Toripalimab is a humanised IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumour immune response. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation, cytokine production, and cytotoxic activity.
Toripalimab pharmacokinetics were characterised using population PK analyses that included data from 574 patients across 5 clinical studies with various solid tumours who received fixed (80 to 480 mg Q2W or Q3W) or weight-based (range: 1 to 10 mg/kg Q2W) dosing, including 92 patients with NPC and 236 patients with OSCC who received toripalimab at doses of 240 mg every 3 weeks in JUPITER-02 and JUPITER-06, respectively.
Toripalimab pharmacokinetic parameters are presented as geometric mean (coefficient of variation [CV]%) unless otherwise noted.
Toripalimab is administered via the intravenous route; therefore, it is completely bioavailable.
Toripalimab is primarily distributed in the plasma with a geometric mean volume of distribution at steady state of approximately 3.8 L (CV=27.4%).
Dedicated metabolism studies were not performed. As a monoclonal antibody, toripalimab is expected to be metabolized into small peptides, amino acids, and small carbohydrates by catabolic pathways or by receptor-mediated endocytosis. The degradation products are eliminated by renal excretion or returned to the nutrient pool without biological effects.
Toripalimab pharmacokinetics followed a 2-compartment model with time-varying clearance (CL). The mean CL was 12.01 mL/h (CV=27%) after the first dose and 8.49 mL/h (CV=24.4%) at steady state. The geometric mean value (CV%) for the terminal half-life is 14 days (32.5%) at steady-state with toripalimab administered at 240 mg Q3W.
Exposure to toripalimab, as expressed by peak concentrations (Cmax), increased dose proportionally over the dose range of 80 to 480 mg Q2W. The geometric mean trough concentrations (Cmin) at steady state were estimated in the population PK model to be 26.3 μg/mL in patients receiving 240 mg every 3 weeks. The mean accumulation of Cmin at steady state is 2.7-fold compared to the Cmin after the first dose.
Toripalimab exposure-response relationships for efficacy are essentially flat over the range of exposures achieved for nasopharyngeal carcinoma in JUPITER-02 and for OSCC in JUPITER-06. The toripalimab exposure-response relationships for safety showed negative (inverse) relationships over the range of exposures achieved; however, this is likely an artifact reflecting toripalimab accumulation.
Anticipated full receptor occupancy of PD-1 in immune cells was achieved at exposures below mean trough concentrations after the first dose and steady state at dose of 240 mg Q3W.
No clinically significant differences in the pharmacokinetics of toripalimab were observed based on age (range: 19 to 85 years), body weight (range: 39 to 164 kg), sex, concomitant chemotherapy, mild or moderate renal impairment, mild hepatic impairment, tumour burden and primary cancer.
The effect of renal impairment based on the estimated creatinine clearance on the clearance and volume of distribution of toripalimab were evaluated using population pharmacokinetic analyses. No differences in clearance or volume of distribution were found between patients with mild (CLcr 60 to 89 mL/min; n=483) or moderate (CLcr 30 to 59 mL/min; n=114) renal impairment and patients with normal renal function. The effect of severe (CLcr 15 to 29 mL/min) renal impairment on the pharmacokinetics of toripalimab has not been studied.
The effects of hepatic impairment using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading system for hepatic dysfunction on the clearance and volume of distribution of toripalimab were evaluated using population pharmacokinetic analyses. No differences in clearance or volume of distribution were found between patients with mild (Grade 1, n=166) hepatic impairment (total bilirubin up to 1.5 times the upper limit of normal (ULN) or total bilirubin within normal limits and aspartate transaminase (AST) or alanine transaminase (ALT) >1 and ≤3 ULN) compared to patients with normal liver function. There was a limited number of patients with moderate (Grade 2, n=1; total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment and no patients with severe (Grade 3; total bilirubin >3 times ULN and any AST) hepatic impairment enrolled in clinical studies of toripalimab.
No studies have been performed to test the potential of toripalimab for carcinogenicity or genotoxicity.
Animal reproduction studies have not been conducted with toripalimab to evaluate its effect on reproduction and foetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the foetus. In murine models of pregnancy, blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in an increase in foetal loss.
Fertility studies have not been conducted with toripalimab. In 4-week and 26-week repeat-dose toxicology studies in cynomolgus monkeys, there were no adverse or notable effects in the male and female reproductive organs. However, those animals were unlikely sexually mature.
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