title: Pharmacokinetics of two randomized trials evaluating the safety and efficacy of indinavir, saquinavir and lopinavir in combination with low-dose ritonavir: the MaxCmin1 and 2 trials.
abstract: Our objective was to identify possible differences in protease inhibitor plasma concentrations between and within three protease inhibitor regimens (indinavir, saquinavir and lopinavir all in combination with low-dose ritonavir) and to relate these differences to safety and efficacy. Data originated from pre-defined pharmacokinetic substudies within two randomized 48-week trials evaluating the safety and efficacy of three protease inhibitor regimens. At weeks 4 and 48, plasma was collected and minimum drug plasma concentrations, C(min), were obtained. Out of 656 randomized patients, 283 patients had available C(min) at week 4. Indinavir, saquinavir and lopinavir C(min) were high when combined with low-dose ritonavir. No significant difference in the proportion of patients experiencing treatment failure could be found according to the C(min) within any treatment arm. A saquinavir C(min) > 2000 ng/ml was associated with an increased risk of gastrointestinal grade 3 or 4 adverse events and higher total cholesterol. Overall, there were no changes in C(min) from week 4 to week 48 in patients who remained on therapy. No association between treatment failure and the C(min) could be demonstrated. Associations between high C(min) and toxicity were identified in the saquinavir arm; therefore, dose reductions may be appropriate in certain patients with C(min) several times above the minimum effective concentration.
authors.affiliation: Department of Infectious Diseases, Odense University Hospital, Odense C, Denmark. ujustesen@health.sdu.dk
authors.forename: Ulrik S
authors.initials: US
authors.lastname: Justesen
authors.forename: Zoe
authors.initials: Z
authors.lastname: Fox
authors.forename: Court
authors.initials: C
authors.lastname: Pedersen
authors.forename: Pedro
authors.initials: P
authors.lastname: Cahn
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.forename: Nathan
authors.initials: N
authors.lastname: Clumeck
authors.forename: Marcello
authors.initials: M
authors.lastname: Losso
authors.forename: Barry
authors.initials: B
authors.lastname: Peters
authors.forename: Niels
authors.initials: N
authors.lastname: Obel
authors.forename: Antonella
authors.initials: A
authors.lastname: Castagna
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Dragsted
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015497:HIV-1; D006801:Humans; D019469:Indinavir / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D011744:Pyrimidinones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use*; D019258:Saquinavir / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019469:Indinavir; D019258:Saquinavir; D019438:Ritonavir