Original Research

Pharmacokinetics and
pharmacodynamics of
calcium-vitamin D3 chewable
1. Introduction tablets: a single-blind,
2. Subjects and methods
3. Results multiple-dose study in
4. Discussion
postmenopausal women
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Monash University on 10/20/12

5. Conclusions
Edgar A Mueller†, Michael Seiberling, Wilhelm Kirch, Adrian Frentzel &
Sonja Trapp
†
Technical University, Institute for Clinical Pharmacology, Medical Faculty, Dresden, Germany

Objective: The objective of this study is to investigate the effect of a newly

developed calcium carbonate-vitamin D3 chewable tablet formulation
(600 mg of calcium + 400 IU of vitamin D3) on serum/urine calcium and serum
parathyroid hormone (PTH) as measures of intestinal calcium absorption
compared to a placebo.
Methods: This is a subject-blind, sequential study in 24 healthy postmeno-
pausal women. Each subject received two placebo tablets once daily for
For personal use only.

3 days (days -3 to -1) immediately followed by two calcium-vitamin D3 tablets

(test) during the subsequent 3 days (days 1 -- 3). Serial blood sampling and
24-h urine collection took place on days -1 and 3. The subjects fasted until
6 h post-dosing. Total urinary calcium excretion (Ae(0 -- 24 h)) and AUC(0 -- 6 h)
for serum calcium were the primary outcome variables and were compared
between treatments using a paired sample t-test.
Results: Ae(0 -- 24 h) increased by 42% (uncorrected, p = 0.0001) and 30%
(creatinine-corrected, p = 0.0001), after intake, compared with the placebo;
serum calcium exposure (AUC(0 -- 6 h)) was also, statistically, significantly
greater. PTH, in serum, decreased by 28% (AUC(0 -- 6 h), p = 0.0001) and 14%
(AUC(0 -- 24 h), p = 0.0009) when compared with the placebo.
Conclusion: Daily intake of 1200 mg of calcium and 800 IU of vitamin D3, with
a new chewable tablet, resulted in increased intestinal calcium absorption
compared to the results from the placebo as confirmed by direct and indirect
pharmacokinetic/pharmacodynamic measures.

Keywords: bioavailability, calcium, chewable tablet, cholecalciferol, parathyroid hormone,

vitamin D

Expert Opin. Drug Metab. Toxicol. (2011) 7(7):785-791

1. Introduction

Calcium is one of the most abundant minerals in the human body. The primary
function of calcium is to form the structure of bones and teeth; the skeleton
accounts for 99% of total calcium stores in the form of hydroxyapatite. Calcium
is also involved in the function of the muscular, cardiovascular, endocrine and ner-
vous systems [1]. The bones are a reservoir of calcium helping to maintain a constant
concentration of this element in blood. Calcium is absorbed in the small intestines
by active vitamin D-mediated and passive transport mechanisms [2]. In plasma,
calcium is present in the free (ionic calcium) and fixed forms (mainly bound to

10.1517/17425255.2011.591378 © 2011 Informa UK, Ltd. ISSN 1742-5255 785

All rights reserved: reproduction in whole or in part not permitted
 Pharmacokinetics and pharmacodynamics of calcium-vitamin D3 chewable tablets
proteins) [3]. Calcium is excreted primarily in the urine and
feces. Urinary calcium loss is determined by glomerular filtra-
tion and tubular reabsorption; the latter is tightly regulated by
the parathyroid hormone (PTH) [4]. In stabilized conditions,
cumulative urinary excretion of calcium can be used as an
indirect measure for calcium absorption from the gastrointes-
tinal (GI) tract as urinary and dietary calcium increase
proportionally [3,5].
Vitamin D is a group of fat-soluble secosteroids; the two
major physiologically relevant forms are vitamin D2 (ergocal-
ciferol) and vitamin D3 (cholecalciferol). The two forms are
metabolized in a similar fashion [6]. Vitamin D3 is produced
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Monash University on 10/20/12
photochemically in the skin from 7-dehydrocholesterol.
Whether it is made in the skin or ingested, vitamin D3 is car-
ried in the bloodstream to the liver, where it is converted into
calcidiol (25-hydroxycholecalciferol). Circulating calcidiol is
then converted (mainly in the kidneys) to calcitriol
(1,25-dihydroxycholecalciferol), the biologically active form
of vitamin D [7]. The renal production of calcitriol is tightly
regulated by systemic PTH levels and serum calcium and
phosphate concentrations [8]. Depending on the vitamin D
source, the absorption of this vitamin varies in humans
between 55 and 99% [5]. For oral vitamin D3, there seems
to be a linear relationship between oral doses and circulating
For personal use only.
calcidiol levels, which is formed from vitamin D3 [9]. The
lipophilic nature of vitamin D3 explains its adipose tissue
distribution and its slow turnover in the body. Studies with
radiolabeled vitamin D3 have shown that the whole-body
half-life is ~ 2 months [10,11].
Vitamin D is an important element of nutrition. It may
play a role in a variety of diseases such as hypertension, auto-
immune disorders and infectious diseases [7]. However, the
classic effect of vitamin D is to facilitate calcium absorption
by mediating active calcium transport across the intestinal
mucosa [12]. Without vitamin D, only 10 -- 15% of dietary
calcium is absorbed [8]. Hence, vitamin D and calcium defi-
ciencies are frequently combined. The latter provides the
scientific rationale to combine calcium and vitamin D3 in a
fixed combination.
The major cause of vitamin D deficiency is lack of
sufficient sun exposure. Even in the sunniest areas, vitamin
D deficiency may occur when most of the skin is shielded
from the sun [8]. Male and female elderly subjects are prone
to vitamin D deficiency because aging is associated with
decreased concentrations of 7-dehydrocholesterol, the precur-
sor of vitamin D3 in the skin [13]. Moreover, the same popu-
lation frequently shows calcium malabsorption [14,15];
females are particularly at risk here because in addition to
the general age-related decrease in calcium absorption there
is a decline that occurs at menopause [15]. These factors
lead to secondary hyperparathyroidism and subsequently to
increased bone loss, osteoporosis and osteoporotic frac-
tures [16,17]. In the pathogenesis of osteoporosis, the pivotal
role of calcium and vitamin D deficiency is well accepted.
The need for calcium and vitamin D supplementation is,
786 Expert Opin. Drug Metab. Toxicol. (2011) 7(7)
therefore, generally appreciated and frequently practiced,
particularly in postmenopausal women and the elderly popu-
lation [3,18]. This therapy is able to reverse and prevent vitamin
D and calcium deficiency and consequently secondary hyper-
parathyroidism [3,19]. The most widely advocated daily dose is
800 IU of vitamin D3 and 1000 -- 1200 mg of calcium [7,8,18];
however, different doses might be required depending on age
and sun exposure.
A new co-formulated chewable tablet has been develo-
ped containing 600 mg of calcium (as carbonate salt) and
400 IU of vitamin D3. The objective of this study was to
assess the effect of calcium-vitamin D3 chewable tablets on
serum and urine calcium levels and serum PTH as compared
with placebo. Cumulative urinary excretion of calcium and
acute PTH suppression are indirect measures of intestinal
calcium absorption [3,5,20].
2. Subjects and methods
This was a single-blind, multiple-dose, sequential study in
healthy postmenopausal women conducted at Covance
Clinical Research Unit AG, Allschwil, Switzerland during
January 2010. Each subject received two placebo chewable
tablets once daily for 3 consecutive days (days -3 to -1) imme-
diately followed by two calcium-vitamin D3 chewable tablets
(test) once daily (i.e., 1200 mg of calcium and 800 IU of vita-
min D3 per day) during the subsequent 3 days (days 1 -- 3).
Subjects were confined to the study center from the evening
before day -3 to the morning of day 4. The sequence was
always placebo--test to avoid possible carryover effects of vita-
min D3 on the second study period; a similar approach has
been applied before [3,21]. Study participants remained
blinded as to the sequence of the study periods. The study
protocol was approved by the pertinent Independent Swiss
Ethics Committee (EKBB). Subjects gave written informed
consent to participate after being informed about the study.
The study medication (Calcium D3-Mepha 600/400 CM,
Kautabletten and matching placebo) was manufactured and
supplied by Mepha LLC, Aesch, Switzerland. Test and pla-
cebo tablets were indistinguishable in appearance and taste
(identical flavor).
Caucasian postmenopausal non-smoking women with a
body mass index (BMI) of 19 -- 29 kg/m2 and aged between
42 and 70 years were judged healthy at screening (i.e., within
3 weeks before first dosing) on the basis of medical history,
physical examination, vital signs measurements, electrocardio-
gram, laboratory assessments, drug and alcohol screens, and
hepatitis and HIV serologies. For inclusion, the women
must have had the last menses ‡ 2 years prior to study start.
Subjects with unusual diet habits and practicing vegetarians
were excluded. Other exclusion criteria included coexisting
serious disease, history or presence of a disorder which
would have interfered with study objectives (e.g., hyper- or
hypoparathyreoidism, calcium deficiency, hypercalcemia,
hypercalciuria, hyperphosphatemia, calcium lithiasis, diabetes

mellitus or creatinine clearance lower than 60 ml/min), aller-
gies requiring treatment, hypersensitivity to any drug (includ-
ing calcium and cholecalciferol), excessive consumption of
caffeinated beverages, bisphosphonate use within the last
5 years and regular use of any medication. Washout periods
before entering the study were 6 months for amiodarone,
3 months for systemic steroids, 1 month for calcium or fluo-
ride supplements, vitamin D preparations, diuretics, estrogens
or estrogen receptor modulators, teriparatide, bile acid
sequestrants and enzyme-inducing agents, and 2 weeks (but
at least five half-lives) for any other drug. Moreover, subjects
were required not to travel to destinations located at a latitude
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Monash University on 10/20/12
between 30 north and 30 south or an altitude of ‡ 1500
meters above sea level and to avoid ultraviolet radiation cabins
or lamps for 7 days before first dosing. Other study restric-
tions included avoidance of milk and milk products, broccoli,
dark-green leafy vegetables, fatty fish, eggs, liver and added
salt for 7 days before initiation of dosing. All these restrictions
also applied during confinement.
All study drug administrations were performed in the
morning after an overnight fast of at least 10 h. Breakfast
was served 1.5 h after dosing, except for days -1 and 3 when
the first meal was ingested 6 h after dosing. On these days,
subjects were additionally requested to drink 1.8 l of non-
For personal use only.
carbonated water. For administration of study medication,
each tablet was shortly chewed and completely swallowed
with 120 ml of water (i.e., in total 240 ml of non-carbonated
for each administration).
Safety assessments included physical examinations, electro-
cardiograms, vital signs measurements (blood pressure, pulse)
and laboratory evaluations (biochemistry, hematology, urinal-
ysis) prior to the study, at multiple times during the trial (vital
signs only) and at study completion (i.e., within 24 h of
last dosing).
Blood sampling for the determination of serum PTH and
calcium was performed over 24 h after the last dose of placebo
(day -1) and test (day 3), thereby following this schedule: pre-
dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 18 and 24 h after dosing. In
addition, pre-dose levels were determined daily. Serum sam-
ples were stored at -20 C (PTH) and at 2 -- 8 C (calcium)
until analysis. In parallel, urine was collected over 24 h on
the same days for the determination of calcium and creatinine
in urine. Collection intervals were 0 -- 6, 6 -- 12 and 12 -- 24 h
after dosing. During urine collections, the urine was kept
refrigerated (2 -- 8 C). After weighing the urine, aliquots
were taken from each collection fraction and stored at
2 -- 8 C until analysis. The subjects have been supervised by
a study nurse to assure that all urine was collected.
2.1 Bioanalytics
Serum PTH and serum calcium as well as urinary excretion of
calcium and creatinine were measured by standardized and
validated laboratory methods. Specifically, calcium in serum
was determined using a colorimetric determination method
(Hitachi 917, Roche Diagnostics, Mannheim, Germany)
Expert Opin. Drug Metab. Toxicol. (2011) 7(7)
Mueller, Seiberling, Kirch, Frentzel & Trapp
without adjustment for serum albumin concentration (intra-
assay precision: 0.9%, normal range: 2.1 -- 2.6 mmol/l). Urine
calcium concentration was assessed by atomic absorption
spectrophotometry (Spectr AA 200 FS, Varian, Darmstadt,
Germany). A two-site chemiluminescence immunoassay
(ADVIA Centaur XP, Siemens Healthcare Diagnostics,
Tarrytown, NY, USA) was used to measure intact PTH in
serum (normal values: 14 -- 72 pg/ml).
2.2 Pharmacokinetic and pharmacodynamic analysis
Calcium and PTH serum concentration--time profiles related
to day -1 and 3 administrations were analyzed by standard
non-compartmental methods using WinNonlin, Version
4.1 (Pharsight Corp., Mountain View, CA, USA) or SAS pro-
cedures (SAS Institute, Cary, NC, USA). Pharmacokinetic
and pharmacodynamic parameters calculated or observed
included for serum calcium: Cmax, tmax, area under the serum
concentration--time curve assessed with the linear trapezoidal
method from 0 to 6 h (AUC(0 -- 6 h)) and AUC(0 -- 24 h); min-
imum concentration (Cmin), time of Cmin (tmin), concen-
tration at 1 h post-dosing (C(1 h)), AUC(0 -- 6 h) and
AUC(0 -- 24 h) for serum PTH and the cumulative urinary
calcium excretion (Ae) for the different urine fractions
(raw values and corrected for creatinine excretion). The
cumulative urinary calcium excretion over the entire 24-h
collection period (Ae(0 -- 24 h)) was additionally calculated.
Creatinine correction of calcium excretion (i.e., divided by
urinary creatinine concentration measured simultaneously)
was performed to account for potential inaccuracies in
urine collection.
2.3 Statistical evaluation
The pharmacokinetic and pharmacodynamic parameters were
statistically compared between treatments (test vs placebo) at a
significance level of 5% (p < 0.05). Statistical analyses were
performed using SAS procedures. With the exception of
the discrete (non-continuous) parameters tmax and tmin data
were log-transformed prior to testing. The comparisons were
made using paired sample t-test with generation of point esti-
mates. Total urinary calcium excretion (Ae(0 -- 24 h)) and
AUC(0 -- 6 h) for serum calcium were the prospectively defined
primary outcome variables. Based on variability data from
previous studies with calcium-vitamin D3 supplements [3,22],
a sample size of 24 subjects was calculated. This ensured at
least 80% power to detect a statistical significance between
treatments if one exists.
3. Results
Twenty-four healthy postmenopausal women were enrolled in
this study and all completed the trial according to protocol.
The mean age was 59.6 ± 6.1 years (range: 46 -- 68 years)
and mean BMI was 24.5 ± 2.4 kg/m2 (range: 19.8 --
29.3 kg/m2). All subjects had a baseline creatinine clearance
higher than 70 ml/min.
787
 Pharmacokinetics and pharmacodynamics of calcium-vitamin D3 chewable tablets

Table 1. Serum and urinary pharmacokinetic parameters of calcium in 24 healthy postmenopausal women on the
third day of once-daily administration of calcium-vitamin D3 chewable tablets (test, day 3) or placebo (day -1).

Test Placebo p Ratio*

Cmax, mmol/l 2.46 ± 0.08 - - -

tmax, h 3 (1 -- 6) - - -
AUC(0 -- 6 h), h·mmol/l 14.35 ± 0.48 14.18 ± 0.52 0.0097 1.01
AUC(0 -- 24 h), h·mmol/l 55.88 ± 1.60 56.45 ± 1.78 0.0015 0.99
Ae(0 -- 6 h), mmol 1.35 ± 0.43 0.82 ± 0.31 0.0001 1.68
Ae(6 -- 12 h), mmol 1.29 ± 0.57 0.90 ± 0.29 0.0001 1.43
Ae(12 -- 24 h), mmol 1.41 ± 0.47 1.23 ± 0.48 0.0603 1.25
Ae(0 -- 24 h), mmol 4.05 ± 1.28 2.94 ± 0.95 0.0001 1.42
Ae(0 -- 24 h), mmol/g 3.46 ± 1.10 2.63 ± 0.77 0.0001 1.30
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Monash University on 10/20/12

creatinine-corrected

All values are presented as mean ± s.d. except tmax which is displayed as median (range); p-value from paired sample t-test.
Cmax, tmax, AUC(0 -- 6 h) and AUC(0 -- 24 h) are based on serum calcium concentrations; Ae-values are based on urinary calcium concentrations.
*Ratio of the geometric means for the comparison of test vs placebo.
Ae: Cumulative urinary calcium excretion.

3.1 Pharmacokinetics Specifically, on days of PTH profiling mean pre-dose con-

Table 1 represents the mean pharmacokinetic parameters for
both serum and urinary calcium assessed on days -1 and
3 of the study. There was a significant increase by 42%
(uncorrected) and 30% (creatinine-corrected) in 24-h urinary
calcium excretion (primary end point) following intake of
For personal use only.
centrations of serum PTH were 32.4 ± 12 (day -1, placebo)
and 30.9 ± 12.6 pg/ml (day 3, test). The lower pre-dose
value on day 3 is most likely a result of the preceding 2-day
treatment with calcium-vitamin D3. Such an effect on PTH
pre-dose levels has been reported previously [3].

calcium-vitamin D3 chewable tablets compared with placebo

administration. With the exception of the 12 -- 24 h collection
interval, a significant difference in favor of test was also
observed for the different urine collection periods. With
regard to serum concentrations of calcium, the administration
of calcium-vitamin D3 tablets resulted in a slight but statisti-
cally significant increase in AUC(0 -- 6 h) (co-primary end
point) compared with placebo. AUC(0 -- 24 h) was slightly
lower in comparison with placebo (p < 0.05). The statistical
result for AUC(0 -- 6 h) and AUC(0 -- 24 h) was facilitated by a
low intra-subject %CV of 1.49 and 0.98%, respectively. Con-
sistent with a rapid homeostatic control of serum calcium [5],
mean pre-dose serum calcium concentrations were stable over
the study course, ranging between 2.33 and 2.38 mmol/l. On
days of pharmacokinetic profiling (days -1 and 3), mean pre-
dose concentrations of serum calcium were 2.33 ± 0.09 and
2.33 ± 0.08 mmol/l, respectively.
3.2 Pharmacodynamics
Table 2 shows the mean PTH parameters assessed on study
days -1 and 3 and Figure 1 displays the time course of serum
PTH on these days. The administration of calcium-
vitamin D3 chewable tablets induced significant decreases in
serum PTH levels compared with placebo. The effect was par-
ticularly pronounced early after intake, with a 42 and 28%
reduction in C(1 h) and AUC(0 -- 6 h), respectively. However,
the statistically significant reduction in serum PTH concen-
trations was maintained over the entire dosing interval as
reflected by a 14% reduction in AUC(0 -- 24 h) compared
with placebo (p < 0.05). Mean pre-dose serum PTH
concentrations slightly decreased over the study course.
3.3 Tolerability
The study medication was well tolerated during this short-
term study. No serious adverse event and no adverse event lead-
ing to discontinuation of study medication were noted during
the study. Most of the adverse events (24 in total) were consid-
ered unrelated to the study medication, except 2 episodes of
rash or pruritus, 1 case of dizziness and 1 case of nausea. These
four adverse events were reported by three subjects while on the
test formulation; they were all transient and of mild severity,
and resolved spontaneously without specific treatment. There
were no clinically relevant changes in clinical laboratory param-
eters, electrocardiograms or vital signs over the study course.
One subject whilst receiving calcium-vitamin D3 had an iso-
lated serum calcium concentration (1 h after last dosing)
slightly above the normal range (2.66 mmol/l).
4. Discussion
The main outcome of this single-blind, multiple-dose, sequen-
tial study was that a new co-formulated calcium-vitamin D3
chewable tablet formulation (containing 600 mg of calcium
and 400 IU of vitamin D3) is effective in healthy postmeno-
pausal women: once daily intake of two chewable tablets for
3 days in the fasting state resulted in increased absorption of
calcium from the GI tract as reflected by statistically significant
increases in 24-h calcium excretion, increased serum calcium
exposure (AUC(0 -- 6 h), p < 0.05) and statistically significant
reductions in serum PTH compared with placebo. In terms
of tolerability, the calcium-vitamin D3 tablet was well tolerated
in this short-term study.

788 Expert Opin. Drug Metab. Toxicol. (2011) 7(7)

 Mueller, Seiberling, Kirch, Frentzel & Trapp

Table 2. Effect of calcium-vitamin D3 chewable tablets (test, day 3) and placebo (day -1) on intact parathyroid
hormone in serum on the third day of once-daily administration to 24 healthy postmenopausal women.

Test Placebo p Ratio*

Cmin, pg/ml 16.75 ± 8.85 - - -

tmin, h 1 (0.5 -- 4) - - -
C(1 h), pg/ml 18.58 ± 8.98 30.29 ± 11.19 0.0001 0.58
AUC(0 -- 6 h), h·pg/ml 143.05 ± 67.79 190.89 ± 68.10 0.0001 0.72
AUC(0 -- 24 h), h·pg/ml 815.43 ± 302.85 951.29 ± 278.32 0.0009 0.86

All values are presented as mean ± s.d. except tmin which is displayed as median (range); p-value from paired sample t-test.
*Ratio of the geometric means for the comparison of test vs placebo.
C(1 h): Serum concentration at 1 h post-dosing; Cmin: Minimum serum concentration; tmin: Time of Cmin.
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Monash University on 10/20/12

70 Test calcium AUC(0 -- 24 h) showed no increase with calcium-

Placebo vitamin D3 in comparison with placebo. It has been previ-
60 ously reported that oral intake of calcium supplements
resulted in significantly increased urinary calcium excretion
50 and/or decreased serum PTH levels which were not paralleled
Serum PTH (pg/ml)

(or to a lesser degree) by increased total serum calcium

40
concentrations [3,16,22]. Hence, urinary calcium excretion
30
appears a robust parameter of intestinal calcium absorp-
tion. The observed increase in cumulative 24-h urinary cal-
20 cium excretion was in good agreement with previous
For personal use only.

studies in which combinations of calcium and vitamin D3

10
0
0 6 12 18
Time (h)
Figure 1. Mean serum concentration--time profiles (linear
scale) of intact parathyroid hormone in 24 healthy post-
menopausal women on the third day of once-daily admin-
istration of calcium-vitamin D3 chewable tablets (test, day 3)
or placebo (day -1). Bars represent 1 s.d.
The presence of endogenous sources of calcium and vita-
min D as well as their homeostatic control in blood make it
difficult to evaluate the relative bioavailability of exogenous
supplementation [5]. Nevertheless, the results of the present
study appear reliable because the trial was performed under
institutionalized and thus strongly standardized conditions
(e.g., in terms of diet and direct exposure to sunlight). More-
over, on days of pharmacokinetic and pharmacodynamic pro-
filing, the influence of food intake on outcome variables was
minimized by prolonging the overnight fasting period until
6 h post-dosing. In analyzing the data, each subject served as
her own control.
In our study, the change in urinary calcium excretion was
more pronounced than that observed in serum calcium expo-
sure (AUC(0 -- 6 h)). This is an expected finding because serum
calcium is strictly and rapidly controlled by homeostatic
mechanisms [3,5]. The latter may also explain why serum
were studied in healthy subjects at similar dosages; there,
increases between 35 and 50% (not creatinine-corrected)
24
were reported [3,22-23].
An acute oral calcium load suppresses PTH secretion; max-
imal suppression is usually obtained between 1 and 2 h after
calcium intake [20]. Therefore, changes in serum PTH levels
have been frequently used as an indirect indicator of intestinal
calcium absorption from calcium supplements [3,5,14,16,20,24-25].
In our study, we observed significant decreases in PTH levels
which were generally in accordance with those previously
reported for healthy women receiving a combination of
calcium and vitamin D3 [5,24].
The design of the present study did not allow for determin-
ing the incremental effect of vitamin D3 on calcium absorp-
tion. This is certainly a limitation of the study. However, it
has been previously shown that calcium absorption from cal-
cium supplements is enhanced when combined with vitamin
D3 [3,12,21]. Hence, no attempts were made to prove this again.
Further, a direct action of vitamin D metabolites on parathy-
roid cells has been observed in vitro [26], which was not
addressed in our study. Another limitation is the lack of
randomization of study periods; the sequence was always pla-
cebo--test to avoid possible carryover effects of vitamin D3 and
its metabolites on the second study period. Given the short
study duration, seasonal effects can certainly be excluded here.
Calcium supplements are generally well tolerated; however,
some patients complain of GI symptoms [1]. In the present
short-term study, the intake of study medication was not asso-
ciated with GI tolerability problems. We observed only one
case of mild nausea which occurred after administration of

Expert Opin. Drug Metab. Toxicol. (2011) 7(7) 789

 Pharmacokinetics and pharmacodynamics of calcium-vitamin D3 chewable tablets
calcium-vitamin D3, but GI adverse events may occur on
long-term use.
5. Conclusions
Based on the results of the present study in healthy postmen-
opausal women, it can be concluded that the daily oral
intake of 1200 mg of calcium and 800 IU of vitamin D3
with a new co-formulated chewable tablet resulted in
increased intestinal calcium absorption in comparison with
placebo as confirmed by direct and indirect pharmacokinetic/
pharmacodynamic measures. The new formulation appears
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Monash University on 10/20/12
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Declaration of interest
This study was supported by Mepha LLC, Aesch,
Switzerland. S Trapp and A Frentzel are full-time employees
of Mepha LLC. EA Mueller, W Kirch and M Seiberling
have no conflicts of interest and have received no payment
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Affiliation
Edgar A Mueller†1, Michael Seiberling2,
Wilhelm Kirch1, Adrian Frentzel3 &
Sonja Trapp3
†
Author for correspondence
1
Technical University,
Institute for Clinical Pharmacology,
Medical Faculty, Fiedlerstrasse 27,
D 01307, Dresden, Germany
Tel: +49 351 458 2815; Fax: +49 351 458 4341;
E-mail: Edgar.Mueller@tu-dresden.de
For personal use only.

2
Covance Clinical Research Unit AG,
Allschwil, Switzerland
3
Mepha LLC, Aesch,
Switzerland

Expert Opin. Drug Metab. Toxicol. (2011) 7(7) 791