Pharmacokinetics and pharmacodynamics of cinacalcet in hepatic impairment : phase I, open-label, parallel-group, single-dose, single-centre study.
OBJECTIVE
The calcimimetic cinacalcet lowers blood para-thyroid hormone (PTH), calcium and phosphorus levels and calcium-phosphorus product in patients with chronic kidney disease receiving dialysis. Cinacalcet is metabolized primarily through oxidative and conjugative pathways. Hepatic disease has the potential to alter cinacalcet metabolism. Thus, it is important to establish the potential for altered cinacalcet metabolism according to the level of hepatic function. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of cinacalcet in subjects with different degrees of hepatic function.


METHODS
This was a phase I, open-label, single-dose, parallel-group, single-centre study that included 24 subjects (six with normal hepatic function and six each with mild, moderate and severe hepatic impairment according to Child-Pugh criteria). Subjects were given a single 50 mg oral dose of cinacalcet. Blood samples were taken for pharmacokinetic (pre-dose and up to 120 hours post-dose) and pharmacodynamic (pre-dose and up to 72 hours post-dose) evaluations. Plasma concentrations of cinacalcet were determined using a validated normal phase turbo ion spray liquid chromatography-mass spectrometry/mass spectrometry assay. Serum ionized calcium levels were determined by standard biochemical measures, and PTH levels were determined using an immunometric intact PTH (iPTH) assay. The primary endpoints of the study were area under the concentration-time curve from 0 to time t (AUC(t)), AUC from 0 to infinity (AUC(infinity)) and maximum plasma concentration (C(max)). Other pharmacokinetic parameters (time to C(max) [t(max)], terminal half-life [t((1/2))(beta)], total body clearance [CL/F] and protein binding) and the effect of cinacalcet on plasma PTH and serum calcium were secondary endpoints.


RESULTS
Total cinacalcet exposure (AUC(infinity)) was comparable in subjects with normal hepatic function and mild hepatic impairment. In subjects with moderate and severe hepatic impairment, mean AUC(infinity) was 2.4- and 4.2-fold higher, respectively, than in healthy subjects. Cinacalcet t((1/2))(beta) was 1.3- and 1.7-fold longer in subjects with moderate and severe hepatic impairment, respectively, compared with subjects with normal hepatic function. Mean C(max) and t(max), as well as protein binding, were similar in all groups. Consistent with the increase in cinacalcet exposure, decreases in iPTH tended to be greater and prolonged in subjects with moderate and severe hepatic impairment. In this study, cinacalcet was well tolerated.


CONCLUSIONS
These data demonstrate that cinacalcet can be used without dose adjustment in patients with mild hepatic impairment. However, increased drug exposure observed in subjects with moderate to severe hepatic impairment indicates that iPTH and serum calcium levels should be monitored closely and physicians should be more cautious about dose titration in patients with moderate or severe hepatic impairment.
Padhi
Desmond
D
Department of Early Development/Medical Sciences, Amgen, Inc., Thousand Oaks, California, USA. dpadhi@amgen.com
Harris
Robert Z
RZ
Salfi
Margaret
M
Noveck
Robert J
RJ
Sullivan
John T
JT
D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D002118:Calcium / Q000097:blood; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000069449:Cinacalcet; D005260:Female; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007118:Immunoassay / Q000379:methods; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009325:Nausea / Q000139:chemically induced
D009281:Naphthalenes; D002118:Calcium; D000069449:Cinacalcet
Nephrol Dial Transplant. 1997 May;12(5):956-60
9175049
Am J Kidney Dis. 2004 Dec;44(6):1070-6
15558528
Br J Surg. 1973 Aug;60(8):646-9
4541913
Clin Pharmacokinet. 1978 Nov-Dec;3(6):478-87
719984
J Pharmacol Exp Ther. 2004 Feb;308(2):627-35
14593085
Nature. 1993 Dec 9;366(6455):575-80
8255296
Kidney Int Suppl. 1999 Dec;73:S14-9
10633458
Drug Metab Dispos. 2004 Dec;32(12):1491-500
15328250
J Am Soc Nephrol. 2004 Aug;15(8):2208-18
15284307
Am J Kidney Dis. 2003 Oct;42(4 Suppl 3):S1-201
14520607
Am J Kidney Dis. 2004 Nov;44(5 Suppl 2):34-8
15486872
Semin Dial. 2005 Jan-Feb;18(1):52-61
15663766
Clin Pharmacokinet. 2005;44(5):509-16
15871636
J Am Soc Nephrol. 2005 Mar;16(3):800-7
15689407
N Engl J Med. 2004 Apr 8;350(15):1516-25
15071126