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Abstract for IMM98009

Immunotoxicity of Saquinavir in Female B6C3F1 Mice

CASRN: 149845-06-7
Chemical Formula: C38H50N6O5.CH4O3S
Molecular Weight: 766.9556
Report Date: October 2004


The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.

Saquinavir (SQV) is a protease inhibitor, targeted to interfere late in the viral life cycle during cleavage of the final viral protein element. The protease inhibitors bind to the catalytic site of the viral protease enzyme that plays a critical role in cleaving the large polyproteins of the immature virus. The protease inhibitors represent an alternate treatment for AIDS patients and, since the protease inhibitors act at a totally different site in the viral cycle, a combination treatment with nucleoside analogues may be effective. Reasons for concern are seen in the potential cross resistance between different protease inhibitors and the potential for drug interactions since the protease inhibitors are metabolized in the liver and some are potent inhibitors of cytochrome p4501.

Saquinavir was nominated to the NTP for toxicological evaluation and was selected for immunotoxicity studies by the project officer. Thus, the purpose of these studies was to determine the potential effects of SQV on the immune system.

The study reported herein was conducted in female B6C3F1 mice. The animals were treated twice daily for 28 days by oral gavage. The in-life phase of the study was conducted between 13 February 1998 and 03 September 1998. Saquinavir was prepared weekly as a solution in the vehicle 0.5% methylcellulose.

The baseline toxicology studies are summarized in Table ES-1. In this study of orally administered SQV at a total dose of 300, 600, and 1200 mg/kg/day for 28 days, there were no effects on body weight or on the rate of weight gain. There were few notable changes among the standard toxicological parameters that were assessed. The reticulocyte count was significantly decreased by 12% at the high dose (1200 mg/kg) level.

Table ES-2 summarizes the immunology studies. A statistically significant increase of 23% was observed at the high dose level of SQV in the absolute number of T cells. The immature CD4+CD8+ cells, when evaluated as absolute values, showed an increase of 46% and 92% at the middle and high dose levels, respectively. The humoral immune response was significantly increased by 41% for AFC/106 spleen cells at the high dose level; however, there was no effect on the anti-sRBC serum titer. There was no effect on cell-mediated immunity when evaluated by the mixed leukocyte (MLR) response. However, cytotoxic T-cell activity showed decreases ranging from 25% to 35% at the low dose level for effector-to-target ratios of 6.25:1, 12.5:1 and 25:1. Overall, Natural Killer cell activity was not altered in SQV-treated mice.

Table ES-3 summarizes the two host resistance studies that were conducted. Overall, exposure to SQV did not affect host resistance to Listeria monocytogenes; however, a statistically significant decrease in host resistance to Listeria monocytogenes was observed at the 600 mg/kg dose level for Challenge B. Exposure to SQV did not alter host resistance to the B16F10 melanoma tumor, a model system which evaluates effects on innate immunity, including natural killer cells and macrophages, as well as the cytotoxic T-cell population of cell-mediated immunity.


Table ES-1
Summary Table for Toxicology Studies
Parameter Overall Effect Specific Results Maximum Effect Dose Comment
Body Weight No Effect
Day 1 No Effect
Day 8 No Effect
Day 15 No Effect
Day 22 No Effect
Day 29 No Effect
Body Weight Changes No Effect
Day 8-1 No Effect
Day 15-1 No Effect
Day 22-1 No Effect
Day 29-1 No Effect
Organ Weights No Effect
Liver No Effect
Spleen No Effect
Lungs No Effect
Thymus No Effect
Kidney No Effect
Hematology No Effect
RBCs No Effect
Hemoglobin No Effect
Hematocrit No Effect
MCV No Effect
MCH No Effect
MCHC Increase 1% 600 mg/kg
Reticulocytes Decrease 12% 1200 mg/kg
Platelets No Effect
Leukocytes No Effect

Table ES-2
Summary Table for Immunology Studies
Parameter Overall Effect Specific Results Maximum Effect Dose Comment
Surface Makers (Absolute Values)
No Effect
Ig+ No Effect
CD3+ Increase 23% 1200 mg/kg
CD4+CD8- No Effect
CD4-CD8+ No Effect
CD4+CD8+ Increase 92% 1200 mg/kg
NK1.1+CD3- No Effect
Mac-3+ No Effect
IgM Humoral Immune Response to Sheep Erythrocytes
IgM AFC/106Cells Increase 41% 1200 mg/kg
Serum Titer No Effect
Mixed Leukocyte Response
No Effect
Responders Only No Effect
Responders + Stimulators No Effect
Total Cells x 107 No Effect
Cytotoxic T Lymphocyte Response
No Effect
6:1 Decrease 35% 300 mg/kg
12.5:1 Decrease 28% 300 mg/kg
25:1 Decrease 25% 300 mg/kg
NK Cell Activity
No Effect
200:1 No Effect
100:1 Decrease 20% 300 mg/kg
50:1 Decrease 27% 300 mg/kg
25:1 Decrease 27% 300 mg/kg
12.5:1 Decrease 31% 300 mg/kg
6.25:1 Decrease 40% 1200 mg/kg

Table ES-3
Summary Table for Host Resistance Studies
Parameter Overall Effect Specific Results Maximum Effect Dose Comment
Listeria monocytogenes No Effect Decrease 8% mortality 600 mg/kg Challenge B
B16F10 No Effect No Effect