Moderate Hepatic Impairment Subjects Research Articles

Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment

The effect of moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of the dual endothelin receptor antagonist aprocitentan was clinically investigated as 25% of aprocitentan is cleared through the liver. Aprocitentan is in clinical development for the treatment of resistant hypertension. This was an open-label, Phase 1 study. Subjects were recruited in two groups (i.e., moderate hepatic impairment (Child–Pugh B; n = 8) and matched healthy subjects (n = 9) and received a single oral dose of 25 mg aprocitentan. Thereafter, they were observed for 14 days. Due to personal reasons one healthy subject discontinued the study. The PK of aprocitentan were similar between subjects with moderate hepatic impairment and healthy subjects, with maximum plasma concentrations (Cmax) reached at 4.0 h. There was no difference in Cmax, indicated by the geometric means ratio (90% confidence interval) of 1.03 (0.86–1.24). There was a lower apparent clearance, a similar apparent volume of distribution, a longer terminal half-life (56.4 h vs 48.3 h in healthy subjects), and an increase in area under the curve from zero to infinity of 23% in moderate hepatically impaired subjects compared to healthy subjects. There were no differences observed in plasma protein binding (range 98.7–99.0%). Aprocitentan was well tolerated, and headache was the only adverse event reported by one subject. In conclusion, there were no clinically relevant differences in PK between subjects with moderate hepatic impairment and healthy subjects. Based on these results, aprocitentan can be administered in subjects with mild and moderate hepatic impairment and dose adjustment is not required.Clinical Trial Registration ClinicalTrials.gov NCT04252495.

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment

Background The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486. Research design and methods This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. Results In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). Conclusions Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. Trial registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596). Key Message HSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects. There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

Apixaban Pharmacokinetics and Pharmacodynamics in Subjects with Mild or Moderate Hepatic Impairment.

BackgroundHepatic impairment can impact apixaban pharmacokinetics and pharmacodynamics by decreasing cytochrome P450-mediated metabolism and factor X production.ObjectiveThis study evaluated the effect of mild or moderate (Child–Pugh A and B) hepatic impairment on apixaban pharmacokinetics, pharmacodynamics, and safety.MethodsThis open-label, parallel-group, single-dose study included eight mildly and eight moderately hepatically impaired subjects, and 16 healthy subjects. Subjects received a single oral apixaban 5-mg dose (day 1). Pharmacokinetic, pharmacodynamic, and safety assessments were completed at prespecified time points. Apixaban maximum plasma concentration and area under the concentration–time curve to infinity were compared between subjects with hepatic impairment and healthy subjects.ResultsApixaban area under the concentration–time curve to infinity point estimates and 90% confidence intervals were 1.03 (0.80–1.32) and 1.09 (0.85–1.41) for subjects with mild and moderate hepatic impairment vs healthy subjects. Maximum plasma concentration results were similar. Mean (standard deviation) apixaban unbound fraction was 6.8% (1.4), 7.9% (1.8), and 7.1% (1.3) in subjects with mild or moderate hepatic impairment and in healthy subjects. Mean change from baseline in international normalized ratio (3 h post-dose) was 14.7%, 12.7%, and 10.7% for subjects with mild or moderate hepatic impairment and healthy subjects, respectively. A direct relationship was observed between apixaban anti-factor Xa activity and plasma concentration across groups. No serious adverse events or discontinuations due to adverse events occurred.ConclusionsMild or moderate hepatic impairment had no clinically relevant impact on apixaban pharmacokinetic or pharmacodynamic measures, suggesting that dose adjustment may not be required.

POS-393 PHARMACOKINETICS OF DAPRODUSTAT AND METABOLITES IN SUBJECTS WITH NORMAL AND IMPAIRED HEPATIC FUNCTION

Daprodustat is a prolyl hydroxylase inhibitor in development for treatment of anemia of chronic kidney disease. This study assessed the effect of mild and moderate hepatic impairment (HI) on daprodustat pharmacokinetics (PK) and pharmacodynamics (PD). In this open-label, non‑randomized, parallel‑study in healthy subjects (HS) and mild and moderate HI subjects (defined by Child-Pugh), a single 6 mg dose of daprodustat was administered to 37 subjects: 9 HS matched to 12 mild HI and 8 HS matched to 8 moderate HI. PK was analyzed for daprodustat and 6 metabolites. Peak exposure (Cmax) of daprodustat was comparable in mild HI and HS; however, overall exposure (AUC) was increased 1.5-fold in mild HI compared with HS. For all metabolites, Cmax AUC in mild HI were increased 1.3- to 2.0-fold compared with HS. In moderate HI, daprodustat Cmax and AUC were increased 2.0-fold compared with HS. Metabolite results aligned with parent drug PK, with a 1.2- to 1.7-fold increase in Cmax and AUC, in moderate HI compared with HS. The only exception was GSK2531401 (M13) Cmax which was similar. Unbound daprodustat concentrations reflect total daprodustat exposure, with a 2.2- and 2.3-fold increase in exposure (free AUC) observed in mild and moderate HI, respectively, compared with HS. Erythropoietin concentrations at baseline and following daprodustat administration were generally higher in mild and moderate HI vs HS. There were no deaths, serious adverse events, or apparent difference in safety between the groups. As daprodustat is titrated to hemoglobin target, the observed increases in exposure in subjects with mild or moderate HI, when compared with HS from this study and historical PK, are not expected to be of clinical significance or pose any safety concerns.

Pharmacokinetics of Imeglimin in Subjects with Moderate Hepatic Impairment.

Imeglimin is a novel oral antidiabetic drug used to treat type 2 diabetes, targeting the mitochondrial bioenergetics. Imeglimin is mainly excreted unchanged by the kidneys and is a substrate of organic cation transporters, which are expressed in the kidney and the liver. The aim of this study was to assess the effect of hepatic impairment on the pharmacokinetics of imeglimin. An open-label, single-dose, parallel-group study was carried out in seven subjects with normal hepatic function and seven subjects with moderate hepatic impairment who received a single dose of imeglimin 1000mg. Blood and urine samples were collected up to 48h after imeglimin administration. Pharmacokinetics were determined using non-compartmental methods. Imeglimin maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with moderate hepatic impairment was 1.3-fold (90% confidence interval [CI] 1.05-1.60) and 1.5-fold (90% CI 1.19-1.82) higher than in subjects with normal hepatic function, but was not considered as clinically meaningful. Higher plasma exposure and amount of imeglimin renally excreted in moderate hepatic impaired subjects, associated with an unchanged elimination rate, suggests that this increase could be linked to a higher oral absorption and/or lower hepatic uptake in this population. Imeglimin was safe and well tolerated in all subjects. EudraCT 2018-001950-83.

Population pharmacokinetics of ospemifene and safety evaluation of pharmacokinetic alterations caused by intrinsic and extrinsic factors .

To develop a population pharmacokinetic (PPK) model to assess factors influencing ospemifene pharmacokinetics and to assess safety for pharmacokinetic alteration observed in drug development. A PPK model was constructed using pooled ospemifene concentrations. Covariates considered before start of the analysis were: age, race, body weight, BMI, albumin, alanine amino-transferase, bilirubin, and creatinine clearance. The expected distribution of ospemifene concentration was derived for the 4 cases in phase-1 studies that increased ospemifene exposure: administration to severe renal impairment subjects (case 1), administration to moderate hepatic impairment subjects (case 2), coadministration with ketoconazole (case 3), or coadministration with fluconazole (case 4). Safety information in a long-term safety trial was used to assess the potential changes in risk of adverse events with ospemifene-exposure increase. The PPK parameter estimates were 9.16L/h for CL/F, 34.3L for V2/F, 16.4L/h for Q/F, 250L for V3/F, and 0.522h^-1 for ka, based on the final model. Distributions of estimated AUC in a phase-3 study largely covered the expected distribution for case 1, case 2, or case 3, but did not overlap the expected distribution for case 4. The incidences of adverse events were not associated with ospemifene exposure in the long-term safety study. We developed an ospemifene PPK model and identified no relevant covariate in the PPK analysis. The drug appears safe to use in renal impairment, moderate hepatic impairment, and when coadministered with ketoconazole. Ospemifene should not be administered with fluconazole. .

The Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Ipragliflozin, a Novel Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor

Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites. In an open-label, single-dose, parallel-group study, 16 subjects (eight with moderate hepatic impairment [Child-Pugh score 7-9] and eight healthy, matched controls) received a single oral dose of 100-mg ipragliflozin. Plasma concentrations of ipragliflozin and its metabolites were determined. Adverse events (AEs) and other clinical laboratory parameters were monitored. All subjects completed the study. Least-squares geometric mean ratios (GMRs) (90% confidence interval [CI]) for maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) of ipragliflozin were 127% (93-173%) and 125% (94-166%), respectively, in moderate hepatic impairment versus controls. No changes in elimination half-life and protein binding of ipragliflozin were observed in moderate hepatic impairment subjects. Least-squares GMRs for C max and AUC∞ of M2, the major metabolite, were respectively 95% (68-133%) and 100% (77-130%) in moderate hepatic impairment versus controls. No deaths, other serious AEs or AEs leading to discontinuation occurred. Moderate hepatic impairment had no clinically relevant effects on the single-dose pharmacokinetics of ipragliflozin and its major metabolite, M2. A single oral dose of ipragliflozin, 100mg, was well tolerated in both healthy subjects and those with moderate hepatic impairment.

Fingolimod (FTY720) in Severe Hepatic Impairment: Pharmacokinetics and Relationship to Markers of Liver Function

The authors assessed the impact of severe hepatic impairment on the disposition of fingolimod--a sphingosine-1-phosphate receptor immunomodulator primarily metabolized by CYP4F2--in 6 patients and 6 matched healthy controls who received a single 5-mg oral dose. Compared with healthy controls, severe hepatic-impaired subjects had a doubled area under the concentration time curve (AUC) and 50% prolonged elimination half-life but a similar peak blood concentration. When these data were combined with those from a previous study in mild and moderate hepatic-impaired subjects, there were significant positive correlations between fingolimod AUC versus bilirubin (r = 0.683) and prothrombin time (r = 0.777) and a significant negative correlation versus albumin (r = 0.578), confirming the importance of liver function for fingolimod clearance. For patients with severe hepatic impairment (Child-Pugh class C), a standard first dose of fingolimod could be given followed by a maintenance dose that is reduced by half from the normal maintenance dose.