Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit

摘要

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ? PD 0200390 is a ligand for the alpha-2-delta protein, an auxiliary subunit of voltage-gated calcium channels, which is the first in a new class being investigated for the treatment of insomnia. ? Preclinical studies showed that PD 0200390 increases slow-wave sleep in rats; in humans, data in healthy volunteers showed that PD 0200390 is safe and well tolerated, and that renal excretion of unchanged drug is the primary route of elimination of PD 0200390. ? This study investigated the effect of renal impairment on the single-dose pharmacokinetics and tolerability of PD 0200390, to determine whether dose adjustments may be required in individuals with renal dysfunction. WHAT THIS STUDY ADDS ? PD 0200390 was well tolerated in subjects with mild, moderate or no renal impairment, whereas the group of patients with severe renal impairment experienced an increased frequency of treatment-associated adverse events. ? The degree of renal impairment had a predictable effect on the clearance of PD 0200390; correlation between key pharmacokinetic parameters (renal and oral clearance, and drug exposure) and changes in renal function were confirmed by regression analysis. ? Dose adjustment may be required when PD 0200390 is administered to patients with impaired renal function, to compensate for increased exposure. AIMS To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr). METHODS In this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min ^?1 ; n = 6); mild RI (CLcr 51 to ≤80 ml min ^?1 ; n = 6); moderate RI (CLcr >30 to 50 ml min ^?1 ; n = 6); and severe RI (CLcr ≤30 ml min ^?1 ; n = 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration–time data. RESULTS PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66–3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/ F ) and renal (CL _R ) clearance rates decreased with deteriorating renal function, whereas area under the concentration–time curve (AUC _0–∞ ) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/ F and CL _R correlated with CLcr ( r = 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group. CONCLUSIONS PD 0200390 pharmacokinetic parameters (CL/ F , CL _R and AUC _0–∞ ) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.