P91
LANTHANUM CARBONATE: SAFETY DATA AFTER 10 YEARS
Marc E De Broe, 1Rosamund J Wilson,2 Svetlana Garafola,3J Brian Copley4
1
Department of Nephrology, Antwerp University, Antwerp, Belgium; 2Spica Consultants,
Marlborough, UK; 3Shire, Lexington, MA, USA; 4Shire, Wayne, PA, USA
INTRODUCTION:
Despite 10 years of post-launch safety monitoring, ~703 000 person-years of worldwide patient
exposure, and strong evidence from published clinical studies, concerns over the long-term
safety of lanthanum carbonate (LaC) persist. The aims of this evaluation were: 1) to present data
from an ongoing, long-term study of LaC safety (SPD405-404; NCT00567723);2) to review the
evidence from key publications pertaining to the long-term safety of LaC.
METHODS:
SPD405-404 study
The objective of this 5-year observational study is to compare all-cause mortality and bone
fracture rates in patients who received LaC with two control groups (patients in the USRDS
database prior to the availability of LaC [historical]; patients in USRDS treated with phosphate
binders other than LaC [concomitant therapy])
Literature review
Relevant LaC pharmacokinetic and safety publications were identified in PubMed and review
articles.
RESULTS:
SPD405-404
An interim analysis (September 2014) showed that the all-cause mortality rate in the LaC test
group (n = 959/2136 [47.2%]; 85% follow-up) was comparable to that in the concomitant
therapy control group (n = 4158/8127 [51.2%]; 85% follow-up) and lower than that in the
historical control group (n = 4893/8127 [60.2%]; 100% follow-up). Bone fracture rates were
similar across the three groups: 5.4%, 6.4%, and 7.0%, respectively.
Literature review Pharmacokinetics The absolute bioavailability of an oral La dose is
extremely low (~0.001%); by comparison, 0.01–0.1% of an aluminum (Al) dose is absorbed
[Pennick 2006]. Whereas Al is principally excreted via the kidneys, renal clearance accounts for
only 1.7% of the total plasma clearance of La; >90% of an oral La dose is eliminated by hepatic
transcellular (endosomal-lysosomal-biliary canaliculus) transport into the bile.[Behets 2004].
The pharmacokinetics of La are similar in patients with ESRD and normal renal function
[Damment 2008]. Bone Analysis of bone biopsy studies after up to 5 years of LaC treatment
revealed no evidence of Al-like accumulation or toxicity, or mineralization defects [D’Haese
2003; Malluche 2008; Behets 2005]. The data indicated a strikingly reduced evolution towards
adynamic bone disease compared with calcium-based binders. The La:Ca molar ratio in bone
after 4.5 years of LaC treatment was estimated to be 2×10–5, compared with an Al:Ca molar
ratio of 6×10–2 following treatment with Al-based binders [Persy 2006], arguing against the
concern that La accumulates to clinically relevant levels in bone.GI tractThe majority of AEs
are GI-related (mainly nausea, diarrhea and flatulence) and areprimarily mild/moderate in
severity, comparable to other phosphate binders [Hutchison 2008]. Liver Patients treated with
LaC for up to 6 years showed little change in liver enzyme or bilirubin levels, and no clinically
relevant increases in the incidence of liver-associated AEswith increasing treatment duration
[Hutchison 2009]. CNS Animal toxicology studies using LaC doses many times higher than
those used in humans demonstrated that La does not cross the intact blood–brain barrier
[Bervoets 2009; Kato 1989; Xu 1994]. The rate of cognitive decline in patients treated with LaC
was similar to that in patients treated with other phosphate binders [Altmann 2007].
CONCLUSIONS: Published studies and interim results from a 5-year observational study
support the long-term safety of LaC. After ~703 000 person-years of worldwide patient
exposure to LaC, there is no evidence at this time that LaC is associated with adverse safety
outcomes in bone, GI tract, liver or CNS.
1