Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumour growth.
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in improved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dual blockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity.
The pharmacokinetics (PK) of nivolumab is linear in the dose range of 0.1 to 10 mg/kg. The geometric mean clearance (CL), terminal half-life, and average exposure at steady state at 3 mg/kg every 2 weeks of nivolumab were 7.9 mL/h, 25.0 days, and 86.6 μg/mL, respectively, based on a population PK analysis.
Nivolumab CL in cHL patients was approximately 32% lower relative to NSCLC. Nivolumab baseline CL in adjuvant melanoma patients was approximately 40% lower and steady state CL approximately 20% lower relative to advanced melanoma. With available safety data, these decreases in CL were not clinically meaningful.
The metabolic pathway of nivolumab has not been characterised. Nivolumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
When nivolumab 1 mg/kg was administered in combination with ipilimumab 3 mg/kg, the CL of nivolumab was increased by 29% and the CL of ipilimumab was increased by 9%, which was not considered clinically relevant. When nivolumab 3 mg/kg was administered in combination with ipilimumab 1 mg/kg, the CL of nivolumab was increased by 1% and the CL of ipilimumab was decreased by 1.5%, which were not considered clinically relevant.
When administered in combination with ipilimumab, the CL of nivolumab increased by 20% in the presence of anti-nivolumab antibodies and the CL of ipilimumab increased by 5.7% in the presence of anti-ipilimumab antibodies. These changes were not considered clinically relevant.
When nivolumab 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks and with 2 cycles of chemotherapy, the CL of nivolumab decreased approximately 10% and the CL of ipilimumab increased approximately 22%, which were not considered clinically relevant.
A population PK analysis suggested no difference in CL of nivolumab based on age, gender, race, solid tumour type, tumour size, and hepatic impairment. Although ECOG status, baseline glomerular filtration rate (GFR), albumin, body weight, and mild hepatic impairment had an effect on nivolumab CL, the effect was not clinically meaningful.
For nivolumab monotherapy, the exposures of nivolumab in adolescents 12 years of age and older who weigh at least 50 kg are expected to be comparable to those in adult patients at the recommended dose. Body weight-based dosing is recommended for adolescents 12 years of age and older who weigh less than 50 kg.
For nivolumab in combination with ipilimumab, the exposures of nivolumab and ipilimumab in adolescents 12 years of age and older are expected to be comparable to those in adult patients at the recommended dose.
The effect of renal impairment on the CL of nivolumab was evaluated in patients with mild (GFR <90 and ≥60 mL/min/1.73 m²; n=379), moderate (GFR <60 and ≥30 mL/min/1.73 m²; n=179), or severe (GFR <30 and ≥15 mL/min/1.73 m²; n=2) renal impairment compared to patients with normal renal function (GFR ≥90 mL/min/1.73 m²; n=342) in population PK analyses. No clinically important differences in the CL of nivolumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Data from patients with severe renal impairment are too limited to draw conclusions on this population.
The effect of hepatic impairment on the CL of nivolumab was evaluated in patients with mild hepatic impairment (total bilirubin 1.0 × to 1.5 × ULN or AST > ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n=92) compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN; n=804) in the population PK analyses. No clinically important differences in the CL of nivolumab were found between patients with mild hepatic impairment and normal hepatic function. Nivolumab has not been studied in patients with moderate (total bilirubin >1.5 × to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin >3 × ULN and any AST).
Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to increase foetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis in the first trimester through delivery, at exposure levels either 8 or 35 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). There was a dose-dependent increase in foetal losses and increased neonatal mortality beginning in the third trimester.
The remaining offspring of nivolumab-treated females survived to scheduled termination, with no treatment-related clinical signs, alterations to normal development, organ-weight effects, or gross and microscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral, immunological, and clinical pathology parameters throughout the 6-month postnatal period were comparable to the control group. However, based on its mechanism of action, foetal exposure to nivolumab may increase the risk of developing immune-related disorders or altering the normal immune response and immune-related disorders have been reported in PD-1 knockout mice.
Fertility studies have not been performed with nivolumab.
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