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.”
Species: general tox
Cynomolgus monkey only (single and multiple dose studies)
“Significantly, adverse reactions unrelated to the targeted effect were seen, neither in single nor in multiple dose studies in the Cynomolgus monkey.”
Species: DART
Cynomolgus monkey (embryo-fetal and subsequent pre- and postnatal studies)
“A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero.”
Species: 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.”
Surrogate used in
No surrogate used; only non-human primates relevant (rodent and canine B-cells do not bind rituximab)
“For primary pharmacodynamics only experiments in non-human primates are relevant. Neither rodent nor canine B-cells bind rituximab.”
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.
Genotox: Ames
Not conducted (ICH S6)
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
Genotox: in vivo
Not conducted (ICH S6)
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required: lack of carcinogenicity studies justified
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
hERG / QT
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.”
Anti-drug antibodies: animals
Anti-rituximab antibodies in monkeys may appear after 2 weeks, making long-term study results inconclusive
“In long-term administration studies the problem of immunogenicity of rituximab in Cynomolgus could make the results inconclusive. Antibodies against rituximab may appear after 2 weeks of treatment.”
Anti-drug antibodies: patients
1.1% (4/356) in low-grade/follicular NHL; 11% (273/2578) in RA
“Using an ELISA assay, anti-rituximab antibody was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent RITUXAN. Three of the four patients had an objective clinical response. A total of 273/2578 (11%) patients with RA tested positive for anti-rituximab antibodies at any time after receiving RITUXAN.”
Label warnings
Boxed warning: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
- Infusion-Related Reactions
- Severe Mucocutaneous Reactions
- Hepatitis B Virus (HBV) Reactivation
- Progressive Multifocal Leukoencephalopathy (PML)
- Tumor Lysis Syndrome (TLS)
- Infections
- Cardiovascular Adverse Reactions
- Renal Toxicity
- Bowel Obstruction and Perforation
- Immunization
- Embryo-Fetal Toxicity
- Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA, PV
- Use in RA Patients Who Have Not Had Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists
HepatotoxicityInfectionsHypersensitivity & infusion reactionsNeurotoxicitySkin reactionsSecondary malignancyCardiovascularNephrotoxicityGastrointestinalEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
Repeat-dose pilot pharmacology/toxicology study in cynomolgus monkeys (16.8 mg/kg doses); duration and recovery not stated
“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.”
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.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
8-week GLP cynomolgus monkey study, weekly IV up to 20 mg/kg; recovery not stated
“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.”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal and subsequent pre- and postnatal studies)
“A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero.”
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.”
PPND / ePPND: when
No reproductive studies at the initial marketing application (lack judged justified); cynomolgus monkey PPND done later
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
Carcinogenicity
Species: 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.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required: lack of carcinogenicity studies justified
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: monkey exposure about equal to human exposure (1:1)
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
B-cell depletion in normal cynomolgus monkeys (peripheral blood and lymphatic tissues)
“The B-cell depleting effect was demonstrated in Cynomolgus monkeys both in peripheral blood and lymphatic tissues.”
Why that model
Monkey anti-rituximab antibodies preclude xenograft studies; no animal model for antineoplastic effect
“Antibodies against rituximab may appear after 2 weeks of treatment. Therefore, no xenograft experiments are feasible. No animal model is available for evaluating the antineoplastic effect.”
Reviewer's view of the efficacy data
EMA: monkey data show only CD20 reduction; no in vivo proof of complement fixation, ADCC or cell killing
“The monkey experiments do not provide any evidence that rituximab can fix complement and mediate ADCC in vivo other than a reduction in CD20 counts. Experimental proof that cell killing really occurs has not been provided.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthCriticised but acceptedBeyond the letter
No long-term animal studies; observation limited to 90 days although B-cell recovery was incomplete
Why: Additional animal studies not indicated
“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.”
“The very short observation time (90 days) in animals is a clear-cut deficiency, but additional animal studies are not indicated.”
Safety marginVerdict not stated
No exposure margin: monkey toxicity study exposures similar to human exposure, based on Cmax only
“Only Cmax data are available suggesting that the exposure levels in the toxicity studies were similar to those attained in humans.”
DARTAcceptedBeyond the letter
No reproductive toxicity studies (nor genotoxicity or carcinogenicity)
“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”
Similar precedents
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