The effect of sevelamer carbonate and lanthanum carbonate on the pharmacokinetics of oral calcitriol

David Pierce, Stuart Hossack, Lynne Poole, Antoine Robinson, Heather Van Heusen, Patrick Martin, Michael Smyth, David Pierce, Stuart Hossack, Lynne Poole, Antoine Robinson, Heather Van Heusen, Patrick Martin, Michael Smyth

Abstract

Background: Lanthanum carbonate and sevelamer carbonate are non-calcium-based phosphate binders used to manage hyperphosphataemia in patients with chronic kidney disease (CKD). Patients with CKD may require intravenous or oral active vitamin D. We investigated the effects of lanthanum carbonate and sevelamer carbonate on the bioavailability of oral calcitriol.

Methods: This was a three-period, crossover study in healthy volunteers. Forty-one individuals were randomized to one of six possible sequences, each consisting of three treatment periods separated by washouts. The treatments were calcitriol (1 μg at lunch), calcitriol with lanthanum carbonate (3000 mg/day) and calcitriol with sevelamer carbonate (7200 mg/day). Serum calcitriol levels were assessed at baseline and throughout the study.

Results: Co-administration of lanthanum carbonate with calcitriol had no significant effect on area under the curve over 48 h (AUC(0-48)) for serum exogenous calcitriol [least-squares (LS) mean, calcitriol with lanthanum carbonate vs calcitriol alone: 429 pg h/mL vs 318 pg h/mL, respectively; P = 0.171]. Similarly, there was no significant effect on maximum concentration (C(max)). In contrast, co-administration with sevelamer was associated with a significant reduction in bioavailability parameters for calcitriol (calcitriol with sevelamer carbonate vs calcitriol alone, LS mean AUC(0-48): 137 pg h/mL vs 318 pg h/mL, respectively; P = 0.024; LS mean C(max): 40.1 pg/mL vs 49.7 pg/mL, respectively; P < 0.001).

Conclusions: Sevelamer carbonate significantly reduces serum concentrations of exogenous calcitriol when administered concomitantly with oral calcitriol, whereas lanthanum carbonate has no significant effect. This should be considered when treating CKD patients who require phosphate binders and oral vitamin D.

Figures

Fig. 1
Fig. 1
Study design. Study medications were administered orally with 240 mL of de-ionized water half-way through ingestion of the meal.
Fig. 2
Fig. 2
Mean serum concentrations of (a) exogenous and (b) total calcitriol after a single dose, with or without co-administration of lanthanum carbonate or sevelamer carbonate. Regimen A: calcitriol 1.0 μg; regimen B: calcitriol 1.0 μg + lanthanum carbonate (1000 mg t.i.d.); regimen C: calcitriol 1.0 μg + sevelamer carbonate (2400 mg t.i.d.).

References

    1. LaClair RE, Hellman RN, Karp SL, et al. Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States. Am J Kidney Dis. 2005;45:1026–1033.
    1. Pesenson A, Maski M, Kaufman J. Prevalence of 25-OH vitamin D deficiency in patients with chronic kidney disease and effects of correction following KDOQI guidelines. Poster Presentation at the American Society of Nephrology Renal Week; San Diego, CA, USA. 2006. pp. 14–19.
    1. Craver L, Marco MP, Martinez I, et al. Mineral metabolism parameters throughout chronic kidney disease stages 1–5—achievement of K/DOQI target ranges. Nephrol Dial Transplant. 2007;22:1171–1176.
    1. Al-Badr W, Martin KJ. Vitamin D and kidney disease. Clin J Am Soc Nephrol. 2008;3:1555–1560.
    1. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503–511.
    1. Kulie T, Groff A, Redmer J, et al. Vitamin D: an evidence-based review. J Am Board Fam Med. 2009;22:698–706.
    1. Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42:1–201.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD) Kidney Int. 2009;76:S1–S130.
    1. Ritz E, Kuster S, Schmidt-Gayk H, et al. Low-dose calcitriol prevents the rise in 1,84-iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial) Nephrol Dial Transplant. 1995;10:2228–2234.
    1. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004–1013.
    1. Bleyer AJ, Burke SK, Dillon M, et al. A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis. 1999;33:694–701.
    1. Hutchison AJ, Maes B, Vanwalleghem J, et al. Efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia: a 6-month, randomized, comparative trial versus calcium carbonate. Nephron Clin Pract. 2005;100:c8–c19.
    1. Suki WN, Zabaneh R, Cangiano JL, et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int. 2007;72:1130–1137.
    1. Wilson R, Zhang P, Smyth M, et al. Assessment of survival in a 2-year comparative study of lanthanum carbonate versus standard therapy. Curr Med Res Opin. 2009;25:3021–3028.
    1. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68:1815–1824.
    1. Braunlin W, Zhorov E, Guo A, et al. Bile acid binding to sevelamer HCl. Kidney Int. 2002;62:611–619.
    1. Autissier V, Damment SJ, Henderson RA. Relative in vitro efficacy of the phosphate binders lanthanum carbonate and sevelamer hydrochloride. J Pharm Sci. 2007;96:2818–2827.
    1. Fraser DR. Vitamin D. Lancet. 1995;345:104–107.
    1. US Prescribing Information Renagel (Sevelamer hydrochloride) Silver Spring, MD, USA: Center for Drug Evaluation and Research; [(20 September 2010, date last accessed)]. .
    1. Hutchison AJ, Barnett ME, Krause R, et al. Long-term efficacy and safety profile of lanthanum carbonate: results for up to 6 years of treatment. Nephron Clin Pract. 2008;110:c15–c23.
    1. Finn WF. Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic maintenance hemodialysis patients. Clin Nephrol. 2006;65:191–202.
    1. Ketteler M, Rix M, Fan S, et al. Efficacy and tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol. 2008;3:1125–1130.
    1. Evenepoel P, Selgas R, Caputo F, et al. Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis. Nephrol Dial Transplant. 2009;24:278–285.
    1. Fan S, Ross C, Mitra S, et al. A randomized, crossover design study of sevelamer carbonate powder and sevelamer hydrochloride tablets in chronic kidney disease patients on haemodialysis. Nephrol Dial Transplant. 2009;24:3794–3799.
    1. Slatopolsky EA, Burke SK, Dillon MA. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. The RenaGel Study Group. Kidney Int. 1999;55:299–307.
    1. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002;62:245–252.
    1. Application Number 021068 and 18044/S025. Clinical Pharmacology and Biopharmaceutics Review(S). Silver Spring, MD, USA: Center for Drug Evaluation and Research. (11 February 2010, date last accessed)
    1. Genzyme Therapeutics. Renvela Prescribing Information. 2008. (11 February 2010, date last accessed)
    1. Finn W, Sprague S, Abboud H, et al. 25-Hydroxyvitamin D levels in patients with CKD Stage 3 and 4 are not affected by lanthanum carbonate: results from a randomized multicentre trial. Nephrol Dial Transplant. 2008;1:ii59.
    1. Plone MA, Petersen JS, Rosenbaum DP, et al. Sevelamer, a phosphate-binding polymer, is a non-absorbed compound. Clin Pharmacokinet. 2002;41:517–523.
    1. Wrong O, Harland C. Sevelamer and other anion-exchange resins in the prevention and treatment of hyperphosphataemia in chronic renal failure. Nephron Physiol. 2007;107:17–33.
    1. Takagi K, Masuda K, Yamazaki M, et al. Metal ion and vitamin adsorption profiles of phosphate binder ion-exchange resins. Clin Nephrol. 2010;73:30–35.
    1. Lemay J, Demers C, Hendy GN, et al. Expression of the 1,25-dihydroxyvitamin D3-24-hydroxylase gene in rat intestine: response to calcium, vitamin D3 and calcitriol administration in vivo. J Bone Miner Res. 1995;10:1148–1157.
    1. Jin SE, Park JS, Kim CK. Pharmacokinetics of oral calcitriol in healthy human based on the analysis with an enzyme immunoassay. Pharmacol Res. 2009;60:57–60.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir