scholarly journals Pharmacokinetics of Fosamprenavir plus Ritonavir in Human Immunodeficiency Virus Type 1-Infected Adult Subjects with Hepatic Impairment

2009 ◽  
Vol 53 (12) ◽  
pp. 5185-5196 ◽  
Author(s):  
María J. Pérez-Elías ◽  
María Larrousse Morellon ◽  
Enrique Ortega ◽  
José Hernández-Quero ◽  
Maribel Rodríguez-Torres ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Lower Plasma ◽  
Severe Hepatic Impairment ◽  
Once Daily ◽  
Dosing Interval ◽  
Normal Hepatic Function ◽  
Immunodeficiency Virus

ABSTRACT The effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (C max), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC(0- τ)], similar values for the concentration at the end of the dosing interval (C τ), and 114% higher unbound C τ values. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavir C max values, 27% lower AUC(0-24) values, 57% lower C τ values, and 21% higher unbound amprenavir C τ values. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavir C max values, 23% lower AUC(0-24) values, 38% lower C τ values, and similar unbound amprenavir C τ values. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC(0-24) values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.

A Phase IIa Study Evaluating Safety, Pharmacokinetics, and Antiviral Activity of GSK2838232, a Novel, Second-generation Maturation Inhibitor, in Participants With Human Immunodeficiency Virus Type 1 Infection

2019 ◽  
Vol 71 (5) ◽  
pp. 1255-1262 ◽  
Author(s):  
Edwin DeJesus ◽  
Sara Harward ◽  
Roxanne C Jewell ◽  
Mark Johnson ◽  
Etienne Dumont ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Second Generation ◽  
Proof Of Concept ◽  
Once Daily ◽  
Immunodeficiency Virus ◽  
Maturation Inhibitor ◽  
Hiv 1

Abstract Background GSK2838232 is a second-generation, potent, small-molecule, oral human immunodeficiency virus type 1 (HIV-1) maturation inhibitor for once-daily administration boosted with a pharmacoenhancer. Methods The phase 2a, proof-of-concept study was an open-label, adaptive dose-ranging design. Safety, pharmacokinetics, and efficacy of GSK2838232 boosted by cobicistat were evaluated in individuals with HIV-1 infection. The study participants (N = 33) received GSK2838232 once daily across a range of doses (20–200 mg) with cobicistat 150 mg for 10 days. Results GSK2838232 was safe and well tolerated with no clinically meaningful changes in safety parameters or adverse events. Exposure (maximum concentration and area under the concentration-time curve from time zero to the concentration at 24 hours postdose) increased 2- to 3-fold with repeated dosing in an approximately dose-proportional manner, reaching steady-state by day 8 with a half-life (t½) from 16.3 to 19.2 hours. Clearance and t½ values were not dependent on dose. Viral load declined from baseline with all GSK2838232 doses. Mean maximum declines from baseline to day 11 in HIV-1 RNA log10 copies/mL with the 20-mg, 50-mg, 100-mg, and 200-mg cohorts were −0.67, −1.56, −1.32, and −1.70, respectively. CD4+ cell counts increased at doses ≥50 mg. Conclusions GSK2838232 with cobicistat was well tolerated and exhibited efficacy as a short-term monotherapy in participants with HIV-1. This positive proof-of-concept study supports the continued development of GSK2838232 for the treatment of HIV as part of combination antiretroviral therapy. Clinical Trials Registration NCT03045861.

scholarly journals 982. Effect of Hepatic Impairment on the Safety and Pharmacokinetics of Rezafungin

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S582-S583
Author(s):  
Jade Huguet ◽  
Voon Ong ◽  
Taylor Sandison ◽  
Rebeca M Melara ◽  
Thomas C Marbury ◽  
...  
Keyword(s):  
Clinical Research ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Research Center ◽  
Parameter Estimates ◽  
Severe Hepatic Impairment ◽  
Single Dose Study ◽  
Equal Distribution ◽  
Normal Hepatic Function ◽  
Clinical Research Center

Abstract Background Rezafungin (RZF) is a novel echinocandin antifungal being developed for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases among immunosuppressed patients. In the Phase 2 and Phase 3 treatment trials of rezafungin compared with caspofungin (STRIVE [NCT02734862] and ReSTORE [NCT03667690], respectively), patients with severe hepatic impairment (HI) were not included due to lack of caspofungin data in this population. Rezafungin was previously evaluated in patients with moderate hepatic impairment. Here we report an open-label, single-dose study on rezafungin in patients with HI (Child-Pugh class C). Methods To investigate the safety, tolerability, and pharmacokinetics (PK) of RZF in subjects with HI and healthy subjects (HS), 8 subjects with HI and 8 HS matched for age, sex, and body mass index (BMI) were enrolled and received a single 400-mg intravenous 1-hour infusion of RZF. Plasma PK sampling was performed at various time points through 336 hours postdose. RZF PK parameters were derived using non-compartmental analysis. Safety was assessed throughout the study. Results The majority of the HI subjects were White (87.5%) and male (75%) while equal distribution between White and Black or African American was observed among HS (50%) and 75% were male. The mean age of HI subjects was 58 years (range, 41–68 years) and 56.6 years (range, 50–61 years) for the HS. Mean BMI was 29.7 kg/m2 (range, 24.5–34.3 kg/m2) for HI subjects and 29.7 kg/m2 (range, 25.4–34.2 kg/m2) for the HS. RZF exposure (Cmax and AUC) in subjects with HI was ~30% lower than that in HS (Table 1), while half-life was generally similar (HI: 121 h, HS:124 h; Figure 1). Three HI subjects had one adverse event (AE) each (bronchitis, worsening hepatic encephalopathy, hyponatremia), all moderate in severity; one HS had 1 AE of infusion site infiltration mild in severity. No AEs were considered related to RZF, and all were resolved or resolving by the end of the study. Table 1. Plasma Rezafungin PK Parameter Estimates in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400 mg IV Infusion of Rezafungin Figure 1. Mean (+SD) Plasma Rezafungin Concentration-Time Profiles in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400-mg IV Infusion of Rezafungin (Semi-Logarithmic Scale) Conclusion RZF was well tolerated in HI subjects and showed modestly reduced exposure that was within the range observed in matched HS. These findings support no RZF dose adjustment in subjects with severe hepatic impairment. Disclosures Voon Ong, PhD, Cidara Therapeutics (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics (Employee, Shareholder) Rebeca M. Melara, M.S., Altasciences (contract research organization) (Employee) Thomas C. Marbury, MD, Orlando Clinical Research Center (Employee, Other Financial or Material Support, Equity owner of Orlando Clinical Research Center) Alena Jandourek, MD, Cidara therapeutics (Consultant) Shawn Flanagan, PhD, Cidara Therapeutics (Employee, Shareholder)

Adherence and Acceptability of Once Daily Lamivudine and Abacavir in Human Immunodeficiency Virus Type-1 Infected Children

2006 ◽  
Vol 25 (6) ◽  
pp. 533-537 ◽  
Author(s):  
Marthe LePrevost ◽  
Hannah Green ◽  
Jacquie Flynn ◽  
Stephen Head ◽  
Margaret Clapson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Once Daily ◽  
Immunodeficiency Virus

scholarly journals Suppression of Virus Load by Highly Active Antiretroviral Therapy in Rhesus Macaques Infected with a Recombinant Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 79 (12) ◽  
pp. 7349-7354 ◽  
Author(s):  
Thomas W. North ◽  
Koen K. A. Van Rompay ◽  
Joanne Higgins ◽  
Timothy B. Matthews ◽  
Debra A. Wadford ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Once Daily ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We have modeled highly active antiretroviral therapy (HAART) for AIDS in rhesus macaques infected with a chimera (RT-SHIV) of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type-1 (HIV-1). Seven RT-SHIV-infected macaques were treated with a combination of efavirenz (200 mg orally once daily), lamivudine (8 mg/kg subcutaneously once daily), and tenofovir (30 mg/kg subcutaneously once daily). Plasma viral RNA levels in all animals were reduced by more than 1,000-fold after 4 weeks and, in six of the seven animals, were reduced to undetectable levels after 10 weeks. Virus loads increased slightly between 12 and 16 weeks of treatment, associated with problems with the administration of efavirenz. After a change in the method of efavirenz administration, virus loads declined again and remained undetectable in the majority of animals for the duration of therapy. Treatment was stopped for three animals after 36 weeks of therapy, and virus loads increased rapidly. Posttreatment RT-SHIV isolates had no mutations associated with resistance to any of the three drugs. Efavirenz treatment was stopped, but lamivudine and tenofovir treatment for two other macaques was continued. The virus load in one of these two animals rebounded; virus from this animal was initially free of drug-resistance mutations but acquired the K65R mutation in reverse transcriptase at 11 weeks after efavirenz treatment was withdrawn. These results mimic HAART of HIV-1-infected humans. The RT-SHIV/rhesus macaque model should be useful for studies of tissue reservoirs and sites of residual replication that are not possible or practical with humans.

scholarly journals Human Immunodeficiency Virus (HIV) Type 1 Reverse Transcriptase Resistance Mutations in Hepatitis B Virus (HBV)-HIV-Coinfected Patients Treated for HBV Chronic Infection Once Daily with 10 Milligrams of Adefovir Dipivoxil Combined with Lamivudine

2002 ◽  
Vol 46 (5) ◽  
pp. 1586-1588 ◽  
Author(s):  
Constance Delaugerre ◽  
Anne-Geneviève Marcelin ◽  
Vincent Thibault ◽  
Gilles Peytavin ◽  
Tony Bombled ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Reverse Transcriptase ◽  
Adefovir Dipivoxil ◽  
Once Daily ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Adefovir dipivoxil (ADV) at a suboptimal concentration for human immunodeficiency virus type 1 (HIV-1) (10 mg once daily) can be used to treat hepatitis B virus (HBV) infection in HIV-1-HBV-coinfected patients and does not, even in the case of uncontrolled HIV-1 replication, select for either ADV mutations at codons 65 and 70 or any other particular HIV-1 reverse transcriptase resistance profile.

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