saquinavir and Diarrhea

The protease inhibitor saquinavir was administered to 100 human immunodeficiency virus type 1 (HIV-1)-infected patients as a single 600-mg oral dose (hard gelatin capsules) with a standard breakfast, including 200 ml of grapefruit juice, during an open-label trial to assess whether diarrhea and/or wasting syndrome has consequences on its pharmacokinetics. Three groups of patients were enrolled: group 1, asymptomatic patients (n = 30); group 2, AIDS symptomatic patients without body weight loss or diarrhea (n = 37); and group 3, AIDS symptomatic patients with severe body weight loss and/or diarrhea (n = 33). Clinical and biological data (covariates) were collected. A population approach was performed with three blood samples per patient to estimate the mean population pharmacokinetic parameters (clearance [CL]/oral bioavailability [F], V/F, k(a), and lag time) and the derived ones (k(el), C(max), T(max), and area under the curve [AUC]). The relationships between groups, exposure (i.e., estimated individual post hoc AUCs), and covariates were explored by using multiple linear regressions. A significant increase in median AUCs (165, 349, and 705 ng. h. ml(-1) for groups 1, 2, and 3, respectively [P < 0.0001]) was observed. The enhancement in saquinavir exposure could be due to the destruction of the transporters in enterocytes and/or to the enlargement of their tight junctions, allowing a paracellular crossing of saquinavir as the illness spreads. Because of grapefruit juice intake by every patient, no implication of CYP3A4 could be assessed. These results strongly suggest that, despite its low intrinsic oral bioavailability, saquinavir can be considered as a relevant treatment for HIV-1-infected patients with diarrhea and/or wasting syndrome. This must be evaluated in a long-term period.

Topics: Adult; Analysis of Variance; Anti-HIV Agents; Diarrhea; Female; HIV Infections; HIV Wasting Syndrome; HIV-1; Humans; Male; Models, Biological; Population; Saquinavir

To study the relationship between toxicity and the exposure to nelfinavir and saquinavir as part of a quadruple drug regimen.. The ADAM study is a randomized study to investigate the feasibility of induction-maintenance therapy in HIV-1 infection.. HIV-1-infected patients with no prior use of antiretroviral treatment started induction therapy consisting of stavudine + lamivudine + nelfinavir + saquinavir for a period of 26 weeks. Data regarding toxicity of the quadruple regimen and exposure to the protease inhibitors were collected.. Seven of the 65 patients enrolled had to switch therapy for reasons of toxicity within the first 26 weeks. Diarrhoea was frequently reported (49 of 65, one discontinuation), but could be relieved by using antidiarrhoeal agents. Laboratory monitoring revealed elevated liver enzymes (leading to four discontinuations) and mild to moderate elevations of triglycerides and cholesterol (nine and 23 of 65, respectively). The exposure to saquinavir and nelfinavir was lower than expected. Abdominal pain was associated with a higher exposure to nelfinavir or saquinavir. The association of nausea and abdominal distension with drug exposure appeared to vary over time.. The quadruple drug regimen was quite well tolerated. Diarrhoea was frequently reported but could be relieved by the use of antidiarrhoeal agents. In comparison with other protease inhibitor combinations, lipid abnormalities in plasma were infrequent and mild. With the exception of diarrhoea, all gastrointestinal complaints observed were found to be associated with the level of exposure to nelfinavir or saquinavir. The exposure to the protease inhibitors was relatively low, although the virologic efficacy of the regimen used was satisfactory.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Diarrhea; Drug Therapy, Combination; Female; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Liver; Male; Middle Aged; Nausea; Nelfinavir; Reverse Transcriptase Inhibitors; Saquinavir; Stavudine

Topics: Acquired Immunodeficiency Syndrome; Colon; Diarrhea; HIV Protease Inhibitors; HT29 Cells; Humans; Indinavir; Intestinal Absorption; Intestinal Mucosa; Nelfinavir; Ritonavir; Saquinavir

A retrospective study was performed to determine whether twice-daily ritonavir 400 mg plus twice-daily saquinavir 400 mg (ritonavir 400/saquinavir 400) was better tolerated than ritonavir 600 mg twice daily (ritonavir 600). A secondary objective was to determine whether the rate of discontinuation due to therapeutic failure differed between the two ritonavir regimens.. The study was a retrospective chart review. Data collected included ritonavir dose; length of ritonavir therapy; reason for discontinuation; HIV-1 RNA prior to and at discontinuation of ritonavir therapy; CD4+ count; and antiretroviral therapy prior to, concomitant with, and initiated after ritonavir therapy.. Patient charts were reviewed in a university teaching hospital clinic.. Patients were identified through a search of the pharmacy database from December 18, 1995, to December 18, 1997. Patients were > 18 years old, but not restricted by gender or race.. The main outcome measures were frequency of discontinuation of ritonavir due to intolerance or due to lack of therapeutic efficacy.. The search identified 116 patients, including 57 patients taking ritonavir 400/saquinavir 400 and 54 patients taking ritonavir 600. Five patients on other ritonavir regimens were excluded. Significantly fewer patients receiving ritonavir 400/saquinavir 400 (14%) discontinued ritonavir due to intolerance compared with ritonavir 600 (37%; p = 0.002). Discontinuations due to therapeutic failure were not significantly different: 8.8% for ritonavir 400/saquinavir 400 and 7.4% for ritonavir 600, despite the fact that ritonavir/saquinavir therapy followed another protease inhibitor in 41 patients (73.2%) compared with 12 patients (24.5%) for ritonavir 600 (p = 0.001).. Ritonavir 400/saquinavir 400 is better tolerated than ritonavir 600.

Topics: Adult; Anti-HIV Agents; Diarrhea; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy; Drug Therapy, Combination; Female; Gastrointestinal Diseases; HIV Infections; Humans; Male; Middle Aged; Nausea; Protease Inhibitors; Retrospective Studies; Ritonavir; Saquinavir; Treatment Outcome; Vomiting

Diarrhea due to infection with Microsporidium (M) or Cryptosporidium (C) raises significant therapeutic challenges in HIV-infected patients. The usefulness of protease inhibitor therapy was evaluated in 20 HIV-positive patients with positive tests for M and/or C. There were 17 men and three women with a mean age of 42.5 years (range, 26-64 years). Two patients had category B disease and 18 category C disease according to the 1993 CDC classification scheme (CD4 count before therapy, 72/mm3; mean viral burden, 4.6 log). Seventeen patients had chronic diarrhea (due to M in 12 cases and to C in five), and the remaining three patients were asymptomatic M carriers. Clinical symptoms resolved after addition to the antiretroviral regimen of indinavir (n = 17) or saquinavir (n = 3). Mean weight gain was 10.5 kg. Karnofsky's index improved. Twelve patients, including one of the three who were asymptomatic at baseline, had negative follow-up stool cultures. The mean CD4 count increase was 125/mm3, and the mean viral burden decrease was 1.285 log. These data suggest that protease inhibitors may be capable of eradicating M and/or C infection refractory to other treatments. The reason for this effect may involve partial restoration of immune function due to inhibition of HIV replication.

Topics: Adult; AIDS-Related Opportunistic Infections; Animals; Anti-HIV Agents; Cryptosporidiosis; Diarrhea; Drug Therapy, Combination; Feces; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunocompetence; Indinavir; Male; Microsporida; Microsporidiosis; Middle Aged; Reverse Transcriptase Inhibitors; Saquinavir; Treatment Outcome

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Delavirdine; Diarrhea; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Virus Replication; Zalcitabine; Zidovudine