Pharmacokinetics and safety of calcium L-threonate in healthy volunteers after single and multiple oral administrations.
ABSTRACT To evaluate the pharmacokinetics of L-threonate after single or multiple oral administrations and its safety profile in healthy Chinese volunteers.
This was an open-label, single- and multiple-dose study. The subjects were assigned to receive a single dose, 675, 2025, or 4050 mg, of calcium L-threonate (n=12) or repeated doses of 2025 mg twice daily for 4 d (n=12). Serial plasma and urine samples were analyzed with HPLC-MS/MS. Pharmacokinetic parameters of L-threonate were calculated using non-compartmental analysis with WinNonlin software.
In the single dose group, C(max) reached at 2.0 h and the mean t(1/2) was approximately 2.5 h. Area under curve (AUC) and C(max) increased with dose escalation, but dose proportionality was not observed over the range of 675 to 4050 mg. AUC and C(max) in the fasted subjects were lower compared with those in the non-fasted subjects. Cumulative urinary excretion of L-threonate over 24 h represented 5.9% of the administered dose with a mean Cl/r of 0.8 L/h. In the multiple-dose study, no accumulation appeared upon repeated doses of 2025 mg twice daily for 4 d. There were no serious adverse events that occurred during this study.
Calcium L-threonate was well tolerated in healthy Chinese subjects, with no pattern of dose-related adverse events. Plasma exposure increased with dose escalation, but linear pharmacokinetics were not observed over the studied doses. L-threonate was absorbed rapidly, and its absorption was enhanced by food intake. No systemic accumulation appeared after repeated administrations.
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ABSTRACT: Purpose Calcium L-threonate is a novel drug that was developed for the treatment of osteoporosis and as a calcium supplement. However, calcium bioavailability of this drug is unknown due to lack of effective evaluation methods. In this study, we sought to measure the bioavailability of calcium L-threonate with a double-label stable isotope method. Methods Fourteen healthy Chinese subjects were enrolled in the clinical study and were given 300 mg calcium L-threonate tablets containing 40 mg 44Ca after an intravenous injection of 4 mg 42Ca solution (as calcium chloride). Fractional urine samples were collected at the following time intervals: 0–3, 3–6, 6–9, 9–13, 13–24, 24–36 and 36–48 h. The abundance ratios of 44Ca/40Ca and 42Ca/40Ca in the urine were determined with thermal-ionization mass spectrometry (TI-MS). The calcium bioavailability was estimated by calculating the true fractional calcium absorption (TFCA) using the abundance ratios of 44Ca/40Ca and 42Ca/40Ca. Results The bioavailability of calcium L-threonate in 14 healthy Chinese subjects was 26.49 ± 9.39 %. There was good agreement between TFCA from the 24 to 36 h and the 36 to 48 h urine pool, indicating that calcium balance was achieved at 24 h after dosing. The TFCA of the subjects did not statistically correlate with total urinary calcium excretion (0–48 h). There were no serious adverse events in this study. Conclusions The bioavailability of calcium L-threonate in humans was successfully determined by estimating TFCA with the double-label stable isotope method, thus providing a useful approach for the evaluation of bioavailability of calcium formulations.European Journal of Clinical Pharmacology 69(5). · 2.74 Impact Factor
Acta Pharmacologica Sinica (2011) 32: 1555–1560
© 2011 CPS and SIMM All rights reserved 1671-4083/11 $32.00
Pharmacokinetics and safety of calcium L-threonate
in healthy volunteers after single and multiple oral
Hong-yun WANG, Pei HU, Ji JIANG*
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking
Union Medical College, Beijing 100730, China
Aim: To evaluate the pharmacokinetics of L-threonate after single or multiple oral administrations and its safety profile in healthy
Methods: This was an open-label, single- and multiple-dose study. The subjects were assigned to receive a single dose, 675, 2025, or
4050 mg, of calcium L-threonate (n=12) or repeated doses of 2025 mg twice daily for 4 d (n=12). Serial plasma and urine samples
were analyzed with HPLC-MS/MS. Pharmacokinetic parameters of L-threonate were calculated using non-compartmental analysis with
Results: In the single dose group, Cmax reached at 2.0 h and the mean t1/2 was approximately 2.5 h. Area under curve (AUC) and Cmax
increased with dose escalation, but dose proportionality was not observed over the range of 675 to 4050 mg. AUC and Cmax in the
fasted subjects were lower compared with those in the non-fasted subjects. Cumulative urinary excretion of L-threonate over 24 h
represented 5.9% of the administered dose with a mean Cl/r of 0.8 L/h. In the multiple-dose study, no accumulation appeared upon
repeated doses of 2025 mg twice daily for 4 d. There were no serious adverse events that occurred during this study.
Conclusion: Calcium L-threonate was well tolerated in healthy Chinese subjects, with no pattern of dose-related adverse events.
Plasma exposure increased with dose escalation, but linear pharmacokinetics were not observed over the studied doses. L-threonate
was absorbed rapidly, and its absorption was enhanced by food intake. No systemic accumulation appeared after repeated adminis-
Keywords: osteoporosis; calcium L-threonate; L-threonic acid; pharmacokinetics; safety; Chinese; open-label, single dose; multiple
Acta Pharmacologica Sinica (2011) 32: 1555–1560; doi: 10.1038/aps.2011.138; published online 10 Oct 2011
Osteoporosis is a bone disease that leads to an increased risk
of fracture. Due to its significant prevalence worldwide, osteo-
porosis is now considered a serious public health concern. In
1992, there were 1.6 million people worldwide suffering from
this disease, and this number is estimated to reach 6 million
by 2050. Aging of populations worldwide is responsible for
the major increase in the incidence of osteoporosis. Osteo-
porosis can be treated with lifestyle changes and medications.
Typical medications include bisphosphonates, estrogen ana-
logs, raloxifene, calcium salts and sodium fluoride. These
medications are classified as antiresorptive or bone ana-
bolic agents. Antiresorptive agents reduce bone resorption,
whereas bone anabolic agents build bone, rather than inhibit
* To whom correspondence should be addressed.
Received 2011-05-26 Accepted 2011-08-17
L-Threonic acid is an active metabolite of vitamin C[5–8]. It
has been reported that L-threonic acid exhibits significant stim-
ulatory action on vitamin C uptake and prolongs the retention
of vitamin C in human T-lymphoma cells[9, 10]. It is also well
known that vitamin C is a marker for osteoblast formation and
has been shown to stimulate procollagen and enhance colla-
gen synthesis[11–14]. Therefore, L-threonic acid may play a role
in the mineralization process through its positive action on
vitamin C. This hypothesis was confirmed in 1999 by Rowe
DJ. It was reported that in vitro treatment with ascorbate-
containing vitamin C metabolites enhanced the formation of
the mineralized nodules and collagenous proteins and that
L-threonate was one of the metabolites that was found to
influence the mineralization process. Recently, a preclinical
study was performed to investigate the effect of L-threonate on
bone resorption of rabbit osteoclasts. This study contained
a total of six culture groups, including one control group and
Wang HY et al
Acta Pharmacologica Sinica
five groups treated with drugs (calcium L-threonate, sodium
L-threonate, alendronate, 17β-estradiol and calcium glucon-
ate). The levels of type I collagen C-telopeptide (CTx) and
bone slice resorptive area were measured. This study found
that L-threonate, especially calcium L-threonate, inhibited the
bone resorption of osteoclasts in vitro; however, the reductive
effects on the CTx level and resorptive area were not as signifi-
cant as alendronate and 17β-estradiol at the same concentra-
Calcium L-threonate ((2R,3S)-2,3,4-trihydroxy butyric acid
calcium) (Figure 1) is a novel drug developed for the treatment
of osteoporosis and as a calcium supplement. Phase I clinical
trials of calcium L-threonate, including tolerance, pharmacoki-
netics and calcium absorption evaluation, were performed in
Peking Union Medical College Hospital. In this paper, the
pharmacokinetics of L-threonate after single or multiple oral
administrations and its safety profile in healthy Chinese vol-
unteers are presented.
Materials and methods
Drugs, chemical standards and reagents
Calcium L-threonate tablets (675 mg/tablet) and chemical
standards of L-threonic acid (purity 99.8%) were provided
by JuNeng Pharmaceutical Co (Beijing, China). HPLC-grade
acetonitrile and acetic acid were purchased from Thermo-
Fisher (New Jersey, USA). Other reagents utilized were all of
analytical grade, and distilled water was produced by a Milli-
Q water purification system (Millipore, Bedford, USA).
This study was conducted in accordance with Good Clinical
Practice regulations, the ethical principles stated in the Dec-
laration of Helsinki, and other applicable regulatory require-
ments. Approval of the study was obtained from the Ethical
Committee of the Peking Union Medical College Hospital
(Beijing, China) prior to subject enrollment. All of the subjects
provided written informed consent after the nature of the
study was fully explained.
The subjects were enrolled based on the following inclusion
criteria: men and women of Han Chinese ethnicity between 19
and 40 years of age with a body mass index of 19 to 25 kg/m2;
and no evidence of clinically significant abnormalities in car-
diac, hepatic, renal, pulmonary, neurological, gastrointesti-
nal, hematological or psychiatric function, as determined by
medical history, physical examination and laboratory screens.
Pregnant and lactating women were excluded from the study.
Female subjects were required to be surgically incapable of
pregnancy or to practice effective double-barrier birth control
methods. Exclusion criteria included a history of a clinically
important disease that, in the opinion of the investigator,
might place the subject at risk; a history of allergy to drugs;
participation in a clinical study during the preceding 4 weeks;
blood donation within a period of 4 weeks prior to study drug
administration; positive test results for HBV, hepatitis C virus
(HCV), or human immunodeficiency virus (HIV); positive test
results for drugs of abuse; or a history of alcohol abuse. Addi-
tionally, all of the enrolled subjects were required to avoid
vitamin C medications 1 month prior to and during the study.
This was a phase I, open-label, single and multiple-dose study.
In the single-dose study, a randomized, 4-way crossover
design was used, and the washout period between dosing was
1 week. Twelve male Chinese subjects were randomized into
4 treatment groups in which they received a single oral dose
of 675, 2025, or 4050 mg calcium L-threonate after an overnight
fasting or 2025 mg within 30 min after consuming breakfast.
A standard meal was provided at 4 and 10 h after dosing.
Serial blood samples (3 mL at each time point) were collected
in heparinized vacutainers at the following time points: 0 (pre-
dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 h. Frac-
tionated urine samples were collected at the following time
intervals: 0 (pre-dose), 0–3, 3–6, 6–9, 9–12, and 12–24 h. In the
multiple-dose study, 14 healthy Chinese subjects (50% male
and 50% female) received an oral dose of 2025 mg after over-
night fasting on the morning of d 1 and d 7, and serial blood
samples (3 mL at each time point) were drawn at the following
time points: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24,
and 48 h. From d 3 to d 6, the subjects received an oral dose
of 2025 mg twice daily with a dose interval of 12 h. Blood
samples prior to dosing (0 h) were collected in the morn-
ing for trough plasma level monitoring. During the study,
blood samples were separated by centrifugation at 2500×g for
10 min, and plasma was collected. The volume of urine
samples at each time interval was recorded, and 10 mL was
collected. All of the plasma and urine samples were stored at
-30 oC until analysis.
All of the subjects were hospitalized in the phase I unit
ward of Peking Union Medical College Hospital during the
study. The subjects were required to refrain from smoking,
alcohol and caffeinated beverages. Strenuous exercise was not
allowed on each dosing day. Medications (including vitamins,
herbal supplements and traditional Chinese medicines) were
not permitted, although paracetamol (acetaminophen) was
allowed as a mild analgesic.
Plasma and urine sample analysis
The concentrations of L-threonate in plasma and urine
samples were determined using the high-performance liquid
chromatography-tandem mass spectrometry (HPLC-MS/
MS) method developed in our lab. Briefly, 0.1 mL volume
of plasma sample was vortexed with 0.3 mL of methanol for
3 min. After centrifugation at 10 000×g for 5 min, 0.2 mL of
Figure 1. Calcium L-threonate, (2R,3S)-2,3,4-trihydroxy butyric acid cal-
Wang HY et al
Acta Pharmacologica Sinica
the supernatant was collected and diluted with 1.5 mL of
water; 20 µL of the sample was injected for analysis. Each
0.1 mL volume of urine was diluted with 2 mL of water and
vortexed for 1 min, and then 20 µL of the sample was injected
for analysis. The analyte was separated on an YMC J’Sphere
C18 column (50 mm×4.6 mm; id, 3.5 µm)(Waters, MA; USA)
with methanol-acetonitrile-10 mmol/L ammonium acetate
(20:5:75, v/v) as the mobile phase and at a flow rate of 0.2 mL/
min. Detection was performed on a Quattro Ultima triple-
quadruple mass spectrometer (Waters, MA, USA) equipped
with an electrospray source (ESI) operated in the negative ion-
ization mode. Multiple reactions monitoring (MRM) was used
to monitor L-threonate by the ion transition of m/z 134.5→74.7.
The linear calibration curves of L-threonate in plasma and
urine were obtained over the concentration range of 0.25 to 50
mg/L and 2.5 to 500 mg/L. Low-, medium-, and high-quality
control samples (plasma: 0.75, 12.5, 40 mg/L; urine: 7.5, 125,
400 mg/L) were analyzed with the study samples to ensure
the quality of analysis.
Pharmacokinetic and statistical analysis
Pharmacokinetic analysis was performed with WinNonlin
software (Pharsight 4.0.1; NC, USA) utilizing non-compart-
mental analysis. The maximum plasma drug concentration
(Cmax) and time to Cmax (tmax) were directly obtained from the
plasma concentration-time curves. The terminal-phase elimi-
nation half-life (t1/2) was calculated as 0.693/λz, where λz was
the slope of the apparent elimination phase of the natural log-
arithmic (ln) transformation of the plasma concentration-time
curve, which was estimated using liner regression. The area
under the plasma concentration-time curve from time zero
to t (AUC0–t), where t is the time of last measurable sample,
was calculated according to the linear trapezoidal rule. The
AUC from time zero to infinity (AUC0–∞) was estimated as
AUC0–t+Ct/λz, where Ct was the plasma concentration of the
last measurable sample. Apparent total clearance (Cl/F) was
calculated as Dose/AUC0–∞ or Dose/AUCss and apparent total
volume of distribution (Vz/F) as calculated as CL/λz. Renal
clearance was estimated as Au0–t/AUC0–t, where Au0–t was the
cumulative amount of drug excreted in urine from time zero
to t (24 h). Attainment of steady state by d 7 was evaluated
by regressing the natural logarithmic (ln) transformation of
trough concentrations on d 3, 4, 5, and 6 over time. Steady-
state was attained if the slope was not statistically different
from zero. The steady-state AUCs (AUCss) over the dosing
interval (τ=12 h) and Cavg (AUCss/τ) were calculated. The
degree of fluctuation (DF%) was calculated as (Cmax–Cmin)/
Cavg×100%. Accumulation ratios were defined as the steady-
state AUC0–τ to the single-dose AUC0-τ ratio or the steady
state Cmax to the single-dose Cmax ratio, namely, RAUC = AUC0–τ
(steady state)/AUC0–τ (single-dose) (τ=12 h) and RCmax=Cmax
(steady state)/Cmax (single-dose), respectively.
Statistical analysis was performed using SPSS software
(version 11.0; SPSS Inc; Chicago, IL, USA). The results
were expressed as the mean±SD. The linearity of plasma
L-threonate pharmacokinetics within the 675 to 4050 mg dose
range was assessed with respect to pharmacokinetic param-
eters underlying drug exposure, ie, AUC and Cmax. After log-
transformation, 90% confidence intervals (CIs) for the ratios
of dose-normalized, geometric mean values of AUC and Cmax
were calculated using mixed-effects models. The approach
was developed by Smith et al on the basis of the criteria for
the assessment of bioequivalence. Dose proportionality is
declared if the CI for the dose ratio is contained within the
limits, 80%–125% for AUC and 70%–143% for Cmax. Based on a
2025 mg dose level, the food intake effect on the pharmacoki-
netics of L-threonate was assessed between the fasted and fed
subjects using a paired-t test, where P≤0.05 was considered
Safety and tolerability were evaluated through adverse events
reported by the investigators and subjects and based on clini-
cal laboratory measurements (blood chemistry, hematology,
urinalysis, and liver functions), 12-lead ECG, physical exami-
nation, and vital signs. Adverse events were assessed by the
investigators with regard to severity (mild, moderate, severe
or life-threatening) and the relationship to the study treatment
(reasonably or possibly related, not reasonably or possibly
Twenty-six healthy Han Chinese volunteers were recruited
and randomized into the phase I clinical study. In the single-
dose study, all of the subjects (12 males) completed the 4-way,
crossover trial. In the multiple-dose study, 14 subjects (7
males and 7 females) were enrolled, and two subjects with-
drew on d 3 due to personal reasons. There were no signifi-
cant differences among the 26 subjects with regard to age,
height, weight, or body mass index (Table 1).
The mean plasma concentration-time curves in 12 healthy
Chinese subjects after oral administration of 675, 2025, or
4050 mg calcium L-threonate are shown in Figure 2, and the
pharmacokinetic parameters are presented in Table 2. The
results indicated that L-threonate was absorbed rapidly with a
Table 1. Subject demographics, mean±SD (range).
7 male, 7 female
BMI*: body mass index
Wang HY et al
Acta Pharmacologica Sinica
median tmax of 2.0 h across all of the dose cohorts. After reach-
ing peak exposure, the plasma disposition of L-threonate was
also rapid, having a mean t1/2 of 2.5 h, which was indepen-
dent of dose. The mean oral apparent total plasma clearance
(Cl/F) and Vz/F were 9.8 L/h and 28.9 L, 14.5 L/h, and 53.6 L,
and 21.3 L/h and 76.5 L for the 675, 2025, and 4050 mg dose
cohorts, respectively. Over the dose range of 675 to 4050 mg,
the mean Cmax increased from 15.5 to 42.8 mg/L and AUC0-∞
increased from 77.7 to 220.9 h·mg/L; however, the 90% CI for
the ratio of dose-normalized, geometric mean values of Cmax
and AUC indicated that there was no apparent dose propor-
tionality over the range of 675 mg to 4050 mg (Table 3).
The effect of food intake on the pharmacokinetics of L-thre-
onate was studied in the 2025 mg dose group, in which 12
subjects received calcium L-threonate after overnight fasting
or breakfast. The results showed that Cmax and AUC in fed
subjects were increased compared to fasted subjects (Figure
3). The mean Cmax increased from 32.3 to 39.1 mg/L, and the
mean AUC0-∞ increased from 152.9 to 203.6 h·mg/L. There
was a statistically significant difference between the fasted
and fed groups using a paired t test (P<0.05); therefore, it was
concluded that the absorption of L-threonate was improved by
Table 2. Pharmacokinetic parameters of L-threonate in healthy Chinese subjects following single oral administration (mean±SD).
675 (n=12) 2025 (n=12) 2025 (fed) (n=12) 4050 (n=12)
tmax (median, h)
Urinary excretion rate (%)
BMI*: body mass index
Table 3. 90% CI for the ratio of dose-normalized, geometric mean values
of AUC and Cmax.
Mean* 90% CI+ Mean* 90% CI+
675 mg: 2025 mg 1.486 1.276–1.697
4050 mg: 2025 mg 0.701 0.491–0.912
CVw (%)# 30.50% 20.25%
CI=(A-B)(+/–)t_value*sqrt(MSE)*sqrt(1/nA+1/nB), where A–B=mean
difference between the treatment A and B under log scale, t_value is
the crirical values from t-distribution with degree of freedom of MSE,
CVw%(within–subject coefficients of variation)=sqrt(exp(MSE)–1)*100,
where MSE is the residual error from ANOVA).
(+): lower limit-upper limit
(#): within-subject coefficients of variation=sqrt[exp(MSE)–1]×100, where
MSE is the residual error from ANOVA
Figure 2. Mean plasma concentration-time curves in healthy Chinese sub-
jects after single oral administration of calcium L-threonate 675, 2025,
and 4050 mg (n=12).
Figure 3. Mean plasma concentration-time curves in healthy Chinese
subjects receiving 2025 mg calcium L-threonate after overnight fasting or
Wang HY et al
Acta Pharmacologica Sinica
Following single administration, urine samples were col-
lected over a period of 24 h. Cumulative urinary excretion
of L-threonate over the collection interval was 10.3%, 4.2%,
and 3.3% of the administered dose of 675, 2025, and 4050 mg,
respectively, with a mean renal clearance of 0.8±0.5 L/h.
The mean plasma concentration-time curves of L-threonate in
12 healthy Chinese subjects following multiple-dose adminis-
tration of 2025 mg calcium L-threonate are presented in Figure
4, and the pharmacokinetic parameters are presented in Table
4. Attainment of steady-state was achieved by d 7 because
the regression slope of natural logarithmic (ln) transformation
of trough concentrations on d 3, 4, 5, and 6 over time was not
statistically different from zero. The mean steady-state t1/2
was 2.1±0.6 h, which was comparable to the value of a single-
dose (2.0±0.7 h). The accumulation index was 1.086 (90% CI,
0.967–1.204) based on AUC0–t and 1.102 (90% CI 1.004–1.2)
based on Cmax, indicating that there was no further accumula-
tion of L-threonate after multiple administrations.
There were no serious adverse events (AEs) reported in this
study. The major adverse event was diarrhea (1/26, 3.8%),
which was observed in one subject after administration of 2025
mg calcium L-threonate during the single-dose period. This
AE was mild, transient, and without fever, nausea or belly-
ache; the subject recovered without medication or other treat-
ment. No additional AEs were reported in this study. There
were no clinically significant changes in laboratory parameters
(clinical chemistry, hematology or urinalysis) or vital signs
after treatment with calcium L-threonate. When compared to
baseline values acquired in the screening period, there were
no clinically significant changes in the ECG data. Therefore,
calcium L-threonate was shown to be safe and well tolerated
in healthy Chinese subjects.
Calcium L-threonate is a novel drug developed for the treat-
ment of osteoporosis. In this study, the pharmacokinetics
and safety of L-threonate in healthy Chinese volunteers were
reported for the first time. This study was divided into two
parts: single- and multiple-dose studies. In the single-dose
study, a 4-way, crossover design was used; 12 male Chinese
subjects received 675, 2025, 2025 (after breakfast) or 4050
mg calcium L-threonate. It indicated that L-threonate was
absorbed rapidly, with Cmax being reached at a median time of
2.0 h. Over the dose range of 675 mg to 4050 mg, the plasma
exposure of L-threonate increased with dose escalation; how-
ever, dose proportionality was not observed. The reason was
not clear, but it could be due to the saturate absorption of
L-threonate. After reaching peak exposure, the disposition of
L-threonate was rapid, as t1/2 ranged from 2.4 to 2.7 h. AUC0–t
contributed to over 98% of the total AUC, indicating that a
sampling period of 48 h was adequate for assessing plasma
exposure of L-threonate. Cumulative urinary excretion of
L-threonate over 24 h represented only 5.9% of the adminis-
tered dose. Because L-threonate is an acidic compound that
has hydroxyl and carboxyl groups, we hypothesized that this
drug might be eliminated as a conjugated form. However, no
phase II metabolites were found in plasma or urine when we
screened the samples using a TOF mass spectrometer (QSTAR
XL, AB Sciex, USA). Therefore, we hypothesize that L-thre-
onate may be involved in the anabolism of other endogenous
substances after administration. The metabolic pathway of
L-threonate is still being investigated in our lab.
In the multiple-dose study, there was no accumulation after
repeated doses of 2025 mg twice per day for 4 d. The mean
t1/2 was similar to that of the single-dose study, indicating
that the elimination rate of L-threonate did not change during
repeated administrations. However, concerning the 2025 mg
dose group, AUC and Cmax in the multiple-dose study were
significantly higher than those of the single-dose study (fasted
group), approximately 30% higher based on the Cmax and AUC.
A combined total of 24 Chinese subjects (18 male, 6 female)
completed this study. Half of the subjects in the multiple-dose
group were male (n=6), and half were female (n=6), whereas
all of the subjects (n=12) in the single-dose group were male.
Therefore, is the difference in AUC and Cmax between the
Table 4. Pharmacokinetic parameters of calcium L-threonate in healthy
Chinese subjects following multiple-dose of 2025 mg calcium L-threonate
tmax (median, h)
d 1 (n=12) d 7 (n=12)
*: DF, degree of fluctuation.
Figure 4. Mean plasma concentration-time curves in healthy Chinese
subjects after multiple doses of 2025 mg calcium L-threonate (n=12).
Wang HY et al
Acta Pharmacologica Sinica
single- and multiple-dose studies due to gender effect? Phar-
macokinetic parameters (Cmax and AUC0–t) were compared
using subject, gender and period as fixed factors using a three-
way ANOVA analysis. This analysis indicated that the differ-
ences among subjects and periods were significant (P<0.01);
however, there was no statistical difference between male and
female subjects (P>0.05). Therefore, the differences in plasma
exposure were due to the study period and individual varia-
tion, and not gender.
The safety evaluation during the study demonstrated that
calcium L-threonate was well tolerated in healthy Chinese
volunteers over the studied dose range. The reported AE was
diarrhea (1/26, 3.8%), which was possibly due to mannitol, an
excipient used in the tablet, increasing the intestinal osmotic
pressure. This reported AE was mild and transient; the sub-
ject recovered without any medication or further treatment.
In summary, this study demonstrated the single- and mul-
tiple-dose pharmacokinetics of calcium L-threonate and its
safety profile in healthy Chinese volunteers. L-threonate was
absorbed rapidly and exhibited dose-related plasma exposure.
After reaching peak exposure, this drug was quickly cleared
from the plasma, but renal excretion was not its major elimi-
nation route. The absorption of L-threonate was enhanced
by food intake, and there was no accumulation after multiple
administrations. Calcium L-threonate was well tolerated in
healthy Chinese volunteers over the studied dose range.
This study was supported by JuNeng Pharmaceutical Co (Bei-
jing, China). The authors thank all of the volunteers enrolled
in this study. We also thank the staff of the clinical ward and
bioanalytical lab of Phase I Unit in Peking Union Medical Col-
Ji JIANG and Pei HU designed the research and revised the
manuscript; Hong-yun WANG performed the research, ana-
lyzed the data, and wrote the paper.
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