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Correlation between atazanavir concentrations, clinical covariates and side effects
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Reported by Jules Levin
CROI 2014 March 3-6 Boston, MA
Cristina Gervasoni1, Paola Meraviglia1, Laurenzia Ferraris1, Simona Landonio1, Valeria Cozzi2, Nitin Charbe2, Agostino Riva1, Giuliano Rizzardini1, Massimo Galli1, Dario Cattaneo2
1Department of Infectious Diseases and 2Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy
Program Abstract:
Background: Although significant relationships have been reported between atazanavir (ATV) trough concentrations and clinical outcome, therapeutic drug monitoring (TDM) of ATV is not routinely adopted in clinical practice. ATV plasma concentrations >150 ng/mL are currently considered the minimum level needed to achieve viral undetectability, while concentrations >800 ng/mL are associated with increased risk of hyperbilirubinemia. No specific associations have been reported between ATV levels and other drug related complications. Similarly, no clinical covariates affecting ATV concentrations have been conclusively identified.
Methodology: ATV trough concentrations were determined in a consecutive series of HIV patients receiving ATV for at least 3 months. The presence of hyperbilirubinemia (total bilirubin >1.8 mg/dL excluding UGT1A1*28 homozygous genotype), dyslipidemia (total cholesterol >200 mg/dL, triglycerides >180 mg/dL or statin therapy) and nephrolitiasis (renal colics without urinary oxalate or urate crystals) were assessed. Multivariate regression analyses were performed using ATV-related complications as the dependent variable and demographic, clinical and laboratory data as independent covariates.
Results: Nearly 45% of 273 enrolled patients (68% on ATV/r 300/100) had ATV concentrations out of the therapeutic drug window (set at 150-800 ng/mL).
Patients with hyperbilirubinemia (n=125), hypercholesterolemia (n=116), hypertriglyceridemia (n=92) or nephrolitiasis (n=13) had ATV concentrations significantly higher (1025±920, 770±858, 838±791 or 1121±886 ng/mL, respectively) compared with those measured in patients without ATV-related complications (n=71; 461±678 ng/mL, p<0.001). The independent significant association between ATV plasma concentrations and drug-related toxicity was confirmed also by multivariate logistic regression analysis (p<0.05). The only factors independently associated with ATV levels were ritonavir use (r=-0.291, p<0.0001) and concomitant statin administration (rosuvastatin in 31/34 cases; r= 0.315, p<0.0001). No effect of tenofovir, patients' age, body weight or body mass index on ATV concentrations was found.
Conclusions: A significant proportion of patients treated with ATV had plasma concentrations exceeding the upper therapeutic threshold. High ATV plasma levels were significantly associated with all the main ATV-related toxicities. TDM in the day-by-day clinical practice may allow an early identification of patients at risk for untoward effects and drug dosage adjustment. Despite rosuvastatin is considered to have a low potential for drug-to-drug interactions with protease inhibitors, our data show that ATV plasma concentrations were significantly influenced by this drug.
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