The effect of severe hepatic impairment on the pharmacokinetics and haematological response of C.E.R.A.

Aim: To examine the effect of severe hepatic impairment (HI) on the pharmacokinetics (PK) and pharmacodynamics (PD) of the continuous erythropoietin receptor activator, C.E.R.A.

Methods: A non-randomised, multicentre, single-dose, open-label study in patients with HI (n=12) and healthy subjects (n=12). After 2 weeks of screening, participants received a single intravenous dose of C.E.R.A. (200 mug), and were then followed for approximately 8 weeks. The area under the concentration-time curve (AUC) from drug administration to last measurable concentration (AUC(last)), and maximum C.E.R.A. concentration (C(max)) were calculated to assess PK. The baseline-corrected area under the effect curve over 22 days (AUE(corr)) for reticulocyte count was the primary PD parameter.

Results: The PK profile was similar in patients and healthy subjects (AUC(last): 6678 vs 6985 ng*h/mL; C(max): 63 vs 75 ng/mL) C.E.R.A. produced a sustained erythropoietic response in bothgroups, with increases in reticulocyte counts peaking 7-9 days post-dose and returning to baseline by Day 22. Although mean AUE(corr) was 64% lower in patients, this may have been an artefact of higher baseline reticulocyte counts. Lower reticulocyte responses in patients did not translate into lower responses for haemoglobin, haematocrit or erythrocytes, suggesting that HI had no clinically relevant effect on the PD of C.E.R.A. C.E.R.A. was well tolerated. Four AEs (none considered drug related) were reported in three patients (mild myocardial ischaemia; mild pyrexia and liver transplant; severe bacterial peritonitis [serious AE]); no AEs were reported in healthy subjects.

Conclusions: Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.