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Gangadhar Sunkara - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and Moderate Hepatic Impairment .
International journal of clinical pharmacology and therapeutics, 2017Co-Authors: Kenneth Kulmatycki, Thomas Langenickel, Wai Hong Ng, Iris Rajman, Priyamvada Chandra, Wei Zhou, Gangadhar SunkaraAbstract:OBJECTIVES: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and Moderate Hepatic Impairment (Child-Pugh class A and B) and matched healthy subjects. METHODS: This study enrolled 32 subjects (n = 8 in each Hepatic Impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe Hepatic Impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. RESULTS: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and Moderate Hepatic Impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and Moderate Hepatic Impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and Moderate Hepatic Impairment by 19 - 109%, respectively. CONCLUSIONS: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with Moderate Hepatic Impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups. .
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pharmacokinetics and safety of sacubitril valsartan lcz696 in patients with mild and Moderate Hepatic Impairment
Principles and Practice of Constraint Programming, 2017Co-Authors: Kenneth Kulmatycki, Thomas Langenickel, Iris Rajman, Priyamvada Chandra, Wei Zhou, Parasar Pal, Tsuhan Lin, Gangadhar SunkaraAbstract:Objectives To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and Moderate Hepatic Impairment (Child-Pugh class A and B) and matched healthy subjects. Methods This study enrolled 32 subjects (n = 8 in each Hepatic Impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe Hepatic Impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Results Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and Moderate Hepatic Impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and Moderate Hepatic Impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and Moderate Hepatic Impairment by 19 - 109%, respectively. Conclusions The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with Moderate Hepatic Impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups. .
Kenneth Lasseter - One of the best experts on this subject based on the ideXlab platform.
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Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin
Clinical Drug Investigation, 2018Co-Authors: Kenneth Duchin, Thomas Marbury, Giorgio Senaldi, Vance Warren, Kenneth Lasseter, Hamim ZahirAbstract:Background and Objectives Mirogabalin is an α_2δ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where Hepatic Impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or Moderate Hepatic Impairment alters the pharmacokinetics of mirogabalin. Methods Serial blood samples were collected for determination of maximum observed concentration, time to maximum concentration, and area under the concentration–time curve until the last quantifiable concentration of the active free form (A200-700) and inactive lactam metabolite (A204-4455) of mirogabalin. Results The A200-700 maximum observed concentration was similar in subjects with mild Hepatic Impairment but lower in subjects with Moderate Hepatic Impairment vs. control subjects. The A204-4455 maximum observed concentration was lower in subjects with mild and Moderate Hepatic Impairment vs. control groups. The A200-700 area under the concentration–time curve until the last quantifiable concentration was slightly lower in subjects with mild Hepatic Impairment and slightly higher in subjects with Moderate Hepatic Impairment vs. control subjects. Peak A204-4455 levels were approximately 22% and 31% lower for subjects with mild and Moderate Hepatic Impairment vs. control individuals, respectively. Exposure to A204-4455 was approximately 37% lower in subjects with mild Hepatic Impairment but unaffected in subjects with Moderate Hepatic Impairment vs. control groups. Two subjects in the mild Hepatic Impairment group reported a treatment-emergent adverse event of mild somnolence. No serious or severe treatment-emergent adverse events, discontinuations as a result of treatment-emergent adverse events, or deaths were reported. Conclusions Mild Hepatic Impairment resulted in lower A200-700 and A204-4455 exposure, while Moderate Hepatic Impairment did not affect A200-700 exposure. Overall, mild-to-Moderate Hepatic Impairment did not have a significant effect on mirogabalin exposure. A single 15-mg dose of mirogabalin was well tolerated by subjects with mild or Moderate Hepatic Impairment.
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Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin
Clinical Drug Investigation, 2018Co-Authors: Kenneth Duchin, Thomas Marbury, Giorgio Senaldi, Vance Warren, Kenneth Lasseter, Hamim ZahirAbstract:Background and Objectives Mirogabalin is an α2δ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where Hepatic Impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or Moderate Hepatic Impairment alters the pharmacokinetics of mirogabalin.
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The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.
Advances in Therapy, 2017Co-Authors: Tomohiro Kusawake, Thomas Marbury, Kenneth Lasseter, Masataka Katashima, James Keirns, Donna Kowalski, Akitsugu Takada, Kota Kato, Michaelene Lewand, Richard A. PrestonAbstract:Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and Hepatic Impairment on the pharmacokinetics of amenamevir. These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with Moderate Hepatic Impairment and mild, Moderate, and severe renal Impairment. In the Hepatic Impairment study, the pharmacokinetic profile of amenamevir in participants with Moderate Hepatic Impairment was generally similar to that of participants with normal Hepatic function. In the renal Impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal Impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal Impairment study. In both studies, amenamevir was safe and well tolerated. The findings of the Hepatic Impairment study indicate that no dosing adjustment is required in patients with Moderate Hepatic Impairment. In the renal Impairment study, systemic amenamevir exposure was increased by renal Impairment. However, it is unlikely that renal Impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal Impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance Astellas Pharma.
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Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics.
The Journal of Clinical Pharmacology, 2016Co-Authors: Sauzanne Khalilieh, Kenneth Lasseter, Ka Lai Yee, Rachael Liu, Li Fan, Rosa I. Sanchez, Patrice Auger, Ilias Triantafyllou, Daria Stypinski, Thomas MarburyAbstract:Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver Impairment, we investigated the effect of Moderate Hepatic Impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with Moderate Hepatic Impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the Impairment group; 6 men, 2 women). Subjects with Hepatic Impairment were required to have chronic, stable Hepatic Impairment with features of cirrhosis of any etiology. Blood sampling revealed that doravirine exposure was similar in both groups. The observed geometric least-squares mean ratio (90% confidence interval; Moderately impaired/healthy subjects) was 0.99 (0.72-1.35) for AUC0-∞ , 0.93 (0.74-1.18) for AUC0-24 h , 0.90 (0.66-1.24) for Cmax , and 0.99 (0.74-1.33) for C24 h . Geometric mean apparent terminal t½ was ∼18 hours for both groups, whereas median Tmax was 2 hours (range, 1-6 hours) and 2.5 hours (range, 1-3 hours) for impaired and healthy individuals, respectively. In addition, doravirine was generally well tolerated. The results demonstrate that Moderate Hepatic Impairment does not have a clinically meaningful effect on doravirine pharmacokinetics. Therefore, dose adjustment should not be necessary in patients with both HIV-1 and Moderate Hepatic Impairment.
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The Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Ipragliflozin, a Novel Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor
Clinical Drug Investigation, 2013Co-Authors: Wenhui Zhang, Kenneth Lasseter, Walter Krauwinkel, James Keirns, Robert W. Townsend, Lisa Plumb, Takeshi Kadokura, Fumihiko Ushigome, Ronald SmuldersAbstract:Background 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. Methods 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. Results 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. Conclusions 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, 100 mg, was well tolerated in both healthy subjects and those with Moderate Hepatic Impairment.
Thomas Marbury - One of the best experts on this subject based on the ideXlab platform.
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Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics.
The Journal of Clinical Pharmacology, 2019Co-Authors: Sheryl Trueman, Thomas Marbury, Mohamedeslam F Mohamed, T Feng, Ana P Lacerda, Ahmed A OthmanAbstract:Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open-label, single-dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15-mg dose of the upadacitinib extended-release formulation in subjects with mild (n = 6) and Moderate (n = 6) Hepatic Impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child-Pugh classification. Relative to subjects with normal Hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration-versus-time profile from time 0 to infinity (AUCinf ) for subjects with mild and Moderate Hepatic Impairment were 1.28 (0.91-1.79) and 1.24 (0.87-1.76), respectively. The central ratios of upadacitinib maximum observed concentration (Cmax ) were 1.04 (0.77-1.39) and 1.43 (1.05-1.95) in subjects with mild and Moderate Hepatic Impairment, respectively, compared with subjects with normal Hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and Moderate Hepatic Impairment has no clinically relevant effect on upadacitinib pharmacokinetics.
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Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.
Clinical Pharmacokinetics, 2019Co-Authors: Ahmed Salem, Thomas Marbury, Nimita Dave, Dale Miles, Suresh Agarwal, Orlando F. Bueno, Rajeev M MenonAbstract:INTRODUCTION Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of Hepatic insufficiency on venetoclax pharmacokinetics. METHODS A phase I study was carried out in 24 women with normal Hepatic function or mild, Moderate, or severe Hepatic Impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or Moderate Hepatic Impairment were similar to subjects with normal Hepatic function. Mean venetoclax AUC in subjects with severe Hepatic Impairment was 2.3- to 2.7-fold higher than in subjects with normal Hepatic function. The half-life of venetoclax in subjects with severe Hepatic Impairment was approximately two-fold longer than in subjects with normal Hepatic function and subjects with mild or Moderate Hepatic Impairment. Unbound fractions of venetoclax in subjects with mild, Moderate, and severe Hepatic Impairment were similar to the subjects with normal Hepatic function. No significant adverse safety events were reported. CONCLUSIONS No venetoclax dosage adjustment is required in subjects with mild or Moderate Hepatic Impairment. In subjects with severe Hepatic Impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.
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Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment
Clinical Pharmacology in Drug Development, 2018Co-Authors: W. Rachel Duan, Thomas Marbury, Jeffrey Schmidt, Cheri E. KleinAbstract:The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following oral administration in women with renal or Hepatic Impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal Impairment (reduced study), and normal Hepatic function versus Hepatic Impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (Hepatic). Intensive pharmacokinetic blood samples were collected. Elagolix exposures were comparable in women with normal renal function and those with Moderate/severe renal Impairment or end-stage renal disease. Elagolix exposures also appeared to be similar in women with normal Hepatic function and women with mild Hepatic Impairment. Elagolix area under the curve in women with Moderate Hepatic Impairment and with severe Hepatic Impairment was approximately 3-fold and 7-fold higher than in women with normal Hepatic function. The adverse event incidence was low, with the main events being mild nausea and headache. No dosage adjustment was needed in women with renal Impairment or women with mild Hepatic Impairment. Although an elagolix dose of 150 mg once daily may be used in women with Moderate Hepatic Impairment for up to 6 months, this elagolix dose should not be used in women with severe Hepatic Impairment.
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Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin
Clinical Drug Investigation, 2018Co-Authors: Kenneth Duchin, Thomas Marbury, Giorgio Senaldi, Vance Warren, Kenneth Lasseter, Hamim ZahirAbstract:Background and Objectives Mirogabalin is an α_2δ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where Hepatic Impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or Moderate Hepatic Impairment alters the pharmacokinetics of mirogabalin. Methods Serial blood samples were collected for determination of maximum observed concentration, time to maximum concentration, and area under the concentration–time curve until the last quantifiable concentration of the active free form (A200-700) and inactive lactam metabolite (A204-4455) of mirogabalin. Results The A200-700 maximum observed concentration was similar in subjects with mild Hepatic Impairment but lower in subjects with Moderate Hepatic Impairment vs. control subjects. The A204-4455 maximum observed concentration was lower in subjects with mild and Moderate Hepatic Impairment vs. control groups. The A200-700 area under the concentration–time curve until the last quantifiable concentration was slightly lower in subjects with mild Hepatic Impairment and slightly higher in subjects with Moderate Hepatic Impairment vs. control subjects. Peak A204-4455 levels were approximately 22% and 31% lower for subjects with mild and Moderate Hepatic Impairment vs. control individuals, respectively. Exposure to A204-4455 was approximately 37% lower in subjects with mild Hepatic Impairment but unaffected in subjects with Moderate Hepatic Impairment vs. control groups. Two subjects in the mild Hepatic Impairment group reported a treatment-emergent adverse event of mild somnolence. No serious or severe treatment-emergent adverse events, discontinuations as a result of treatment-emergent adverse events, or deaths were reported. Conclusions Mild Hepatic Impairment resulted in lower A200-700 and A204-4455 exposure, while Moderate Hepatic Impairment did not affect A200-700 exposure. Overall, mild-to-Moderate Hepatic Impairment did not have a significant effect on mirogabalin exposure. A single 15-mg dose of mirogabalin was well tolerated by subjects with mild or Moderate Hepatic Impairment.
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Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin
Clinical Drug Investigation, 2018Co-Authors: Kenneth Duchin, Thomas Marbury, Giorgio Senaldi, Vance Warren, Kenneth Lasseter, Hamim ZahirAbstract:Background and Objectives Mirogabalin is an α2δ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where Hepatic Impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or Moderate Hepatic Impairment alters the pharmacokinetics of mirogabalin.
Richard A. Preston - One of the best experts on this subject based on the ideXlab platform.
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single center evaluation of the pharmacokinetics and safety of the angiotensin ii receptor antagonist azilsartan medoxomil in mild to Moderate Hepatic Impairment
The Journal of Clinical Pharmacology, 2018Co-Authors: Caroline Dudkowski, Richard A. Preston, Aziz Karim, Zhen Zhao, Alberto B Alonso, Dyal C GargAbstract:Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M-II, and minor metabolites. The objective of this study was to determine the effect of mild to Moderate Hepatic Impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase 1 parallel-group study that examined the single-dose (day 1) and multiple-dose (days 4–8) — 40 mg — pharmacokinetics of AZL and M-II in 16 subjects with mild and Moderate Hepatic Impairment by Child-Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or Moderate Hepatic Impairment did not cause clinically meaningful increases in exposure to AZL and M-II. Mild or Moderate Hepatic Impairment had no clinically meaningful effect on the plasma protein binding of AZL and M-II. Single and multiple doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with mild and Moderate Hepatic Impairment.
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The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.
Advances in Therapy, 2017Co-Authors: Tomohiro Kusawake, Thomas Marbury, Kenneth Lasseter, Masataka Katashima, James Keirns, Donna Kowalski, Akitsugu Takada, Kota Kato, Michaelene Lewand, Richard A. PrestonAbstract:Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and Hepatic Impairment on the pharmacokinetics of amenamevir. These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with Moderate Hepatic Impairment and mild, Moderate, and severe renal Impairment. In the Hepatic Impairment study, the pharmacokinetic profile of amenamevir in participants with Moderate Hepatic Impairment was generally similar to that of participants with normal Hepatic function. In the renal Impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal Impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal Impairment study. In both studies, amenamevir was safe and well tolerated. The findings of the Hepatic Impairment study indicate that no dosing adjustment is required in patients with Moderate Hepatic Impairment. In the renal Impairment study, systemic amenamevir exposure was increased by renal Impairment. However, it is unlikely that renal Impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal Impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance Astellas Pharma.
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Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib.
The Journal of Clinical Pharmacology, 2016Co-Authors: Linh Nguyen, Thomas Marbury, Richard A. Preston, Jaymes Holland, David A. Ramies, Richard Mamelok, Natacha Benrimoh, Sabrina Ciric, Douglas M. Heuman, Edith A. GavisAbstract:Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or Hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or Moderate Impairment of renal function; 12 healthy subjects were matched to the Moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or Moderate Hepatic Impairment; 10 healthy males were matched to the Moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and Moderate renal Impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and Moderate Hepatic Impairment, respectively. The percentage of unbound drug was slightly higher in both Moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or Moderate renal Impairment. Subjects with mild or Moderate Hepatic Impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.
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The effect of renal and Hepatic Impairment on the pharmacokinetics of ospemifene, a tissue-selective estrogen agonist/antagonist.
American Journal of Therapeutics, 2015Co-Authors: Richard A. Preston, Thomas Marbury, Toshihiro Wajima, Shelli GrahamAbstract:Ospemifene is a nonestrogen tissue-selective estrogen agonist/antagonist approved to treat Moderate to severe dyspareunia due to vulvar and vaginal atrophy in postmenopausal women. Three single-dose, open-label, parallel-group pharmacokinetic studies examined the pharmacokinetics of ospemifene in postmenopausal women with (1) mild Hepatic Impairment (n = 7), (2) Moderate Hepatic Impairment (n = 8), and (3) severe renal Impairment (n = 8) compared with a similar number of matched healthy controls. The study durations ranged from 8 to 12 days. Study participants received a single oral dose of ospemifene 60 mg on day 1 and blood samples were collected serially. The geometric mean ratios (Hepatic or renal Impairment/healthy) and 90% confidence intervals (CIs) for area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and maximum concentration (Cmax), respectively, of ospemifene were 90.86% (90% CI, 65.95%-125.19%) and 79.48% (90% CI, 65.95%-95.79%) in the mild Hepatic Impairment study; 128.62% (90% CI, 87.13%-189.88%) and 101.12% (90% CI, 66.17%-154.52%) in the Moderate Hepatic Impairment study, and 119.63% (90% CI, 81.37%-175.88%) and 79.30% (90% CI, 52.85%-118.99%) in the severe renal Impairment study. Overall, there was no clinically important effect of Hepatic or renal Impairment on the pharmacokinetics of ospemifene, indicating that dosing does not need to be adjusted in postmenopausal women with mild or Moderate Hepatic Impairment or in subjects with severe renal Impairment.
Kenneth Kulmatycki - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and Moderate Hepatic Impairment .
International journal of clinical pharmacology and therapeutics, 2017Co-Authors: Kenneth Kulmatycki, Thomas Langenickel, Wai Hong Ng, Iris Rajman, Priyamvada Chandra, Wei Zhou, Gangadhar SunkaraAbstract:OBJECTIVES: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and Moderate Hepatic Impairment (Child-Pugh class A and B) and matched healthy subjects. METHODS: This study enrolled 32 subjects (n = 8 in each Hepatic Impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe Hepatic Impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. RESULTS: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and Moderate Hepatic Impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and Moderate Hepatic Impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and Moderate Hepatic Impairment by 19 - 109%, respectively. CONCLUSIONS: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with Moderate Hepatic Impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups. .
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pharmacokinetics and safety of sacubitril valsartan lcz696 in patients with mild and Moderate Hepatic Impairment
Principles and Practice of Constraint Programming, 2017Co-Authors: Kenneth Kulmatycki, Thomas Langenickel, Iris Rajman, Priyamvada Chandra, Wei Zhou, Parasar Pal, Tsuhan Lin, Gangadhar SunkaraAbstract:Objectives To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and Moderate Hepatic Impairment (Child-Pugh class A and B) and matched healthy subjects. Methods This study enrolled 32 subjects (n = 8 in each Hepatic Impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe Hepatic Impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Results Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and Moderate Hepatic Impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and Moderate Hepatic Impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and Moderate Hepatic Impairment by 19 - 109%, respectively. Conclusions The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with Moderate Hepatic Impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups. .