The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring

Gatti, Giorgio; Biagio, Antonio Di; Casazza, R; Pascalis, Cleta De; Bassetti, Matteo; Cruciani, Mario; Vella, Stefano; Bassetti, Dante

doi:10.1097/00002030-199910220-00011

Cited by 160 publications

(87 citation statements)

References 12 publications

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“…35 In the present study, we used the concentration of ritonavir for doing in vitro experiments from 0 to 40 lM and in vivo 30 mg/kg/day used for treatment of AIDS patients. Constitutive and strong NF-jB activation was reported to be a characteristic of LCL and important for LCL growth and survival.…”

Section: Discussionmentioning

confidence: 99%

An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells

Dewan

Tomita

Katano

et al. 2008

Intl Journal of Cancer

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Epstein-Barr Virus (EBV)-associated immunoblastic lymphoma occurs in immunocompromised patients such as those with AIDS or transplant recipients after primary EBV infection or reactivation of a preexisting latent EBV infection. In the present study, we evaluated the effect of ritonavir, an HIV protease inhibitor, on EBV-positive lymphoblastoid B cells in vitro and in mice model. We found that it induced cell-cycle arrest at G 1 -phase and apoptosis through down-regulation of cell-cycle gene cyclin D2 and antiapoptotic gene survivin. Furthermore, ritonavir suppressed transcriptional activation of NF-jB in these cells. Ritonavir efficiently prevented growth and infiltration of lymphoma cells in various organs of NOD/SCID/cc null mice at the same dose used for treatment of patients with AIDS. Our results indicate that ritonavir targets NF-jB activated in tumor cells and shows anti-tumor effects. These data also suggest that this compound may have promise for treatment or prevention of EBV-associated lymphoproliferative diseases that occur in immunocompromised patients.

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Section: Discussionmentioning

confidence: 99%

An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells

Dewan

Tomita

Katano

et al. 2008

Intl Journal of Cancer

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“…For some antiretroviral drugs, increased levels in plasma have been shown to be associated with increased toxicity (6,11,12,15).…”

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confidence: 99%

Clinical Pharmacokinetics of Nelfinavir and Its Metabolite M8 in Human Immunodeficiency Virus (HIV)-Positive and HIV-Hepatitis C Virus-Coinfected Subjects

Regazzi¹,

Maserati

Villani³

et al. 2005

Antimicrob Agents Chemother

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In order to evaluate the potential risk of nelfinavir (NFV) accumulation in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients with liver disease, we investigated the concentrations of NFV and M8, the active metabolite of NFV, in plasma HIV-positive (HIV؉) patients coinfected with HCV. A total of 119 HIV؉ subjects were included in our study: 67 HIV؉ patients, 32 HIV؉ and HCV-positive (HCV؉) patients without cirrhosis, and 20 HIV؉ and HCV؉ patients with cirrhosis. Most of the enrolled patients (chronically treated) were taking NFV at the standard dosage of 1,250 mg twice a day. To assay plasma NFV and M8 concentrations, patients underwent serial plasma samplings during the dosing interval at steady state. Plasma NFV and M8 concentrations were measured simultaneously by a high-performance liquid chromatography method with UV detection. The HIV؉ and HCV؉ patients with and without cirrhosis had significantly lower NFV oral clearances than the HIV؉ and HCV-negative individuals (28 and 58% lower, respectively; P < 0.05), which translated into higher areas under the concentration-time curves for cirrhotic and noncirrhotic patients. The NFV absorption rate was significantly lower in cirrhotic patients, resulting in a longer time to the maximum concentration in serum. The mean ratios of the M8 concentration/NFV concentration were significantly lower (P < 0.05) in HIV؉ and HCV؉ subjects with cirrhosis (0.06 ؎ 0.074) than in the subjects in the other two groups. The mean ratios for M8 and NFV were not statistically different between HIV؉ and HCV-negative patients (0.16 ؎ 0.13) and HIV؉ and HCV؉ patients without cirrhosis (0.24 ؎ 0.17), but the interpatient variability was high. Our results indicate that the pharmacokinetics of NFV and M8 are altered in HIV؉ and HCV؉ patients, especially those with liver cirrhosis. Therefore, there may be a role for therapeutic drug monitoring in individualizing the NFV dosage in HIV-HCV-coinfected patients.

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“…With regard to saquinavir concentration, the boosting effects of different doses of ritonavir ranging from 100 to 400 mg b.i.d. are similar (15), and with the 100-mg dose, the toxic effects of higher doses are minimized (11). Lopinavir was the first commercially marketed PI coformulated with ritonavir to achieve good bioavailability.…”

mentioning

confidence: 99%

Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

Ribera¹,

López²,

Díaz³

et al. 2004

Antimicrob Agents Chemother

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Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), 85.1 g/ml ⅐ h; maximum concentration of drug in serum (C max ), 10.0 g/ml; trough concentration of drug in serum (C trough ), 7.3 g/ml; and minimum concentration of drug in serum (C min ), 5.5 g/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC 0-12 , 22.9 g/ml ⅐ h; C max , 2.9 g/ml; C trough , 1.6 g/ml; and C min , 1.4 g/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitorbased antiretroviral regimen for patients with several prior virologic failures.

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The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring

Cited by 160 publications

References 12 publications

An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells

An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells

Clinical Pharmacokinetics of Nelfinavir and Its Metabolite M8 in Human Immunodeficiency Virus (HIV)-Positive and HIV-Hepatitis C Virus-Coinfected Subjects

Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

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