COMPO, Inserm U1068 Centre de Recherche en Cancérologie de Marseille & Inria Sophia Antipolis, Marseille, France.
Oncologie multidisciplinaire et innovations thérapeutiques, Nord University Hospital of Marseille, Marseille, France.
CPT Pharmacometrics Syst Pharmacol. 2023 Nov;12(11):1795-1803. doi: 10.1002/psp4.13063.
Atezolizumab is an anti-PDL1 approved for treating lung cancer. A threshold of 6 μg/mL in plasma has been associated with target engagement. The extent to which patients could be overexposed with the standard 1200 mg q3w dosing remains unknown. Here, we monitored atezolizumab peak and trough levels in 27 real-world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic (PK) parameters were calculated using a population approach and optimal dosing-intervals were simulated with respect to the target trough levels. No patient had plasma levels below 6 μg/mL. The results showed that the mean trough level after the first treatment was 78.3 ± 17 μg/mL, that is, 13 times above the target concentration. The overall response rate was 55.5%. Low-grade immune-related adverse events was observed in 37% of patients. No relationship was found between exposure metrics of atezolizumab (i.e., minimum plasma concentration, maximum plasma concentration, and area under the curve) and pharmacodynamic end points (i.e., efficacy and toxicity). Further simulations suggest that the dosing interval could be extended from 21 days to 49 up to 136 days (mean: 85.7 days, i.e., q12w), while ensuring plasma levels still above the 6 μg/mL target threshold. This observational, real-world study suggests that the standard 1200 mg q3w fixed-dose regimen of atezolizumab results in significant overexposure in all the patients. This was not associated with increased side effects. As plasma levels largely exceed pharmacologically active concentrations, interindividual variability in PK parameters did not impact efficacy. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy.
阿特珠单抗是一种抗 PD-L1 药物，已被批准用于治疗肺癌。在血浆中，6μg/mL 被认为与药物靶标结合相关。目前尚不清楚标准的 1200mg、每 3 周给药 1 次的方案，在多大程度上会使患者药物暴露过度。在此，我们在 27 例接受阿特珠单抗治疗的肺癌患者中进行了常规治疗药物监测，监测了阿特珠单抗的血药峰浓度和谷浓度。采用群体药代动力学方法计算了个体药代动力学参数，并针对目标谷浓度模拟了最佳给药间隔。没有患者的血浆浓度低于 6μg/mL。结果显示，首次治疗后的平均谷浓度为 78.3±17μg/mL，即 13 倍于目标浓度。总的客观缓解率为 55.5%。37%的患者出现了低级别免疫相关不良事件。未发现阿特珠单抗的暴露指标（即最小血浆浓度、最大血浆浓度和曲线下面积）与药效学终点（即疗效和毒性）之间存在相关性。进一步的模拟表明，给药间隔可从 21 天延长至 49 天，甚至 136 天（平均 85.7 天，即每 12 周 1 次），同时确保血药浓度仍保持在 6μg/mL 以上的目标阈值。这项观察性的真实世界研究表明，在所有患者中，标准的 1200mg、每 3 周给药 1 次的固定剂量方案导致了显著的药物暴露过度，这与增加副作用无关。由于血药浓度大大超过了具有药理活性的浓度，因此个体间药代动力学参数的差异并不影响疗效。我们的数据表明，在与疗效相关的目标阈值基础上，可显著延长给药间隔。
