title: Metabolic and kidney disorders correlate with high atazanavir concentrations in HIV-infected patients: is it time to revise atazanavir dosages?
abstract: BACKGROUND
  Ritonavir-boosted atazanavir (ATV/r) is a relatively well tolerated antiretroviral drug. However, side effects including hyperbilirubinemia, dyslipidemia, nephrolithiasis and cholelithiasis have been reported in the medium and long term. Unboosted ATV may be selected for some patients because it has fewer gastrointestinal adverse effects, less hyperbilirubinemia and less impact on lipid profiles.
  
  
  METHODS
  We investigated the distribution of ATV plasma trough concentrations according to drug dosage and the potential relationship between ATV plasma trough concentrations and drug-related adverse events in a consecutive series of 240 HIV-infected patients treated with ATV/r 300/100 mg (68%) or ATV 400 mg (32%).
  
  
  RESULTS
  43.9% of patients treated with ATV/r 300/100 mg had ATV concentrations exceeding the upper therapeutic threshold. A significant and direct association has been observed between the severity of hyperbilirubinemia and ATV plasma trough concentrations (ATV concentrations: 271 [77-555], 548 [206-902], 793 [440-1164], 768 [494-1527] and 1491 [1122-1798] ng/mL in patients with grade 0, 1, 2, 3 and 4 hyperbilirubinemia, respectively). In an exploratory analysis we found that patients with dyslipidemia or nephrolitiasis had ATV concentrations significantly higher (582 [266-1148], and 1098 [631-1238] ng/mL, respectively) (p<0.001), as compared with patients with no ATV-related complications (218 [77-541] ng/mL).
  
  
  CONCLUSIONS
  A significant proportion of patients treated with the conventional dosage of ATV (300/100) had plasma concentrations exceeding the upper therapeutic threshold. These patients that are at high risk to experience ATV-related complications may benefit from TDM-driven adjustments in ATV dosage with potential advantages in terms of costs and toxicity.
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Cristina
authors: C
authors: Gervasoni
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Paola
authors: P
authors: Meraviglia
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Davide
authors: D
authors: Minisci
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Laurenzia
authors: L
authors: Ferraris
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Agostino
authors: A
authors: Riva
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Simona
authors: S
authors: Landonio
authors: Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy.
authors: Valeria
authors: V
authors: Cozzi
authors: Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy.
authors: Nitin
authors: N
authors: Charbe
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Lara
authors: L
authors: Molinari
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy; School of Clinical Medicine, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa.
authors: Giuliano
authors: G
authors: Rizzardini
authors: Clinical Pharmacology Unit, Consiglio Nazionale delle Ricerche Institute of Neuroscience, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy; E. Medea Scientific Institute, Bosisio Parini, Italy.
authors: Emilio
authors: E
authors: Clementi
authors: Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
authors: Massimo
authors: M
authors: Galli
authors: Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy.
authors: Dario
authors: D
authors: Cattaneo
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D050171:Dyslipidemias / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006932:Hyperbilirubinemia / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D053040:Nephrolithiasis / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology; D019438:Ritonavir / Q000009:adverse effects; D019562:Viral Load / Q000187:drug effects
chemical_list: D017320:HIV Protease Inhibitors; D000069446:Atazanavir Sulfate; D019438:Ritonavir