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Health surveillance data

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Administrative data

Endpoint:
health surveillance data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
April to July 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study conducted to good scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Calcium Load During Administration of Calcium Carbonate or Sevelamer in Individuals with Normal Renal Function
Author:
Heinrich T, Heidt H, Hafner V, Schmidt-Gray H, Jenetzky E, Walter-Sack I, Mikus G & Bommer J
Year:
2008
Bibliographic source:
Nephrol Dial Transplant, 23(9): 2861-2867

Materials and methods

Study type:
biological effect monitoring
Endpoint addressed:
basic toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study evaluated the effect of calcium carbonate (CC) and sevelamer hydrochloride (SEV), a calcium free phosphate binder, on serum Ca and urinary Ca excretion in healthy individuals.
Twelve healthy male individuals were included in a monocentre, randomised, single-blind, placebo-controlled, three-way crossover phase I study. Concurrently with their meals, participants received 4x2 tablets of SEV (800 mg), CC (500 mg) or placebo for 6 days with 1-week washout between the treatment periods. During the study, weekly blood samples were taken and 24-h urine was collected each day for measurement of calcium, magnesium, phosphorous, chloride and intact parathyroid hormone (iPTH).
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Calcium carbonate
EC Number:
207-439-9
EC Name:
Calcium carbonate
Cas Number:
471-34-1
Molecular formula:
CH2O3.Ca
IUPAC Name:
calcium carbonate
Details on test material:
Calcium carbonate: Dreisacarb®, GRY-Pharma, Kirchzarten

Method

Type of population:
general
Ethical approval:
confirmed and informed consent free of coercion received
Remarks:
The study was approved by the Ethics Committee of the Medical Faculty of the University of Heidelberg
Details on study design:
PARTICIPANTS
Twelve healthy male participants (eleven Caucasian and one African participant) were included. Participants were between 19 and 27 years old and mentally and physically healthy including normal mineral metabolism as defined by medical history, physical examination, electrocardiogram and routine laboratory analyses. None of the participants had taken any medication for 2 months prior or during the study. All participants were non-smokers. Exclusion criteria included inability to communicate with the investigator, a history of allergic reactions, blood donation or participation in a clinical trial within the last 2 months or excessive alcohol drinking (>30 g alcohol per day).

PROCEDURE
The study was conducted as a randomised, single-blind, placebo-controlled, threefold crossover phase I study with three treatment periods. 4 g calcium carbonate was administered daily for a treatment period of 6 days. A placebo (P tablets 10 mm Lichtenstein®) was also administered to some patients. Between treatment periods a washout time of 7 days was required. During the treatment periods, after an overnight fast, participants received the first daily dose. The remaining doses were taken with meals at intervals of ~4 h.

SAMPLING
Urine was collected for 24 h on each study day (Day 1 = pre-dose and Days 2-7 = during treatment). Venous blood samples (7.5 mL) were drawn before the administration of the study drugs on Days 1-6 and on the morning of Day 7. For determination of iPTH and vitamin D on the 1st, 3rd, 5th and 7th day of each period, 2.7 mL blood samples were drawn before administration of the study drugs.

Results and discussion

Results:
See Tables 1, 2 and 3.

Mean daily total urinary excretion of calcium was significantly higher in calcium carbonate treated participants compared to those receiving placebo. Mean 24 h calcium excretion during the 6 day treatment was 6.60±2.62 mmol [265±105 mg] for calcium carbonate versus 4.95±1.63 mmol [198±65 mg] for placebo. Alimentary Ca intake as assessed by analysis of the dietary records was comparable between the treatment groups. Additional calcium supply due to calcium carbonate intake was associated with diminished fractional absorption of calcium in the calcium carbonate group (8.7%) as compared to placebo (13.3%).
Mean daily creatinine excretion was significantly higher under calcium carbonate treatment compared to placebo. Mean daily creatinine clearance was also increased for calcium carbonate treatment compared to placebo but this difference was not statistically significant after correction for multiple testing.

Any other information on results incl. tables

Table 1: Mean 24 h urinary excretion data

Variable

Placebo mean

(95% CI)

Calcium carbonate mean

(95% CI)

Treatment effect

Treatment contrast: placebo versus calcium carbonate

Calcium (mmol)

4.95 (3.99-5.92)

6.60 (5.21-8.00)

P<0.001

P<0.001

(mg)

198 (160-237)

265 (209-321)

-

-

Phosphorous (mmol)

34.7 (29.6-39.7)

31.2 (26.3-36.2)

P=0.001

ns§ (P=0.013)

(mg)

1074 (917-1231)

968 (815-1121)

-

-

Magnesium (mmol)

4.89 (4.15-5.62)

5.36 (4.69-6.02)

ns

-

Creatinine (g)

1.78 (1.62-1.94)

2.01 (1.80-2.21)

P=0.001

P<0.001*

Urine volume (mL)

1880 (1312-2448)

1979 (1429-2530)

ns (P=0.071)

-

Calcium/ creatinine (mmol/g)

2.84 (2.39-3.29)

3.38 (2.73-4.03)

ns§ (P=0.006)

-

Phosphorous/ creatinine (mmol/g)

19.5 (17.5-21.6)

15.6 (14.0-17.3)

P<0.001

P<0.001

Magnesium/ creatinine (mmol/g)

2.78 (2.40-3.16)

2.72 (2.40-3.04)

ns

-

Creatinine clearance (mL/min/1.73 m2)

114 (105-123)

126 (115-137)

ns§ (P=0.023)

-

Chloride (mmol)

185 (154-216)

195 (159-231)

ns

-

Chloride/ creatinine (mmol/g)

106 (85-126)

98 (84-112)

ns (P=0.096)

-

* Significant sphericity deviation

§ Not significant after correction for multiple testing

ns = not significant

 

 

Table 2: Mean serum concentrations

Variable

Placebo mean

(95% CI)

Calcium carbonate mean

(95% CI)

Treatment effect

Treatment contrast: placebo versus calcium carbonate

Calcium (mmol)

2.35 (2.29-2.40)

2.37 (2.29-2.44)

ns

-

(mg/dL)

9.42 (9.18-9.62)

9.50 (9.18-9.78)

-

-

Phosphorous (mmol)

1.27 (1.18-1.37)

1.29 (1.18-1.39)

ns

-

(mg/dL)

3.94 (3.66-4.25)

3.99 (3.66-4.31)

-

-

Magnesium (mmol)

0.839 (0.784-0.894)

0.845 (0.787-0.903)

ns

-

Alkaline phosphatase (AP) (U/L)

56.8 (51.6-62.0)

60.1 (53.6-66.5)

ns§ (P=0.027*)

-

Total protein (g/L)

70.9 (69.0-72.7)

71.9 (69.4-74.4)

ns (P=0.064)

-

Albumin (g/L)

49.1 (47.7-50.4)

48.8 (46.7-51.0)

ns

-

Chloride (mmol)a

102 (101-102)

102 (100-103)

ns

-

Creatinine (mg/dL)a

0.968 (0.898-1.039)

1.002 (0.927-1.077)

ns§ (P=0.017)

-

1,25-dihydroxyvitamin D3 (ng/L)a

59.9 (50.1-69.7)

58.3 (50.7-65.8)

ns

-

25-hydroxyvitamin D3 (µg/L)

23.8 (16.9-30.6)

27.1 (20.8-33.4)

ns

-

IPTH (ng/L)

39.3 (34.3-44.4)

39.4 (33.4-45.3)

ns

-

* Significant sphericity deviation

§ Not significant after correction for multiple testing

ns = not significant

aData for n=11 subjects

  

Table 3: Mean daily calcium load during the 6 day treatment periods

Test material

Oral Ca intake

Urinary Ca excretiona

Fraction of Ca absorbedb

Placebo

Food: 37.2±1.1.7 mmol (1490±468 mg)

4.95±1.63 mmol [198±65 mg]

13.3%

Calcium carbonate

Total intake: 76 mmol (3046 mg)

[36.0±10.5 mmol (food), 40 mmol (medication); 1443±421 mg (food), 1600 mg (medication)]

6.60±2.62 mmol [265±105 mg]

8.7%

Data represent mean values ± SD for n=12

aUrinary calcium excretion represents intestinal calcium absorption

bCalculated as (urinary Ca excretion / oral Ca intake) * 100

Applicant's summary and conclusion

Conclusions:
The study revealed that intake of calcium carbonate as compared to placebo was associated with an increase in the total amount of calcium absorbed and increased urinary calcium excretion in healthy individuals while serum calcium concentrations remained unaffected.
The study was performed in healthy subjects with intact renal function and normal mineral metabolism. From the results, there is no reason to suspect an increased mineral storage in the organism and soft tissue calcification, as may occur in patients with impaired renal function.

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