Pharmacokinetics of Lopinavir/Ritonavir in HIV/Hepatitis C Virus–Coinfected Subjects With Hepatic Impairment

Peng, Joanna; Pulido, Federico; Causemaker, Sonja J.; Li, Jianling; Lorenzo, Alicia; Cepeda, Concepción; Cabanillas, Juan A. García; DaSilva, Barbara; Brun, Scott; Arribas, José Ramón

doi:10.1177/0091270005284853

Cited by 39 publications

(29 citation statements)

References 9 publications

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“…This observation was based on the measurement of plasma levels of LPV and ATV and comparisons made between patients with and without cirrhosis. A recent multiple-dose study found that the C min of LPV was higher in HIV-infected patients with chronic hepatitis than in control subjects [23]. However, in accordance with our findings, no significant differences in LPV plasma levels were seen in the group of patients with liver disease when patients with cirrhosis were compared with those with mild hepatic impairment.…”

Section: Discussionsupporting

confidence: 90%

Influence of Liver Fibrosis Stage on Plasma Levels of Antiretroviral Drugs in HIV‐Infected Patients with Chronic Hepatitis C

Barreiro¹,

Rodrı́guez-Nóvoa

Labarga³

et al. 2007

J INFECT DIS

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Section: Discussionsupporting

confidence: 90%

Influence of Liver Fibrosis Stage on Plasma Levels of Antiretroviral Drugs in HIV‐Infected Patients with Chronic Hepatitis C

Barreiro¹,

Rodrı́guez-Nóvoa

Labarga³

et al. 2007

J INFECT DIS

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“…For example, for subjects with moderate hepatic impairment, amprenavir AUC (0-) values increased 51 to 70% in the ritonavir-boosted setting versus 2.5-fold in the unboosted amprenavir study; similarly, for subjects with severe hepatic impairment, amprenavir AUC (0-) values increased 80% in the ritonavirboosted setting versus 4.5-fold in the unboosted amprenavir study. Ritonavir exposure [AUC (0-) ] also increased 93 to 120% for subjects with moderate hepatic impairment and 180% for subjects with severe hepatic impairment, and the increases were of a magnitude similar to those reported for lopinavir/ritionavir (3).…”

Section: Discussionsupporting

confidence: 71%

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

Pérez-Elías

Morellón

Ortega

et al. 2009

Antimicrob Agents Chemother

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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-) ], similar values for the concentration at the end of the dosing interval (C ), and 114% higher unbound C 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 values, and 21% higher unbound amprenavir C 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 values, and similar unbound amprenavir C 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.

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“…Our data are in agreement with those of other studies reporting that hepatic impairment does alter the pharmacokinetics of ATV. 13,24 In our patients, the 400 mg OD unboosted regimen in HIV+/HCV-negative subjects provided significantly lower ATV trough concentrations than did the standard dosage of 300ATV + 100RTV OD (median 0.23 versus 0.85 mg/mL; P , 0.0001). The same difference between the 2 ATV regimens was also confirmed in HIV+/HCV-positive patients (0.52 mg/mL for the 400 OD and 0.96 mg/mL for the 300/100 OD, respectively).…”

Section: Discussionmentioning

confidence: 59%

“…Results from other studies support the concept that the intrinsic clearance of PIs in patients with liver disease is only partially affected after being inhibited by low-dose RTV coadministration, because no significant changes in drug pharmacokinetics in mild liver dysfunction with morphologic evidence of cirrhosis were observed. [23][24][25][26][27] This PK study has some limitations. First of all, it was based on a retrospective observational TDM data set and not on a controlled protocol.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Monitoring and Variability of Atazanavir in HIV-Infected Patients, With and Without HCV Coinfection, Receiving Boosted or Unboosted Regimens

Regazzi¹,

Villani²,

Gulminetti³

et al. 2011

Therapeutic Drug Monitoring

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Background: Adequate plasma trough concentrations (C trough ) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection. Methods:We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 mg/mL, based on the proposed therapeutic range (0.15-0.85 mg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV2, HIV+/HCV+, and HIV+/HCV+ with cirrhosis.Results: In the whole study population, we observed a large variability and found suboptimal C trough levels (,0.15 mg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) mg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median C trough of 0.70 (0.43-1.0) mg/mL, with no statistical difference when compared with HIV+/HCV2 infected patients. For the 400ATV OD (n = 90) dosage regimen, the total median ATV C trough was 0.40 (0.23-1.0) mg/mL. In this group, we found a statistically significant difference between HIV+/HCV2 and HIV+/HCV+-infected patients: median C trough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) mg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the C trough median value was 0.42 (0.13-0.75) mg/mL, and there was a significant difference when compared with HIV patients without coinfection.Conclusions: Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIVinfected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure.

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Pharmacokinetics of Lopinavir/Ritonavir in HIV/Hepatitis C Virus–Coinfected Subjects With Hepatic Impairment

Cited by 39 publications

References 9 publications

Influence of Liver Fibrosis Stage on Plasma Levels of Antiretroviral Drugs in HIV‐Infected Patients with Chronic Hepatitis C

Influence of Liver Fibrosis Stage on Plasma Levels of Antiretroviral Drugs in HIV‐Infected Patients with Chronic Hepatitis C

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

Therapeutic Monitoring and Variability of Atazanavir in HIV-Infected Patients, With and Without HCV Coinfection, Receiving Boosted or Unboosted Regimens

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