carbamates and Hepatic Insufficiency studies

Hepatic Insufficiency: Conditions in which the LIVER functions fall below the normal ranges. Severe hepatic insufficiency may cause LIVER FAILURE or DEATH. Treatment may include LIVER TRANSPLANTATION.

Research Excerpts

Excerpt	Relevance	Reference
" Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals."	2.87	Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment. ( Brainard, DM; Curtis, C; Lasseter, K; Lawitz, E; Ling, KHJ; Marbury, T; Mathias, A; Mogalian, E; Moorehead, L; Murray, B; Osinusi, A; Perry, R, 2018)
" Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study."	2.84	Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor. ( Angus, P; Butterton, JR; Caro, L; Fandozzi, C; Fraser, IP; Gane, E; Guo, Z; Ho, M; Iwamoto, M; Marbury, T; Panebianco, D; Reitmann, C; Smith, WB; Talaty, J; Uemura, N; Wenning, L; Yeh, WW, 2017)
" Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line."	2.80	Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment. ( Awni, WM; Bernstein, BM; Ding, B; Dutta, S; Khatri, A; Lawitz, EJ; Marbury, TC; Menon, RM; Mullally, VM; Podsadecki, TJ, 2015)
" Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592)."	1.51	Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function. ( Barnes, CN; Borin, MT; Bourdet, DL; Lo, A; Pendyala, S, 2019)

Research

Studies (7)

Authors

Clinical Trials (4)

Trial Overview

Trial Outcomes

Apparent Terminal Half-life (t1/2) of Grazoprevir

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	0 (0.00)	29.6817
2010's	7 (100.00)	24.3611
2020's	0 (0.00)	2.80

Authors	Studies
Borin, MT	1
Lo, A	1
Barnes, CN	1
Pendyala, S	1
Bourdet, DL	1
Caro, L	1
Wenning, L	1
Guo, Z	1
Fraser, IP	1
Fandozzi, C	1
Talaty, J	1
Panebianco, D	1
Ho, M	1
Uemura, N	1
Reitmann, C	1
Angus, P	1
Gane, E	1
Marbury, T	2
Smith, WB	1
Iwamoto, M	1
Butterton, JR	1
Yeh, WW	1
Mogalian, E	1
Brainard, DM	1
Osinusi, A	1
Moorehead, L	1
Murray, B	1
Ling, KHJ	1
Perry, R	1
Curtis, C	1
Lawitz, E	2
Lasseter, K	1
Mathias, A	1
Khatri, A	2
Menon, RM	1
Marbury, TC	1
Lawitz, EJ	1
Podsadecki, TJ	1
Mullally, VM	1
Ding, B	1
Awni, WM	1
Bernstein, BM	1
Dutta, S	1
Chtioui, H	1
Buclin, T	1
Menon, R	1
Poordad, F	1
Gutierrez, JA	1
Kakuda, TN	1
Picchio, G	1
Beets, G	1
Vandevoorde, A	1
Van Remoortere, P	1
Jacquemyn, B	1
Luo, D	1
Ouwerkerk-Mahadevan, S	1
Vijgen, L	1
Van Eygen, V	1
Beumont, M	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
The Effect of Moderate Hepatic Impairment on the Pharmacokinetics Following Single-Dose Inhaled Administration of TD-4208[NCT02581592]	Phase 1	16 participants (Actual)	Interventional	2015-11-30	Completed
The Effect of Severe Renal Impairment on the Pharmacokinetics Following Single-Dose Inhaled Administration of TD 4208[NCT02578082]	Phase 1	16 participants (Actual)	Interventional	2015-12-31	Completed
An Open-label, 3-Part, Multiple Dose Study to Investigate the Influence of Hepatic Insufficiency on the Pharmacokinetics of Grazoprevir (MK-5172)[NCT01390428]	Phase 1	50 participants (Actual)	Interventional	2011-07-28	Completed
A Phase 2 Open-label Study to Investigate the Efficacy, Safety and Pharmacokinetics of 12 Weeks of Treatment With Simeprevir, Daclatasvir and Sofosbuvir, Followed by a 5-Year Post-treatment Long-term Follow-up, in Treatment-naïve and Treatment-experienced[NCT02262728]	Phase 2	40 participants (Actual)	Interventional	2014-09-30	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Day 10 in order to determine the plasma t1/2 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI. (NCT01390428)
Timeframe: Day 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 1 for Participants With Mild HI and Moderate HI and Healthy Matched to Mild HI and Moderate HI

Intervention	hr. (Geometric Mean)
Part 1-Mild HI	54.24
Part 1-Healthy Matched to Mild HI	35.85
Part 2-Moderate HI	39.59
Part 2-Healthy Matched to Moderate HI	39.80
Part 3-Severe HI	42.00
Part 3-Healthy Matched to Severe HI	31.02

Blood samples were collected at 24 hours post-dose on Day 1 in order to determine the plasma C24 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI. (NCT01390428)
Timeframe: Day 1 at 24 hours postdose

Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 1 for Participants With Severe HI and Healthy Matched to Severe HI

Intervention	nM (Geometric Mean)
Part 1-Mild HI	21.4
Part 1-Healthy Matched to Mild HI	11.5
Part 2-Moderate HI	17.7
Part 2-Healthy Matched to Moderate HI	5.90

Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 10

Intervention	nM (Median)
Part 3-Severe HI	15.6
Part 3-Healthy Matched to Severe HI	1.86

Blood samples were collected at 24 hours post-dose on Day 10 in order to determine the plasma C24 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI. (NCT01390428)
Timeframe: Days 10 at 24 hours postdose

Area Under the Concentration Time-curve From 0 to 24 Hours (AUC0-24) of Grazoprevir

Intervention	nM (Geometric Mean)
Part 1-Mild HI	32.6
Part 1-Healthy Matched to Mild HI	17.0
Part 2-Moderate HI	48.9
Part 2-Healthy Matched to Moderate HI	13.6
Part 3-Severe HI	55.0
Part 3-Healthy Matched to Severe HI	5.89

Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Days 1 and 10 in order to determine the plasma AUC0-24 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI. (NCT01390428)
Timeframe: Days 1 and 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

Maximum Concentration (Cmax) of Grazoprevir

Intervention	uM*hr (Geometric Mean)
	Day 1	Day 10
Part 1-Healthy Matched to Mild HI	1.42	3.74
Part 1-Mild HI	1.71	6.20
Part 2-Healthy Matched to Moderate HI	0.321	0.874
Part 2-Moderate HI	1.61	4.21
Part 3-Healthy Matched to Severe HI	0.0592	0.257
Part 3-Severe HI	1.17	3.00

Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Days 1 and 10 in order to determine the plasma Cmax of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI. (NCT01390428)
Timeframe: Days 1 and 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

Time to Peak Concentration (Tmax) of Grazoprevir

Intervention	uM (Geometric Mean)
	Day 1	Day 10
Part 1-Healthy Matched to Mild HI	0.305	1.02
Part 1-Mild HI	0.257	1.40
Part 2-Healthy Matched to Moderate HI	0.0580	0.106
Part 2-Moderate HI	0.433	0.631
Part 3-Healthy Matched to Severe HI	0.0157	0.0304
Part 3-Severe HI	0.238	0.396

Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Days 1 and 10 in order to determine the plasma Tmax of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI. (NCT01390428)
Timeframe: Days 1 and 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

Percentage of Participants With On-treatment Failure

Intervention	hr. (Median)
	Day 1	Day 10
Part 1-Healthy Matched to Mild HI	2.50	3.01
Part 1-Mild HI	3.50	3.00
Part 2-Healthy Matched to Moderate HI	1.75	2.00
Part 2-Moderate HI	2.00	3.00
Part 3-Healthy Matched to Severe HI	1.50	1.00
Part 3-Severe HI	1.75	1.75

On-treatment failure is defined as participants who do not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of study drug treatment. (NCT02262728)
Timeframe: Week 12

Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12)

Intervention	Percentage of Participants (Number)
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	0
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	0

Participants were considered to have achieved SVR12 if the hepatitis C virus ribonucleic acid (HCV RNA) was less than (<) lower limit of quantification (LLOQ; 15 international unit per milliliter [IU/mL]) detectable or undetectable at 12 weeks after the end of study drug treatment. (NCT02262728)
Timeframe: Week 24

Intervention	Units per Liter (U/L) (Mean)
	Baseline : ALT	Baseline : AST	Follow-Up Week 24 : ALT	Follow-Up Week 24 : AST
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	137.8	119.1	34.8	39.2
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	60.9	83.5	32.3	35.0

Intervention	ng.h/mL (Mean)
	Simeprevir : Week 2	Simeprevir : Week 8	Daclatasvir : Week 2	Daclatasvir : Week 8	Sofosbuvir : Week 2	Sofosbuvir : Week 8	GS-331007 : Week 2	GS-331007 : Week 8
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	113835	98568	16487	15574	2870	2746	17900	18132
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	142162	207221	17858	20787	3915	3933	21118	22829

Intervention	nanogram per milliliter (ng/mL) (Mean)
	Simeprevir : Week 2 (reference)	Simeprevir : Week 8 (test)	Daclatasvir : Week 2	Daclatasvir : Week 8	Sofosbuvir : Week 2	Sofosbuvir : Week 8	GS-331007 : Week 2	GS-331007 : Week 8
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	6976	6029	1187	1072	1571	1276	1403	1404
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	7726	10498	1145	1210	1615	1527	1561	1594

Intervention	ng/mL (Mean)
	Simeprevir : Week 2	Simeprevir : Week 8	Daclatasvir : Week 2	Daclatasvir : Week 8	Sofosbuvir : Week 2	Sofosbuvir : Week 8	GS-331007 : Week 2	GS-331007 : Week 8
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	3133	2639	414	442	NA	NA	419	443
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	4363	6955	519	660	NA	NA	441	523

Intervention	Percentage of Participants (Number)
	Week 1 : >= 15 IU/mL	Week 1 : < 100 IU/mL	Week 1: < 15 IU/mL undetect/detectable	Week 1 : < 15 IU/mL detectable	Week 1 : < 15 IU/mL Undetectable	Week 2 : >= 15 IU/mL	Week 2 : < 100 IU/mL	Week 2: < 15 IU/mL undetect/detectable	Week 2 : < 15 IU/mL detectable	Week 2: < 15 IU/mL undetectable (vRVR)	Week 4 : >= 15 IU/mL	Week 4 : < 100 IU/mL	Week 4: < 15 IU/mL undetect/detectable	Week 4 : < 15 IU/mL detectable	Week 4 : < 15 IU/mL undetectable (RVR)	Week 6 : >= 15 IU/mL	Week 6 : < 100 IU/mL	Week 6: < 15 IU/mL undetect/detectable	Week 6 : < 15 IU/mL detectable	Week 6 : < 15 IU/mL undetectable	Week 8 : >= 15 IU/mL	Week 8 : < 100 IU/mL	Week 8: < 15 IU/mL undetect/detectable	Week 8 : < 15 IU/mL detectable	Week 8 : < 15 IU/mL undetectable	Week 10 : >= 15 IU/mL	Week 10 : < 100 IU/mL	Week 10: < 15 IU/mL undetect/detectable	Week 10 : < 15 IU/mL detectable	Week 10 : < 15 IU/mL undetectable	Week 12 : >= 15 IU/mL	Week 12 :< 100 IU/mL	Week 12: < 15 IU/mL undetect/detectable	Week 12 : < 15 IU/mL detectable	Week 12 : < 15 IU/mL undetectable
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	72.2	61.1	27.8	11.1	16.7	10.5	94.7	89.5	36.8	52.6	0	100.0	100.0	5.6	94.4	0	100.0	100.0	5.3	94.7	0	100.0	100.0	0	100.0	0	100.0	100.0	0	100.0	0	100.0	100.0	0	100.0
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	76.2	38.1	23.8	19.0	4.8	47.6	71.4	52.4	19.0	33.3	9.5	100.0	90.5	28.6	61.9	0	100.0	100.0	20.0	80.0	0	100.0	100.0	4.8	95.2	0	100.0	100.0	0	100.0	0	100.0	100.0	0	100.0

carbamates and Hepatic Insufficiency

Research Excerpts

Research

Studies (7)

Authors

Clinical Trials (4)

Trial Overview

Trial Outcomes

Apparent Terminal Half-life (t1/2) of Grazoprevir

Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 1 for Participants With Mild HI and Moderate HI and Healthy Matched to Mild HI and Moderate HI

Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 1 for Participants With Severe HI and Healthy Matched to Severe HI

Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 10

Area Under the Concentration Time-curve From 0 to 24 Hours (AUC0-24) of Grazoprevir

Maximum Concentration (Cmax) of Grazoprevir

Time to Peak Concentration (Tmax) of Grazoprevir

Percentage of Participants With On-treatment Failure

Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12)

Absolute Values of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels at Follow-up Week 24 (Week 36)

Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours After Dosing (AUC[0-24]) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)

Maximum Plasma Concentration (Cmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)

Minimum Plasma Concentration (Cmin) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)

Percentage of Participants With On-Treatment Virologic Response

Percentage of Participants With SVR 4 Weeks After End of Study Drug Treatment (SVR4) and SVR 24 Weeks After End of Study Drug Treatment (SVR24)

Pre-dose (Trough) Concentration (C0h) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)

Time to Reach Maximum Plasma Concentration (Tmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)

Trials

Other Studies

Intervention	Percentage of participants (Number)
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	78.9
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	85.7

Intervention	Percentage of Participants (Number)
	SVR 4	SVR 24
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	100	100
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	100	100

Intervention	Hours (Median)
	Simeprevir: Week 2	Simeprevir: Week 8	Daclatasvir: Week 2	Daclatasvir: Week 8	Sofosbuvir: Week 2	Sofosbuvir: Week 8	GS-331007: Week 2	GS-331007: Week 8
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	6.00	6.00	3.00	2.50	1.00	1.75	4.00	4.00
SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B	8.00	8.00	4.00	4.00	2.00	2.00	4.00	4.00

Article	Year
Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor. Antimicrobial agents and chemotherapy, 2017, Volume: 61, Issue:12 Topics: Adolescent; Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Ther	2017
Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment. Clinical pharmacokinetics, 2018, Volume: 57, Issue:11 Topics: Adolescent; Adult; Aged; Antiviral Agents; Carbamates; Drug Combinations; Drug Therapy, Combination;	2018
Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment. Journal of hepatology, 2015, Volume: 63, Issue:4 Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A Inhib	2015
Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease. Journal of viral hepatitis, 2017, Volume: 24, Issue:4 Topics: Adult; Aged; Antiviral Agents; Carbamates; Drug-Related Side Effects and Adverse Reactions; Female;	2017

Article	Year
Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function. International journal of chronic obstructive pulmonary disease, 2019, Volume: 14 Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzamides; Carbamates; Female; Hepatic Insufficiency; H	2019
Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function. International journal of chronic obstructive pulmonary disease, 2019, Volume: 14 Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzamides; Carbamates; Female; Hepatic Insufficiency; H	2019
Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function. International journal of chronic obstructive pulmonary disease, 2019, Volume: 14 Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzamides; Carbamates; Female; Hepatic Insufficiency; H	2019
Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function. International journal of chronic obstructive pulmonary disease, 2019, Volume: 14 Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzamides; Carbamates; Female; Hepatic Insufficiency; H	2019
Pharmacokinetics in hepatic impairment: Mind the protein binding. Journal of hepatology, 2015, Volume: 63, Issue:6 Topics: Anilides; Carbamates; Female; Hepatic Insufficiency; Hepatitis C, Chronic; Humans; Macrocyclic Compo	2015
Reply to "Pharmacokinetics in hepatic impairment: Mind the protein binding". Journal of hepatology, 2015, Volume: 63, Issue:6 Topics: Anilides; Carbamates; Female; Hepatic Insufficiency; Hepatitis C, Chronic; Humans; Macrocyclic Compo	2015