Dostarlimab is a humanised mAb of the IgG4 isotype that binds to PD-1 receptors and blocks the interactions of binding with its ligands PD-L1 and PD-L2. The inhibition of PD-1 pathway-mediated immune response results in inhibition of T-cell function such as proliferation, cytokine production, and cytotoxic activity. Dostarlimab potentiates T-cell responses, including anti-tumour immuno responses through blockade of PD-1 binding to PD-L1 and PD-L2. In syngeneic mouse tumour models, blocking PD-1 activity resulted in decreased tumour growth.
Dostarlimab was characterised using population PK analysis from 546 patients with various solid tumours, including 150 patients with EC. When dosed at the recommended therapeutic dose (500 mg administered intravenously every 3 weeks for 4 doses, followed by 1,000 mg every 6 weeks), dostarlimab shows an approximate two-fold accumulation (Cmin) starting cycle 4 through cycle 12, consistent with the terminal half-life t(1/2).
Dostarlimab is administered via the intravenous route and therefore estimates of absorption are not applicable.
The mean volume of distribution of dostarlimab at steady state is approximately 5.3 L (CV % of 12.3 %).
Dostarlimab is a therapeutic mAb IgG4 that is expected to be catabolised into small peptides, amino acids, and small carbohydrates by lysosome through fluid-phase or receptor-mediated endocytosis. The degradation products are eliminated by renal excretion or returned to the nutrient pool without biological effects.
The mean clearance is 0.007 L/h (CV % of 31.3 %) at steady state. The t1/2 at steady state is 25.4 days (CV % of 24.0 %).
Exposure (both maximum concentration [Cmax] and the area under the concentration-time curve, [AUC0-tau] and [AUC0-inf]) was approximately dose proportional.
Based on exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety when doubling the exposure of dostarlimab. Full receptor occupancy as measured by both the direct PD-1 binding and interleukin 2 (IL-2) production functional assay was maintained throughout the dosing interval at the recommended therapeutic dosing regimen.
A population PK analysis of the patient data indicates that there are no clinically important effects of age (range: 24 to 86 years), gender or race, ethnicity, or tumour type on the clearance of dostarlimab.
Renal impairment was evaluated based on the estimated creatinine clearance [CLCR mL/min] (normal: CLCR ≥90 mL/min, n = 173; mild: CLCR = 60-89 mL/min, n = 210; moderate: CLCR = 30-59 mL/min, n = 90; severe: CLCR = 15-29 mL/min, n = 3 and ESRD: CLCR < 15 mL/min, n = 1). The effect of renal impairment on the clearance of dostarlimab was evaluated by population pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of dostarlimab were found between patients with mild or moderate renal impairment and patients with normal renal function. There are limited data in patients with severe renal impairment.
Hepatic impairment was evaluated as defined using the US National Cancer Institute criteria of hepatic dysfunction by total bilirubin and AST (Normal: total bilirubin (TB) & AST < = upper limit of normal (ULN), n = 425; mild: TB > ULN to 1.5 ULN or AST > ULN, n = 48; and moderate: TB > 1.5-3 ULN, any AST, n = 4). The effect of hepatic impairment on the clearance of dostarlimab was evaluated by population pharmacokinetic analyses in patients with mild hepatic impairment compared to patients with normal hepatic function. No clinically important differences in the clearance of dostarlimab were found between patients with mild hepatic impairment and normal hepatic function. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment.
Nonclinical data reveal no special hazard for humans based on repeat-dose toxicity studies of duration up to 3 months in the cynomolgus monkey. No studies have been performed to assess the potential of dostarlimab for carcinogenicity or genotoxicity. Animal reproduction and development toxicity studies have not been conducted with dostarlimab. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss. These results indicate a potential risk that administration of dostarlimab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.
No notable effects on the male and female reproductive organs were observed in monkeys in the 1-month and 3-month repeat-dose toxicology studies; however, these results may not be representative at all of the potential clinical risk because of the immaturity of the reproductive system of animals used in the studies. Therefore, fertility toxicity remains unknown.
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