Atazanavir Plasma Concentrations Vary Significantly Between Patients and Correlate with Increased Serum Bilirubin Concentrations

Smith, Don; Jeganathan, Sarangapany; Ray, John E.

doi:10.1310/0kx0-h9vh-99ee-5d0l

Cited by 53 publications

(50 citation statements)

References 13 publications

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“…These data suggest that higher doses of atazanavir may be required in very-large patients to achieve the same exposures. Unlike the results of several previous studies (17,19,21), we did not detect a strong and statistically significant correlation between atazanavir concentrations and total bilirubin levels. The atazanavir AUC and C max values were very weakly (positively) correlated with total bilirubin concentrations (0.02 and 0.04, respectively) in this study.…”

Section: Discussioncontrasting

confidence: 99%

Pharmacokinetics of Antiretroviral Regimens Containing Tenofovir Disoproxil Fumarate and Atazanavir-Ritonavir in Adolescents and Young Adults with Human Immunodeficiency Virus Infection

Kiser

Fletcher²,

Flynn

et al. 2008

Antimicrob Agents Chemother

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The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects >18 to <25 years old receiving (>28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC 0-24 ), maximum concentration of drug in serum (C max ), concentration at 24 h postdose (C 24 ), and total apparent oral clearance (CL/F) values were 35,971 ng ⅐ hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC 0-24 , C max , C 24 , and CL/F values were 2,762 ng ⅐ hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P < 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C max and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.

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Section: Discussioncontrasting

confidence: 99%

Pharmacokinetics of Antiretroviral Regimens Containing Tenofovir Disoproxil Fumarate and Atazanavir-Ritonavir in Adolescents and Young Adults with Human Immunodeficiency Virus Infection

Kiser

Fletcher²,

Flynn

et al. 2008

Antimicrob Agents Chemother

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show abstract

“…We could not find any suggestion of a relation between drug concentrations and discontinuation due to CNS effects in our dataset Only 3/58 of our ATV samples were below the suggested cut-off of 150 ng/ml at week 4. This is in line with previous reports on the use of ritonavir to boost ATV [22][23][24][25]. The support cited for the suggested cut-off level of 150 ng/ml in treatment-naïve patients was generated in an observational cohort of whom only 33% were protease inhibitor (PI)-naïve [2,26], and other researchers have not been able to validate it [24].…”

Section: Discussionsupporting

confidence: 82%

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

Josephson

Andersson

Flamholc

et al. 2009

Eur J Clin Pharmacol

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“…Sobre esta última, un estudio de asignación aleatoria, abierto y multicéntrico, observó que menos de 1% de los pacientes suspende tratamiento como consecuencia de la hiperbilirrubinemia, ictericia o ictericia escleral antes de la semana 48; sin observarse diferencias en la calidad de vida de los pacientes (con o sin hiperbilirrubinemia). A lo largo del estudio, se observó además una menor tolerancia a LPV/r al provocar mayor diarrea y náuseas que su comparador (ATV/r) [5][6][7] .…”

Section: Discussionunclassified

Incidencia de reacciones adversas a medicamentos en pacientes que inician o cambian terapia anti-retroviral

Bernal

Vásquez

Giadalah

et al. 2013

Rev. chil. infectol.

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Atazanavir Plasma Concentrations Vary Significantly Between Patients and Correlate with Increased Serum Bilirubin Concentrations

Abstract: ATV concentrations showed considerable interpatient variability. Bilirubin concentrations are an indicator of high ATV concentrations and may prove to be useful in selecting patients for therapeutic drug monitoring (TDM).

Cited by 53 publications

References 13 publications

Pharmacokinetics of Antiretroviral Regimens Containing Tenofovir Disoproxil Fumarate and Atazanavir-Ritonavir in Adolescents and Young Adults with Human Immunodeficiency Virus Infection

Pharmacokinetics of Antiretroviral Regimens Containing Tenofovir Disoproxil Fumarate and Atazanavir-Ritonavir in Adolescents and Young Adults with Human Immunodeficiency Virus Infection

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

Incidencia de reacciones adversas a medicamentos en pacientes que inician o cambian terapia anti-retroviral

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