Insulin degludec: pharmacokinetics in patients with renal impairment.
Ontology highlight
ABSTRACT: Background
Insulin degludec is a new-generation basal insulin with an ultra-long duration of action. We evaluated the pharmacokinetic properties of insulin degludec in subjects with normal renal function; mild, moderate or severe renal impairment; or end-stage renal disease (ESRD) undergoing hemodialysis.Methods
Thirty subjects (n = 6 per group) received a single subcutaneous dose of 0.4 U/kg insulin degludec. Blood samples up to 120 h post-dose and fractionated urine samples were collected.Results
The ultra-long pharmacokinetic properties of insulin degludec were preserved in subjects with renal impairment, with no statistically significant differences in absorption or clearance, compared with subjects with normal renal function. In subjects with ESRD, pharmacokinetic parameters were similar whether the insulin degludec pharmacokinetic assessment period included hemodialysis or not, and total exposure was comparable to subjects with normal renal function. Simulated mean steady-state pharmacokinetic profiles were comparable between groups.Conclusion
This study indicated dose adjustments due to impaired renal function should not be required for insulin degludec.
SUBMITTER: Kiss I
PROVIDER: S-EPMC3899495 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:We report the findings of a single-dose, randomized, three-period cross-over, clinical trial in healthy Chinese individuals (n = 24) comparing the pharmacokinetics of insulin degludec/liraglutide (IDegLira) with its individual components. Furthermore, we report a population pharmacokinetic analysis of a 26-week, phase III, treat-to-target, randomized trial of 720 Chinese individuals with type 2 diabetes. Participants were randomized to IDegLira, degludec or liraglutide, all once daily with metformin. The pharmacokinetic profiles of IDegLira were similar to its individual components. Dose proportionality was indicated for both IDegLira components. Although there were no relevant covariate effects on degludec exposure, liraglutide exposure was inversely correlated with bodyweight. In conclusion, for the Chinese population, the pharmacokinetics of the fixed-ratio combination IDegLira is similar to that of its individual components.
| S-EPMC9017614 | biostudies-literature
Project description:Background and objectiveInsulin degludec is a basal insulin with a slow and distinct absorption mechanism resulting in an ultra-long, flat, and stable pharmacokinetic profile in patients with diabetes mellitus. The aim of this study was to examine the effect of hepatic impairment on the single-dose pharmacokinetics of insulin degludec.MethodsTwenty-four subjects, allocated to one of four groups (n=6 per group) based on level of hepatic impairment (normal hepatic function, Child-Pugh grade A, B, or C), were administered a single subcutaneous dose of 0.4 U/kg insulin degludec. Blood samples up to 120 h post-dose and fractionated urine samples were collected to measure pharmacokinetic parameters.ResultsNo difference was observed in pharmacokinetic parameters [area under the 120-h serum insulin degludec concentration-time curve (AUC120 h), maximum insulin degludec concentration (C max), and apparent clearance (CL/F)] for subjects with impaired versus normal hepatic function after a single dose of insulin degludec. The geometric mean [coefficient of variation (CV) %] AUC120 h values were 89,092 (16), 83,327 (15), 88,944 (23), and 79,846 (19) pmol·h/L for normal hepatic function and mild, moderate, and severe hepatic impairment, respectively. Simulated steady-state insulin degludec pharmacokinetic profiles showed an even distribution of exposure across a 24-h dosing interval regardless of hepatic function status.ConclusionsThe ultra-long pharmacokinetic properties of insulin degludec were preserved in subjects with hepatic impairment and there were no statistically significant differences in absorption or clearance compared with subjects with normal hepatic function.
| S-EPMC3899454 | biostudies-literature
Project description:Bempedoic acid is an ATP citrate lyase inhibitor approved for the treatment of hypercholesterolemia. The objective of this phase I study was to assess the pharmacokinetics (PKs) and safety of bempedoic acid in 24 subjects with normal renal function or mild, moderate, or severe renal impairment. All subjects received a single oral bempedoic acid 180-mg dose and PK parameters were monitored for up to 23 days. Resulting estimates of area under the concentration-time curve exposure following bempedoic acid treatment were 1.5-fold, 2.2-fold, and 2.2-fold higher in subjects with mild, moderate, or severe renal impairment, respectively, compared with subjects with normal renal function. With decreases in renal function, plasma free fraction was increased up to 20.1%, whereas total and unbound clearances were decreased by 55.2% and 62.6%, respectively, in subjects with severe renal impairment relative to those with normal renal function. These observed decreases in total and unbound oral clearance in subjects with decreased renal function are not explained by the increases in free fraction and might therefore also be attributable to changes in bioavailability or intrinsic clearance. Bempedoic acid was generally well-tolerated and the incidence and type of adverse events were not affected by the degree of renal impairment. In conclusion, bempedoic acid exposures in subjects with renal impairment were increased up to approximately two-fold with no safety signals identified, consistent with findings in phase III patients with mild or moderate renal impairment. No dose adjustments are necessary for patients with mild or moderate renal impairment.
| S-EPMC8932715 | biostudies-literature
Project description:This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50-80 ml/min, 30-49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m(2) (Cycle 1), 20 mg/m(2) (Cycle 2) and 27 mg/m(2) (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m(2), proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.
| S-EPMC3740399 | biostudies-literature
Project description:Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.).
| S-EPMC4291359 | biostudies-literature
Project description:Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ?80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0-?), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.).
| S-EPMC6105803 | biostudies-literature
Project description:Background and objectiveZibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously investigated in patients with either renal impairment or hepatic impairment, but the impact of both pathologies on PK was not evaluated. This study evaluated the PK and tolerability of a single oral dose of zibotentan in participants with concurrent moderate renal impairment and moderate hepatic impairment versus control participants.MethodsTwelve participants with moderate renal and hepatic impairment and 11 healthy matched control participants with no clinically significant liver or kidney disease were enrolled in an open-label, parallel-group study design. After administration of a single oral dose of zibotentan 5 mg, blood and urine sampling was performed. Pharmacokinetic parameters were determined for each of the two cohorts and compared. Comparisons between the cohorts were based on the geometric least squares mean ratio for the primary endpoints, which were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) and from time zero to the time of the last measurable concentration (AUClast), and maximum plasma drug concentration (Cmax) on Day 1 through 120 h post-dose. Secondary endpoints included apparent total body clearance (CL/F) on Day 1 through 120 h post-dose. Safety endpoints were assessed up to discharge.ResultsIn total, 11 participants with concurrent moderate renal and hepatic impairment, and 11 controls, completed the study. Zibotentan was generally well tolerated, and no new clinically significant safety findings were observed. Total exposure (AUC∞ and AUClast) was approximately 2.10-fold higher in participants with concurrent moderate renal and hepatic impairment versus controls, while Cmax and total nonrenal body clearance were similar among all groups. A regression-based post hoc analysis, comparing exposure and CL/F in patients with concurrent impairment to patients with either renal or hepatic impairment alone, showed that CL/F with concurrent impairment was approximately half of that in controls and was positively correlated with reduction of renal function. Inclusion of the data on concurrent moderate renal and hepatic impairment in the regression analysis led to a narrower confidence interval for the predicted mean CL/F in participants with moderate hepatic impairment.ConclusionThe presented findings advance the understanding of the PK of zibotentan in both renal impairment and hepatic impairment, with and without overlapping pathologies, and will thus increase the confidence of dose selection in future studies, particularly in vulnerable patient populations with concurrent renal and hepatic impairment.Trial registrationClinicalTrials.gov identifier: NCT05112419.
| S-EPMC10684621 | biostudies-literature
Project description:Background: The opioid analgesic hydromorphone has a low renal excretion ratio; however, exposure after oral administration is several times higher in those with moderate or severe renal impairment. Objectives: We evaluated the impact of renal impairment on the steady-state pharmacokinetics of intravenously administered hydromorphone in patients with cancer being treated for pain. Design: This was an open-label, prospective, parallel-comparison, interventional clinical pharmacology study. Setting/Subjects: This study was conducted at one hospital in Japan. Using creatinine clearance (CLcr) values, patients were grouped according to kidney function: CLcr ≥90 mL/min (normal), 60-<90 mL/min (mild impairment), 30-<60 mL/min (moderate impairment), or <30 mL/min (severe impairment). Measurements: Hydromorphone was administered by constant infusion to patients at the same constant dose rate as at the time of enrollment. Hydromorphone and its glucuronide metabolite concentrations in plasma and urine were measured by liquid chromatography-mass spectrometry. Pharmacokinetic parameters at steady state were assessed using noncompartmental analysis. Results: Thirty-two patients were enrolled (normal, n = 3; mild, n = 10; moderate, n = 15; and severe, n = 4). Adjusted geometric mean ratios for hydromorphone steady-state clearance (CLss) for patients with impaired versus normal renal function were 0.69 (90% confidence interval [CI], 0.41-1.14), 0.52 (90% CI, 0.31-0.84), and 0.55 (90% CI, 0.30-1.02) for mild, moderate, or severe impairment, respectively. Exposures to the metabolite hydromorphone-3-glucuronide generally increased with renal impairment. No adverse event was reported. Conclusion: Hydromorphone CLss in patients with impaired renal function (moderate and severe) was decreased ∼50% of that of normal renal function.
| S-EPMC10278029 | biostudies-literature
Project description:Background Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non-small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.
| S-EPMC8426299 | biostudies-literature
Project description:Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].).
| S-EPMC4249404 | biostudies-literature