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Pharmacokinetic analysis of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in individuals with renal impairment compared to healthy controls
© Scheerans et al; licensee BioMed Central Ltd. 2011
- Published: 1 August 2011
- High Performance Liquid Chromatography
- Renal Impairment
- Guanylate Cyclase
- Severe Renal Impairment
- Decompensated Heart Failure
Cinaciquat (CIN) is a guanylate cyclase (sGC) activator that induces cyclic GMP generation and vasodilation preferentially in diseased vessels . CIN has the potential to increase cardiac output in patients with acute decompensated heart failure . CIN is predominantly and rapidly cleared by the liver , and thus, it was not expected that the kidney function would have an influence on CIN clearance. Nevertheless, we determined the pharmacokinetics of CIN in individuals with renal impairment and age- and gender-matched healthy volunteers with normal renal function .
In this non-randomized, non-blinded study, individuals were grouped on the basis of their creatinine clearance (CLcr) obtained from a 24 hour urine collection:
• Group 1 (healthy control): CLcr > 80 mL/min
• Group 2 (mild renal impairment): CLcr 50 - 80 mL/min
• Group 3 (moderate renal impairment): CLcr 30 < 50 mL/min
• Group 4 (severe renal impairment): CLcr < 30 mL/min (not on dialysis).
34 individuals received a single 4 hour infusion of 400 µg CIN at a constant rate of 100 µg/h. Plasma concentrations of CIN were determined by high performance liquid chromatography with mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis in WinNonlin Professional (version 4.1.a).
Pharmacokinetic parameters of CIN in healthy controls and individuals with mild, moderate and severe renal impairment, showing values as geometric mean (coefficient of variation, %) except for fu which is expressed as arithmetic mean (standard deviation).
Renal function group
Group 1: Healthy control (n=9)
Group 2: Mild renal impairment (n=8)
Group 3: Moderate renal impairment (n=9)
Group 4: Severe renal impairment (n=8)
The pharmacokinetic results are similar to previous results observed in healthy young men . The CL of CIN is dependent on hematocrit, which is reduced in renal impairment. However, as hematocrit changes are limited in magnitude (i.e. 0.3-0.5), the effect is on CL is also clearly limited. Thus, no dose adjustment of CIN is recommended for renal impairment.
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