kz, respectively. The area under the first
moment curve (AUMC) was also estimated by the method of
trapezoids. MRT0–t and MRT0–1, the mean residence time
(MRT) from 0 to the last quantifiable data point and from 0
to infinity, were calculated as AUMC0–t/AUC0–t and AUMC0–1/
AUC0–1, respectively.
Statistical analysis
Mean and SD were calculated for the demographics of sub-
jects and main pharmacokinetic parameters. Median was also
presented for Tmax. Evaluating the statistical differences in
the demographics of subjects between the two groups using
one-way analysis of variance (ANOVA), and comparing Tmax
using non-parametric paired Wilcoxon test were both con-
ducted by SAS V9.3 (SAS Institute Inc., Cary, NC, USA).
Statistical analysis on main pharmacokinetic parameters (Tmax
excluded) was performed using WinNonlin version 6.3
(Pharsight Corporation, St. Louis, MO, USA). p Value less than
0.05 was considered statistically significant. Calculation of
power for main pharmacokinetic parameters (Cmax, AUC0–72 h,
AUC0–t and AUC0–1) was also performed by WinNonlin ver-
sion 6.3. The study design and the sample size were consid-
ered suitable for bioequivalence demonstration if calculated
power was more than 0.8000. The statistical differences in
the natural logarithmic-transformed pharmacokinetic parame-
ters (Cmax, AUC0–72 h, AUC0–t and AUC0–1) between two for-
mulations were evaluated using one-way ANOVA. The two
formulations were considered to be bioequivalent if the 90%
confidence intervals (CIs) of GMRs for Cmax, AUC0–72 h, AUC0–t
and AUC0–1 of Sr were within the pre-specified comparability
bounds of (0.8000, 1.2500) (US FDA, 2002).
Results and discussion
Subjects and tolerability
A total 36 healthy subjects were recruited and completed the
study. The demographic characteristics of subjects are sum-
marized in Table 1. No significant differences in demographic
characteristics of subjects were found between the two
groups in the study.
Demographic characteristics
Body weight (kg) Body height (m) BMI (kg/m2)
63.2 ± 5.5 (52.276.2) 1.71 ± 0.05 (1.561.84) 21.6 ± 1.5 (19.024.3)
62.3 ± 5.0 (52.271.0) 1.70 ± 0.05 (1.631.81) 21.5 ± 1.5 (19.424.3)
64.0 ± 5.9 (54.276.2) 1.71 ± 0.06 (1.561.84) 21.8 ± 1.6 (19.024.1)
460 D. ZHANG ET AL.

Figure 2. Mean serum concentration-time profiles of Sr in healthy Chinese male subjects after single oral administration of test and reference formulations contain-
ing 2 g strontium ranelate. Data are shown as mean ± SD (n ¼ 18).

Table 2. Main pharmacokinetic parameters of Sr in healthy male Chinese sub- and reference formulations containing 2 g strontium ranelate
jects after single oral administration of strontium ranelate granules (test for- are displayed in Figure 2, with main pharmacokinetic param-
mulation) and strontium ranelate for suspension (reference formulation)
containing 2 g strontium ranelate. Data are shown as mean ± SD unless other-
eters summarized in Table 2. The statistical results of bioequi-
wise noted (n ¼ 18). valence evaluation of the two oral formulations of 2 g
Pharmacokinetic parameters Test formulation Reference formulation strontium ranelate in healthy Chinese male subjects are sum-
Cmax (mg/mL) 6.97 ± 1.78 6.78 ± 1.80 marized in Table 3.
Tmax (h)a 3.04 ± 0.81 (3.00) 3.46 ± 0.88 (3.50) The median Tmax values of Sr were observed 3 h and 3.5 h
AUC0–72 h (mgh/mL) 199 ± 51 187 ± 38
AUC0–t (mgh/mL) 303 ± 89 278 ± 54
for test formulation and reference formulation, respectively,
AUC0–1 (mgh/mL) 337 ± 109 305 ± 60 with p value more than 0.05. There was no significant differ-
t1/2 (h) 83.39 ± 13.97 79.34 ± 15.45 ence found in Cmax, AUC0–72 h, AUC0–t and AUC0–1 of Sr
CL (L/h) 6.47 ± 1.88 6.86 ± 1.69
Vd (L) 761 ± 211 777 ± 202
between two formulations. The GMRs and 90% CIs of GMRs
MRT0–t (h) 61.7 ± 6.4 59.9 ± 5.8 for Cmax, AUC0–72 h, AUC0–t and AUC0–1 of Sr were entirely
MRT0–1 (h) 90.9 ± 16.5 86.4 ± 16.5 within the pre-specified interval of (0.8000, 1.2500). Thus, the
a
Shown as mean ± SD (median). two oral formulations of strontium ranelate showed the simi-
lar rate and extent of absorption, and were bioequivalent.
During the study, 6 of 36 subjects reported a total of nine As one of the human body trace elements, the vast major-
AEs (five events in 4 subjects receiving test formulation and ity of Sr is found in bones, while only tiny amount dissolves
four events in 2 subjects receiving reference formulation), in the extracellular fluid (Pors Nielsen, 2004). A dynamic bal-
including urethra infection (1 subject), proteinuria (1 subject), ance exists between Sr in bones and blood by constantly
abnormal urine findings (1 subject), leucopenia (1 subject), exchanging, and Sr in blood is primarily excreted via urine.
hyperglycemia (2 subjects), bilirubinemia (1 subject), and Because of its complex bone metabolism in vivo, the overall
bilirubinuria (2 subjects). All the AEs were mild in severity biological half-life of Sr is relatively long by averaging all
and resolved by study completion. Bilirubinemia and bilirubi- excretion paths. In this study, the large Vd and long t1/2 of Sr
nuria were considered as possibly treatment-related, and were consistent with its enrichment in bone tissue and slow
other AEs were considered as unlikely to the treatment. elimination from the human body. Thus, endogenous Sr can
Bilirubinemia and bilirubinuria occurred in one subject receiv- be detected in human serum without any recent exogenous
ing reference formulation, and bilirubinuria occurred in supplement, and its level can be adjusted steady by control-
another subject receiving test formulation. There were no ling the intake of diet and drinking. The level of endogenous
clinically significant findings in the physical examination, vital Sr was monitored during 24 h in healthy Chinese volunteers
signs, 12-lead ECG or chest X-ray. Overall, strontium ranelate who abstained from products rich in Sr before the pilot bioe-
was generally well tolerated in healthy Chinese male subjects quivalence study, and proved to be steady. Therefore, in
following single oral administration of 2 g strontium ranelate. both pilot and formal study, the concentration of exogenous
Sr in serum samples at each time point after the drug admin-
istration were calculated by subtracting the level of endogen-
Pharmacokinetics and bioequivalence
ous Sr at pre-dose from the measured concentrations.
Mean serum concentration-time profiles of Sr in healthy The generic drug (strontium ranelate granules) in this
Chinese male subjects after single oral administration of test study is a modified formulation of the brand-name drug with

Table 3. Bioequivalence evaluation of strontium ranelate granules (test formulation) and strontium ranelate for suspension (reference formulation) containing 2 g
strontium ranelate (n ¼ 18).
Geometric mean
Pharmacokinetic parameters Test formulation
Cmax (mg/mL) 6.76
AUC0–72 h (mgh/mL) 193
AUC0–t (mgh/mL) 291
AUC0–1 (mgh/mL) 322
the name of OsseorV (strontium ranelate for suspension). It
R
was the first time to carry out the bioequivalence study of
these two formulations in Chinese, so it was unknown
whether the drug was highly variable, and it was hardly to
determine the sample size before the study. A pilot bioequi-
valence study was conducted with a crossover design, so
that the intra-subject and inter-subject CV could be deter-
mined. It would be helpful to design the formal study rea-
sonably in terms of the sample size and study design
(crossover or parallel design). After statistical analysis on
main pharmacokinetic parameters of the pilot study, the
inter-subject and intra-subject CV for Cmax, AUC0–72 h, AUC0–t
and AUC0–1 of Sr were 4.4% and 19.5%, 10.3% and 18.7%,
9.8% and 19.0%, and 7.6% and 20.2%, respectively. The inter-
subject and intra-subject CV were all less than 21.0%, and
the former is much lower than the latter, which indicated
that oral formulations of strontium ranelate were not highly
variable drugs in Chinese. Thus, parallel design might be bet-
ter than crossover design for the bioequivalence study of
oral formulations of strontium ranelate (Zhang et al., 2015).
Especially for the drug such as strontium ranelate, of which
the half-life is long, the crossover design would lead to lon-
ger washout period and greater possibilities of subject with-
drawal, while the parallel design would improve these
problems. Therefore, parallel design was used in the formal
study. The sample size was determined to be 18 based on
the results calculated by nQuery Advisor 7.0. The result of
power for the formal study was about 88%, showing that the
sample size was adequate. Parallel design greatly shortened
the period of time, and also reduced the possibility of sub-
ject withdrawal in the bioequivalence study. It was consistent
with the relevant consideration of FDA for oral immediate
release drugs with a long elimination half-life (>24 h), recom-
mending that a nonreplicate, single-dose, crossover study
could be conducted with an adequate washout period, and if
the crossover study was problematic, a parallel design could
be used (US FDA, 2002, 2010b).
Moreover, for a long elimination half-life drug, sampling
time should be adequate to ensure completion of gastro-
intestinal transit of the drug product and absorption of the
drug substance (which usually occurs within approximately
2–3 days), whatever a crossover or parallel design was used.
Cmax and a suitable truncated AUC could be used to charac-
terize peak and total drug exposure, respectively. For drugs
with low intra-subject variability in distribution and clearance,
an AUC truncated at 72 h (AUC0–72 h) could be used in place
of AUC0–t or AUC0–1 (US FDA, 2002), such as amiodarone
HCl tablet (US FDA, 2010a), warfarin sodium tablet (US FDA,
2012), azithromycin extended release suspension (US FDA,
2008a), and bicalutamide tablet (US FDA, 2008b), etc. The
XENOBIOTICA 461
Reference formulation GMR 90% CI Power
6.54 1.0344 0.90851.1777 0.8832
183 1.0513 0.93801.1783 0.9425
272 1.0691 0.94741.2063 0.9191
299 1.0794 0.95001.2264 0.8920
results in this study confirmed that Cmax and AUC0–72 h were
enough for the bioequivalence evaluation of oral formula-
tions of strontium ranelate.
Conclusions
In this study, pharmacokinetic properties and bioequivalence
of two strontium ranelate formulations after single oral
administration in healthy Chinese subjects were evaluated.
Considering the long elimination half-life of Sr, a parallel
design was used for the bioequivalence study, and a min-
imum sample size of 18 were used due to the low intra-
subject and inter-subject variabilities of the two formulations.
Cmax and AUC0–72 h could respectively characterize peak and
total drug exposure for the bioequivalence evaluation. Test
formulation was bioequivalent to the reference formulation,
and two formulations were generally well tolerated in
healthy Chinese subjects following single oral administration.
Disclosure statement
No potential conflict of interest was reported by the authors.
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