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Toxicological information

Health surveillance data

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Administrative data

Endpoint:
health surveillance data
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Absolute Bioavailability and Disposition of Lanthanum in Healthy Human Subjects Administered Lanthanum Carbonate
Author:
Pennick, M. et al.
Year:
2006
Bibliographic source:
J. Clin. Pharmacol., 46:738-746

Materials and methods

Study type:
medical monitoring
Endpoint addressed:
basic toxicokinetics
Principles of method if other than guideline:
Randomized, open-label, parallel-group, phase I study conducted to investigate absolute bioavailability and excretory routes for systemic lanthanum in healthy subjects.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lanzhanum chloride
- Analytical purity: no data

Method

Type of population:
general
Ethical approval:
confirmed, but no further information available
Remarks:
The final protocol and subject-informed consent documentation were approved by the Ravenscourt Ethics Committee (UK) prior to the start of the study
Details on study design:
Refer to any other information on materials and methods.

Results and discussion

Results:
Lanthanum chloride infusion was well tolerated. The mean ± SD plasma concentration of lanthanum increased from a baseline of < 0.05 ng/mL to a maximum of 5.1 ± 0.9 ng/mL at 3.3 ± 0.8 hours after the start of the infusion. Plasma lanthanum concentrations subsequently declined triphasically, with a mean ± SD terminal elimination half-life of 37 ± 22 hours (range 15-77 hours). Lanthanum plasma exposure (mean ± SD, AUC) after intravenous dosing was 38.9 ± 10.5 ng h/mL. The total clearance of lanthanum (55 ± 16 mL/min) was low relative to average hepatic blood flow (1470 mL/min). Lanthanum was widely distributed after infusion, with an apparent volume of distribution of 164 ± 84 L. Intravenous administration confirmed low renal clearance (0.95 ± 0.60 mL/min), just 1.7% of total plasma clearance. Fecal lanthanum excretion was not quantifiable after intravenous administration owing to high and variable background fecal lanthanum and constraints on the size of the intravenous dose.
Lanthanum was poorly absorbed after oral administration of lanthanum carbonate. A mean Cmax of 0.32 +- 0.13 ng/mL was reached at 4.5 +- 0.8 h after dosing. Thereafter lanthanum concentrations declined bi- or triphasically. The mean terminal elimination half-life was 35 +- 12 hours (range 16 to 48 hours). Lanthanum plasma concentrations were generally blow the limit of quatification from 48 h after administration of the substance. The terminal elimination half-life is therefore to be treated with caution and may well be shorter. The AUC was 3.9 +- 2.5 ng h/mL indicating a low oral availability. Mean bioavailabilty was calculated to be 0.00127 +- 0.00080% (range: 0.00015 to 0.00224%) after oral adminsitration of Lanthanum carbonate. 313 +- 338 ng of lanthanum was ecreted inthe urine within 48 h after dosing representing 0.000031 +- 0.000034% of the dose. Renal clearance was 1.36+- 1.43 mL/min.

Any other information on results incl. tables

Summary of pharmacokinetic parameters

Parameter

i.v dose (N=8)

Oral dose (N=8)

Cmax (ng/mL)

5.07 +- 0.95

0.320 +- 0.133

T max (h)

3.30 +- 0.77

4.50 +- 0.756

AUC0-t (ng h/mL)

36.90+-9.85

3.90 +- 2.45

AUC0-∞(ng h/mL)

38.90 +- 10.50

4.79 +- 3.451

T1/2 (h)

37.4 +- 22.02

34.50 +- 12.02

ClT(mL/min)

55.0 +- 15.50

-

Vz (L)

164.0 +- 83.80

-

Aeu (ng)

2105.0 +- 1295.0

313.0 +- 338.03

% of dose in urine

1.75 +- 1.08

0.000031 +- 0.000034

CLR(mL/min)

0.95 +- 0.60

1.36 +- 1.433

CLR(as % of CL)

1.73 +- 1.10

-

F (%)

-

0.00127+- 0.00080

1n= 3 , extrapolated tail area was > 20% of the total area in 5 subjects extrapolation therefore not reliable.

2due to low plasma levels half lives were determined over a time period that was lss than twice this value.

3N=7

Applicant's summary and conclusion