Registration Dossier

Administrative data

Endpoint:
health surveillance data
Type of information:
experimental study
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): Lanthanum carbonate
- 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:
Orally administered lanthanum carbonate tablets were well tolerated. Lanthanum was poorly absorbed after oral administration of lanthanum carbonate. A mean ± SD Cmax of 0.32 ± 0.13 ng/mL was reached at 4.5 ± 0.8 hours after dosing. Thereafter, lanthanum plasma concentrations seemed to decline biphasically or triphasically, with a mean terminal elimination half-life of 35 ± 12 hours (range, 16-48 hours). However, lanthanum plasma concentrations were generally below the limit of quantification after 48 hours postdose, and estimates of terminal elimination half-life should therefore to lanthanum was low, with a mean ± SD AUC of 3.9 ± 2.5 ng h/mL. Mean ± SD absolute bioavailability was extremely low at 0.00127% ± 0.00080%, ranging from 0.00015% to 0.00224% in the 8 subjects receiving oral lanthanum. After oral administration, only 0.000031% ± 0.000034% of the dose was eliminated in the urine over 168 hours (ie, a total of 313 ± 338 ng), almost all within the first 48 hours after dosing. This reflects the poor absorption of lanthanum after oral dosing and the predominance of nonrenal plasma clearance mechanisms. Renal clearance after oral administration was 1.36 ± 1.43 mL/min.

Any other information on results incl. tables

Possibly related adverse events were mild and moderate headaches and moderate nausea/vomiting. Unrelated adverse events include mild dizziness.

Applicant's summary and conclusion

Conclusions:
The low absolute bioavailability and systemic exposure following oral administration of the carbonate salt, together with the negligible renal clearance, are important attributes for a phosphate binder used in an ESRD population.