Rituxan
rituximab
Species
Monkey
Longest study
8 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Cynomolgus monkey only
“For primary pharmacodynamics only experiments in non-human primates are relevant. Neither rodent nor canine B-cells bind rituximab.”
Why that species
Rodent and canine B-cells do not bind rituximab; single dose lyses monkey B-cells, showing relevant activity
“such studies are unnecessary because B-cells in cynomolgus monkeys are lysed by a single dose of rituximab, which is evidence of relevant activity even if affinity and CD20 expression may be different in humans and primates.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Weekly dose of rituximab up to 20 mg/kg (= 276 mg/m2 ) was generally well tolerated over up to 8 weeks of treatment in a further GLP toxicity study in Cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
8 weeks
“Weekly dose of rituximab up to 20 mg/kg (= 276 mg/m2 ) was generally well tolerated over up to 8 weeks of treatment in a further GLP toxicity study in Cynomolgus monkeys.”
Pivotal GLP studies
GLP cynomolgus monkey study, weekly IV up to 20 mg/kg for up to 8 weeks
“Weekly dose of rituximab up to 20 mg/kg (= 276 mg/m2 ) was generally well tolerated over up to 8 weeks of treatment in a further GLP toxicity study in Cynomolgus monkeys.”
Route in tox
IV
“Rituximab was given in all preclinical safety studies as an i.v. injection, and the formulation was well tolerated locally.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; omission considered justified
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
Carcinogenicity
Not conducted
“No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN or to determine potential effects on fertility in males or females.”
Reproductive & developmental
Monkey EFD and PPND: decreased B cells and immunosuppression in offspring, restored within 6 months postpartum
“Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.”
Safety pharmacology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First doseopen answer page →
First-in-human starting dose
Based on monkey pilot study relating multiple-dose rituximab exposure to B-cell depletion
“A repeated pilot pharmacology/toxicology experiment in Cynomolgus monkeys (using 16.8 mg/kg doses) demonstrated the relationship between exposure of multiple injections of rituximab to the degree of B–cell depletion in the peripheral blood and bone marrow, as well as within the lymphatic tissues. This experiment formed the basis for the initial dose escalating study in humans.”
NOAEL / key findings
No toxicity beyond expected B-cell depletion in blood and lymphoid tissues; no NOAEL stated
“No effect other than the expected pharmacological depletion of B–cells in peripheral blood as well as in lymphatic tissues was observed in toxicity studies.”
Risksopen answer page →
Immune & cytokine safety
B-cell depletion only; T-cells unaffected, no infections; monkey anti-chimeric antibodies formed
“T–cells or other cells of the non-CD20+ lymphocyte lineage were not affected in any of the experiments.”
Biodistribution & persistence
Half-life 3-7 days in rats and monkeys after single doses
“Single dose pharmacokinetics was performed in rats and cynomolgous monkeys. In both species t½ was 3-7 days.”
Modality-specific risk
Prolonged B-cell depletion; incomplete B-cell recovery 90 days post dose, low animal exposure, no long-term studies
“The major concerns were the low level of exposure in Cynomolgus as compared to human level of exposure (1:1) and the lack of long-term animal studies, since B-cell recovery was not complete 90 days post dose.”