Four trails and two manuscripts published in the same issue of Jan 2013 in NEJM this week re the use of this agent in anemia of both ESRD and CKD patients.
1. PEARL 1 and 2( use of this agent randomized comparison to darbopoietin) in CKD patients and EMERALD 1 and 2( use of this agent randomized comparison to erythropoietin) in ESRD patients.
2. Both studies showed non inferiority in terms of Hgb control of 10-12 goal as set by the investigators.
3. Cardiovascular end points of MI, Stroke and other cardiac outcomes were similar in both groups in the ESRD study( EMERALD)
4. In the CKD study( PEARL), there were more significant cardiovascular events in the peginesatide arm.
5. AKI and unexplained back pain was also noted more in the CKD group peginesatide arm.
6. Neither the two articles nor the editorial could explain the reason for the increased cardiac events or AKI or back pain with the agent( hgb levels were similar and doses in HD were higher than CKD patients)
7. Benefits of using this agent:- once a month as oppose to more frequent dosing in HD patients
8. Caution: new agent, cost and at this point perhaps not recommended in CKD patients.
When you pubmed the drug name " peginesatide" only 27 articles appear ( 2 are listed above). What do they say regarding this agent? One question that comes up is regarding the clearance, distribution and metabolism of this agent. It seems that pharmcology related studies suggest that this agent is cleared via the kidneys and primarily localized to the hematopoetic sites as concentrations of this agent build up. The molecule is 45kDa molecular weight and low volume of distribution. The mean half-life is 25.0 ± 7.6 hours following intravenous administration and 53.0 ± 17.7 hours following subcutaneous administration in healthy subjects. The mean half-life in dialysis patients is 47.9 ± 16.5 hours following intravenous administration. Mean systemic clearance is 0.5 ± 0.2 mL/hr·kg and mean volume of distribution is 34.9 ± 13.8 mL/kg following intravenous administration in dialysis patients. No accumulation is observed following administration every 4 weeks following intravenous or subcutaneous administration( source: Rxlist.com). The pharmacokinetics of peginesatide in patients with CKD on dialysis are not altered by age, gender or race based on population pharmacokinetic analyses. There is something about dialysis or ESRD that less likely balances out the negative effects of this agent found in CKD patients in terms of cardiovascular mortality.
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