title: High variability of indinavir and nelfinavir pharmacokinetics in HIV-infected patients with a sustained virological response on highly active antiretroviral therapy.
abstract: OBJECTIVE
  To describe plasma concentrations of indinavir alone or combined with ritonavir, and of nelfinavir and its active metabolite M8, and to measure their variabilities in HIV-infected patients treated with a stable antiretroviral regimen and experiencing a sustained virological response for at least 12 months.
  
  
  METHODS
  In this prospective trial, blood samples were drawn during a 6-hour time interval between two doses at enrolment to assess protease inhibitor (PI) pharmacokinetic parameters, and 4 months later to assess plasma trough and peak concentrations. Safety and adherence assessments and laboratory data were collected during an 8-month period. PI pharmacokinetic characteristics were analysed using a non-compartmental approach. Inter- and intrapatient variabilities were estimated using a linear mixed-effect model. The impact of different covariates on plasma trough concentrations was investigated. Eighty-eight patients were analysed: 42 treated with indinavir and 46 with nelfinavir.
  
  
  RESULTS
  The interquartile range (IQR) of the plasma trough concentration corrected for the sampling time (Ccalc) was 116-374 microg/L for indinavir alone and 163-508 microg/L for indinavir/ritonavir. Ritonavir significantly increased indinavir elimination half-life and plasma exposure. For nelfinavir, the IQR of Ccalc was 896-2059 microg/L for three-times-daily administration and 998-2124 microg/L for twice-daily administration. Variabilities were high for both PIs. Intrapatient variability for indinavir alone (and indinavir + ritonavir) was 76% (107%) and interpatient variability was 58% (10%) in adherent patients. Intrapatient variability for nelfinavir three times daily (and twice daily) was 41% (74%) and interpatient variability was 62% (50%). Intrapatient variability was lowered in patients with a high adherence level.
  
  
  CONCLUSIONS
  Although performed in a homogeneous population, this study documented a high interpatient but also intrapatient variability of indinavir and nelfinavir pharmacokinetics, which should be taken into account when interpreting therapeutic drug monitoring. Once patients have reached a sustained virological response, plasma PI monitoring may have a limited impact.
authors.affiliation: Internal Medicine Unit, Bicêtre University Hospital, AP-HP, Kremlin Bicêtre, France. cecile.goujard@bct.aphp.fr
authors.forename: Cécile
authors.initials: C
authors.lastname: Goujard
authors.forename: Mayeule
authors.initials: M
authors.lastname: Legrand
authors.forename: Xavière
authors.initials: X
authors.lastname: Panhard
authors.forename: Bertrand
authors.initials: B
authors.lastname: Diquet
authors.forename: Xavier
authors.initials: X
authors.lastname: Duval
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vincent
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Catherine
authors.initials: C
authors.lastname: Leport
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Bonnet
authors.forename: Dominique
authors.initials: D
authors.lastname: Salmon-Céron
authors.forename: France
authors.initials: F
authors.lastname: Mentré
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
mesh_terms: D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D019469:Indinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D019888:Nelfinavir / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010349:Patient Compliance; D011446:Prospective Studies; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D017320:HIV Protease Inhibitors; C495123:hydroxy-t-butylamidenelfinavir; D019469:Indinavir; D019888:Nelfinavir; D019438:Ritonavir