Is the unbound concentration of atazanavir of interest in therapeutic drug monitoring?
To date, therapeutic drug monitoring (TDM) is carried out with antiretrovirals and is usually based on total concentrations (Ct). However, for some patients, TDM does not reflect efficacy or the avoidance of toxicity as is the case for atazanavir (ATV), a HIV protease inhibitor. As the unbound concentration (Cu) is the pharmacological active form, the aim of the study was to evaluate the value of Cuand the unbound fraction (fu, fu= Cu/Ct) for the TDM of ATV. The variability of Cuand the corresponding fuof ATV was explored in 43 patients treated with ATV for an average of 13.5 months. Cuwas determined by coupling ultrafiltration and liquid chromatography. As ATV is highly bound to alpha-1 acid glycoprotein (AAG), the correlation between fuand AAG was also evaluated. The viral load was monitored to evaluate the patients' virologic response, while total plasma bilirubin and unconjugated plasma bilirubin were used as biomarkers of ATV toxicity. Median trough Cuand Ctwere 37.9 μg/L (Interquartile range (IQR) 20.6-94.9 μg/L) and 628.6 μg/L (IQR 362.7-1078.1 μg/L), respectively. fu, Cuand Ctshowed high variability, but the fuvariability was not correlated with the AAG level. The unbound concentration and fraction were unrelated to the virologic response (P = 0.21 and P = 0.65 for Cuand fu, respectively) nor to the unconjugated bilirubin (Pearson correlation coefficient (ρ), ρ = 0.22; P = 0.17 for Cu). Neither total nor unbound concentrations of ATV fully explained hyperbilirubinaemia or virologic failure. From this study, we conclude that unbound ATV did not appear to be more relevant than Ct.
Laboratoire de Pharmacocinétique et de Toxicologie, Institut Fédératif de Biologie Purpan, Centre Hospitalier Universitaire, Toulouse, France.|Institut Universitaire du Cancer Toulouse Oncopole - CRCT, Université de Toulouse, Inserm, UPS, Toulouse, Midi-Pyrénées, France.
David
D
Metsu
Laboratoire de Pharmacocinétique et de Toxicologie, Institut Fédératif de Biologie Purpan, Centre Hospitalier Universitaire, Toulouse, France.
Patrick
P
Seraissol
Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire, Toulouse, France.
Pierre
P
Delobel
Laboratoire de Biochimie, Institut Fédératif de Biologie Purpan, Centre Hospitalier Universitaire, Toulouse, France.
Christel
C
Cinq-Frais
COREVIH Midi-Pyrénées-Limousin, Toulouse, France.
Lise
L
Cuzin
Laboratoire de Virologie, Institut Fédératif de Biologie Purpan, Centre Hospitalier Universitaire, Toulouse, France.
Jacques
J
Izopet
Institut Universitaire du Cancer Toulouse Oncopole - CRCT, Université de Toulouse, Inserm, UPS, Toulouse, Midi-Pyrénées, France.
Etienne
E
Chatelut
Laboratoire de Pharmacocinétique et de Toxicologie, Institut Fédératif de Biologie Purpan, Centre Hospitalier Universitaire, Toulouse, France.|Institut Universitaire du Cancer Toulouse Oncopole - CRCT, Université de Toulouse, Inserm, UPS, Toulouse, Midi-Pyrénées, France.
Peggy
P
Gandia
D000328:Adult; D000069446:Atazanavir Sulfate / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002853:Chromatography, Liquid / Q000379:methods; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology; D008297:Male; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
D015415:Biomarkers; D017320:HIV Protease Inhibitors; D000069446:Atazanavir Sulfate; D001663:Bilirubin
atazanavir; therapeutic drug monitoring; unbound concentration