Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment.
Ontology highlight
ABSTRACT:
SUBMITTER: Torres R
PROVIDER: S-EPMC4418347 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment.
Torres Rosarelis R Kramer William G WG Baroldi Paolo P
Journal of clinical pharmacology 20150204 5
Tasimelteon is a circadian regulator that resets the master clock in the suprachiasmatic nuclei of the hypothalamus by binding to both melatonin MT1 and MT2 receptors making it a dual melatonin receptor agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open-label studies evaluated the pharmacokinetics of tasimelteon and its main metabolites after a single 20 mg do ...[more]
Similar Datasets
Project description:The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with mild, moderate and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 ?g or 400 ?g was administered. The PK parameters were derived from plasma concentration-time profiles.Exposure increased with the severity of hepatic impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-? ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with mild hepatic impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate hepatic impairment when compared with healthy subjects. The two subjects with severe hepatic impairment showed similar dose-normalized exposure to that of subjects with moderate hepatic impairment. A 1.7-fold increase in the AUC0-? of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment.
| S-EPMC4972153 | biostudies-other
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
Project description:Background and aimsThe pharmacokinetics (PK) and single-dose tolerability of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist being developed for once-weekly treatment of type 2 diabetes (T2D), weight management, and nonalcoholic steatohepatitis, was evaluated in subjects with renal impairment versus healthy subjects with normal renal function.MethodsForty-five subjects, categorized by baseline renal status, i.e. mild (n = 8, estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73m2), moderate (n = 8, eGFR 30-59 mL/min/1.73m2), severe renal impairment (n = 7, eGFR < 30 mL/min/1.73m2), end-stage renal disease requiring dialysis (n = 8), and normal renal function (n = 14, eGFR ≥ 90 mL/min/1.73m2), received a single subcutaneous dose of tirzepatide 5 mg. Tirzepatide plasma concentrations up to 648 h postdose were measured to compute PK parameters. The primary analysis evaluated the ratios of area under the plasma concentration-time curves (AUCs) and maximum plasma drug concentration (Cmax) of renal impairment versus the normal renal function group (90% confidence interval [CI]). In addition, the relationship between PK parameters and continuous variables of renal function was assessed by linear regression.ResultsTirzepatide exposure was similar across renal impairment groups and healthy subjects. The 90% CI of ratios of AUCs and Cmax comparing each renal impairment group versus normal renal function spanned unity, except for a 25-29% increase in AUCs in the moderate renal impairment group. There was no significant relationship between tirzepatide exposure and eGFR. Few adverse events were reported across the renal impairment and normal renal function groups. The majority were mild in severity and of a gastrointestinal nature in the renal impairment groups.ConclusionThere were no clinically relevant effects of renal impairment on tirzepatide PK. Dose adjustment may not be required for patients with renal impairment.Clinical trial registrationClinicalTrials.gov NCT03482024.
| S-EPMC8332596 | biostudies-literature
Project description:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Linagliptin is an oral, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved in the United States, Europe and elsewhere in 2011 for the treatment of type 2 diabetes mellitus. • The elimination of linagliptin is primarily non-renal. Therefore, a potential effect of hepatic impairment on the elimination of linagliptin may have important implications for dosing recommendations. WHAT THIS STUDY ADDS: • This study shows that mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing as compared with normal hepatic function. • No linagliptin dose adjustment is required in patients with any degree of hepatic impairment. AIM: To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability. METHOD: This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects. RESULTS: In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects [AUC(?,ss) geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and C(max,ss) GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUC(?,ss) GMR 85.5%, 90% CI 70.2%, 104.2% and C(max,ss) GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and C(max) was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or C(max) and renal excretion of unchanged linagliptin (? 7%) were comparable across groups. Median plasma DPP-4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady-state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated. CONCLUSION: Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment.
| S-EPMC3394131 | biostudies-literature
Project description:Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open-label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100-mg dose. Subjects with hepatic impairment classified as Child-Pugh A (mild hepatic impairment) or Child-Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were Cmax and AUC0-? of nintedanib. Thirty-three subjects received nintedanib (8 in each of the Child-Pugh A and Child-Pugh B groups and 17 controls). The shape of the plasma concentration-time curve for nintedanib was similar between Child-Pugh A or B and healthy subjects. Nintedanib exposure was ?2-fold higher in Child-Pugh A subjects and ?8-fold higher in Child-Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child-Pugh B subjects (37.5%), no Child-Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child-Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment.
| S-EPMC5836871 | biostudies-literature
Project description:Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. This phase 1 nonrandomized, open-label, multicenter, 2-part study evaluated the pharmacokinetics, safety, and tolerability of oral gepotidacin 1500 mg in 3 different hepatic settings (normal, moderate impairment, and severe impairment). Gepotidacin was safe and generally tolerated in all subjects. Compared to subjects with normal hepatic function, gepotidacin plasma area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) and maximum concentration significantly increased by 1.7- and 1.9-fold, respectively, in severe hepatic impairment; increases in moderate impairment were not statistically significant. No significant effect was observed for gepotidacin plasma elimination half-life (geometric mean range, 8.2-9.1 hours) across hepatic groups. Renal clearance increased in moderate (16%) and severe (52%) hepatic impairment vs normal. The mean fraction of gepotidacin dose excreted in urine increased with increasing hepatic impairment (normal, 7.5%; moderate, 11.2%; and severe, 19.9%). Urine gepotidacin concentrations remained high for 12 hours in all hepatic groups after dosing. Saliva gepotidacin concentrations displayed a linear relationship with plasma concentrations (R2 = 0.76). The ratio of saliva AUC to unbound plasma AUC and elimination half-life were not affected by hepatic impairment. These data indicate that gepotidacin dose adjustment is not required in mild to moderate hepatic impairment; severe hepatic impairment may require increases in dosing interval or dose reduction.
| S-EPMC8248074 | biostudies-literature
Project description:Solithromycin, a new macrolide and the first fluoroketolide, is in late-stage clinical development and, like older macrolides, is primarily metabolized and excreted through liver-dependent mechanisms. This study evaluated the safety and pharmacokinetics of solithromycin in patients with chronic liver disease. This open-label, multiple-dose study in subjects with hepatic impairment and in healthy control subjects (matched for age, weight, and sex) enrolled 8 Child-Pugh class A (mild), 8 class B (moderate), and 8 class C (severe) patients and 9 healthy controls. Subjects (n = 33) received one 800-mg dose on day 1 followed by once-daily doses of 400 mg on days 2 through 5. The most commonly reported adverse events were mild diarrhea and mild headache, and no significant differences were noted between hepatically impaired subjects and healthy controls. The pharmacokinetics of plasma solithromycin in subjects with mild and moderate impairment was similar to that in control subjects. In subjects with severe impairment, total exposure to solithromycin at steady state (area under the plasma concentration-time curve [AUC0-tau]) was decreased compared to that in control subjects, which may have been related to the higher body mass index of individuals in this group. No greater accumulation was noted in any hepatically impaired cohort on day 5 compared to that in control subjects. No decrease in dosage is therefore needed when administering solithromycin to patients with mild, moderate, or severe hepatic impairment. Solithromycin was well tolerated in this patient population, and no significant differences in safety, compared to healthy controls, were noted.
| S-EPMC4505280 | biostudies-literature
Project description:Zibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure.Open-label studies investigated the PK and tolerability of zibotentan in subjects with hepatic or renal impairment, compared with those with normal organ function. In the hepatic and renal studies, respectively, subjects were divided into categories using Child-Pugh classification or 24-hour urine creatinine clearance (mild, moderate, or severe impairment and normal function). Each subject received a single oral dose of zibotentan 10 mg and PK sampling was undertaken. Within the hepatic study, AUC and Cmax were expressed as the ratio of geometric means and 90% CI for each impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure was considered if the upper 90% CI for the ratio exceeded 2. In the renal study, AUC, Cmax and t1/2 were analyzed using linear regression fitting effects for creatinine clearance and age.In the hepatic and renal studies respectively, 32 subjects (eight per group) and 48 subjects received treatment (n = 18 normal, n = 12 mild, n = 9 moderate, n = 9 severe). Zibotentan Cmax was not significantly affected by hepatic or renal impairment. Compared with the normal function group, zibotentan AUC was 40% (1.40; 90% CI 0.91-2.17), 45% (1.45; 90% CI 0.94-2.24) and 190% (2.90; 90% CI 1.88-4.49) higher in subjects with mild, moderate and severe hepatic impairment, respectively, and 66% (1.66; 90% CI 1.38-1.99), 89% (1.89; 90% CI 1.50-2.39) and 117% (2.17; 90% CI 1.64-2.86) higher in subjects with mild, moderate and severe renal impairment, respectively. In both studies mean t1/2 increased and zibotentan clearance decreased with the degree of impairment. Headache was the most common AE in all groups.Zibotentan absorption was unchanged, however, exposure was higher in subjects with hepatic or renal impairment due to slower clearance. This increased exposure did not result in differences in the range or severity of AEs observed.ClinicalTrials.gov: NCT00672581 and AstraZeneca study number D4320C00016 (renal trial; conducted in Germany).
| S-EPMC3070638 | biostudies-literature
Project description:PurposeDolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.MethodsThis was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance.ResultsDTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma.ConclusionsThe modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.
| S-EPMC3889630 | biostudies-literature
Project description:The development of new insulin sensitizers is an unmet need for the treatment of type 2 diabetes. We investigated the effect of GFT505, a dual peroxisome proliferator-activated receptor (PPAR)-?/? agonist, on peripheral and hepatic insulin sensitivity.Twenty-two abdominally obese insulin-resistant males (homeostasis model assessment of insulin resistance>3) were randomly assigned in a randomized crossover study to subsequent 8-week treatment periods with GFT505 (80 mg/day) or placebo, followed by a two-step hyperinsulinemic-euglycemic insulin clamp with a glucose tracer to calculate endogenous glucose production (EGP). The primary end point was the improvement in glucose infusion rate (GIR). Gene expression analysis was performed on skeletal muscle biopsy specimens.GFT505 improved peripheral insulin sensitivity, with a 21% (P=0.048) increase of the GIR at the second insulin infusion period. GFT505 also enhanced hepatic insulin sensitivity, with a 44% (P=0.006) increase of insulin suppression of EGP at the first insulin infusion period. Insulin-suppressed plasma free fatty acid concentrations were significantly reduced on GFT505 treatment (0.21±0.07 vs. 0.27±0.11 mmol/L; P=0.006). Neither PPAR? nor PPAR? target genes were induced in skeletal muscle, suggesting a liver-targeted action of GFT505. GFT505 significantly reduced fasting plasma triglycerides (-21%; P=0.003) and LDL cholesterol (-13%; P=0.0006), as well as liver enzyme concentrations (?-glutamyltranspeptidase: -30.4%, P=0.003; alanine aminotransferase: -20.5%, P=0.004). There was no safety concern or any indication of PPAR? activation with GFT505.The dual PPAR?/? agonist GFT505 is a liver-targeted insulin-sensitizer that is a promising drug candidate for the treatment of type 2 diabetes and nonalcoholic fatty liver disease.
| S-EPMC3781493 | biostudies-literature