Immunotoxicity evaluation of nelfinavir in rats.
The objective of these investigations was to determine whether exposure to the HIV-1 protease inhibitor nelfinavir compromises immune function in Sprague Dawley rats. Animals (20/sex per group) were exposed orally for 1 or 6 months to nelfinavir at doses of 0 (1% carboxymethylcellulose vehicle), 100, 300 or 1000 mg/kg per day. Animals were observed daily for morbidity/mortality and for clinical signs of toxicity. Body weights were recorded weekly (weeks 1-14) and then monthly thereafter and at study termination. At termination (1 month or 6 months; 10/sex per group), serum was collected and retained for toxicokinetic analysis. The spleen, thymus and liver were removed from each animal and weighed; thymuses and liver were discarded after weighing. Spleens were prepared and immunophenotyping, natural killer (NK) cell activity, and proliferative responses to mitogenic stimuli (e.g., concanavalin A, Salmonella typhimurium) were evaluated. There were no treatment-related effects on immune cell populations (absolute or percent values) or in proliferative responses. At the 1-month interval, a decrease in NK cell activity (0.45-fold control) was noted in male rats at 100 and 1000 mg/kg per day but not at the middle dose of 300 mg/kg per day. Female rats at 1 month were noted for an increase in NK cell activity (1.4-fold control) at 100 mg/kg per day, but there was no difference in the NK response between vehicle-treated animals and those exposed to higher doses of nelfinavir. No effects on NK activity were noted in female animals after 6 months of nelfinavir treatment. Assay difficulties prevented evaluation of male rats at the 6-month interval. Taken together, the absence of a dose-response effect for NK activity in male rats treated for 1 month, the lack of suppressive effects in females treated for either 1 or 6 months, and the unchanged splenic NK cell numbers in nelfinavir-treated animals at both 1 and 6 months suggest that the decreased NK activity noted in male rats at 1 month is not biologically relevant. It was therefore concluded that, under the experimental conditions used, oral treatment with nelfinavir for 1 or 6 months at doses up to 1000 mg/ kg per day is not immunosuppressive in rats. C8hr values following nelfinavir treatment at 1000 mg/kg per day for 6 months were between 1- and 2.7-fold the reported Cmax values in humans.
Burns-Naas
Leigh Ann
LA
Worldwide Safety Sciences, Pfizer Global Research and Development, San Diego, CA 92121, USA. Leighann.burns@pfizer.com
White
Kimber L
KL
McCay
J Ann
JA
Ivett
James
J
Webber
Stephanie
S
Zorbas
Mark
M
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D017320:HIV Protease Inhibitors / Q000276:immunology* / Q000633:toxicity*; D007107:Immune System / Q000187:drug effects; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D019888:Nelfinavir / Q000276:immunology* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000276:immunology
D017320:HIV Protease Inhibitors; D019888:Nelfinavir