Assessment of pharmacodynamic equivalence and tolerability of lanthanum carbonate oral powder and tablet formulations: a single-center, randomized, open-label, 2-period crossover study in healthy subjects.
BACKGROUND
Phosphate binders are commonly used in tablet form to help patients with hyperphosphatemia limit their absorption of dietary phosphate. These patients frequently have a heavy tablet burden so alternative formulations provide choice and may support adherence. Lanthanum carbonate (LC) is a phosphate binder currently available as a chewable tablet. This study was conducted to support an application for marketing authorization for the oral powder formulation within the European Union.


OBJECTIVE
The goal of this study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of an oral powder formulation of LC compared with the reference chewable tablet formulation.


METHODS
A Phase I, single-center, randomized, open-label, 2-period, crossover study to assess pharmacodynamic equivalence of the 2 formulations was conducted in healthy adults aged 18 to 55 years receiving a diet standardized for phosphate content. Individuals were randomized to receive a different formulation in each period, taking 10 doses of 1000-mg LC at 3000 mg/d per period with an intervening washout of ≥14 days. The primary pharmacodynamic variable was mean daily excretion of urinary phosphorus over 3 days while receiving LC. Pharmacodynamic equivalence was confirmed if the 90% CI for the difference between formulations in least squares (LS) mean excreted urinary phosphorus was within ±20% of the LS mean value for the tablet formulation. Secondary end points included determination of pharmacokinetic parameters and assessment of tolerability by recording of adverse events.


RESULTS
In total, 72 individuals entered the study. They were predominantly men (72.2%), with a mean (SD) age of 31.4 (8.26) years and a BMI of 25.8 (2.45) kg/m(2). The LS mean (SE) excreted urinary phosphorus was 16.8 (0.48) mmol/d during administration of LC tablets (±20% = ±3.35 mmol/d). The corresponding value during administration of LC oral powder was 15.2 (0.48) mmol/d; 90% CI for the difference between formulations was -2.38 to -0.82 mmol/d, confirming pharmacodynamic equivalence. The most common adverse events were gastrointestinal, and no serious adverse events were recorded.


CONCLUSIONS
In this multiple-dose study, the oral powder and tablet formulations of LC were well tolerated and met the regulatory criteria for pharmacodynamic equivalence in these healthy volunteers. ClinicalTrials.gov identifier: NCT00880750.
Shire Pharmaceutical Development Ltd, Basingstoke, United Kingdom. dpierce@shire.com
David
D
Pierce
Stuart
S
Hossack
Antoine
A
Robinson
Pinggao
P
Zhang
Patrick
P
Martin
D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007811:Lanthanum / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D011208:Powders; D012016:Reference Values; D013607:Tablets
D011208:Powders; D013607:Tablets; C119467:lanthanum carbonate; D007811:Lanthanum