Abstract：
Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems.
Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments).
In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%).
Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.
Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments).
In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%).
Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.
摘要：
背景：口服靶向疗法显示了高的药代动力学（PK）患者间变异性。尽管暴露与许多这些药物的疗效呈正相关，这些仍然使用一刀切的方法给药。因此,个人曝光不足或曝光过度的可能性很高，可能导致次优结果。治疗药物监测，这是根据测量的全身药物浓度个性化给药，可以解决这些问题。
方法：患者被纳入这项前瞻性多中心研究（www.trialregister.nl；NL6695）如果他们开始使用24种参与的口服靶向疗法之一进行治疗。主要结果是将曝光不足患者的比例减半，与历史数据比较。在4、8和12周后进行PK采样，此后每12周。如果Cmin低于预定目标和可控制的毒性，提出了药代动力学指导的干预措施(即检查依从性和药物-药物相互作用，同时摄入食物，分裂摄入时刻或剂量增量)。
结果：总计，包括600名患者，其中426名患者可评估主要结果，552名患者具有≥1个PK样本，因此可评估总体分析。与历史数据相比，药代动力学指导的给药在第三次PK测量时将曝光不足患者的比例降低了39.0％（95％置信区间28.0％至49.0％）。在第三次PK测量时，426例患者中有110例（25.8%）暴露量较低。总的来说,294名患者(53.3%)在治疗期间的某个时间点具有低于预设目标的≥1个PK样本。其中166例患者（56.5%），进行了药代动力学指导的干预，在152名可评估的患者中，有113名成功（74.3%）。
结论：药代动力学指导的口服靶向治疗的剂量优化在临床实践中是可行的，并且大大降低了患者的比例。
方法：患者被纳入这项前瞻性多中心研究（www.trialregister.nl；NL6695）如果他们开始使用24种参与的口服靶向疗法之一进行治疗。主要结果是将曝光不足患者的比例减半，与历史数据比较。在4、8和12周后进行PK采样，此后每12周。如果Cmin低于预定目标和可控制的毒性，提出了药代动力学指导的干预措施(即检查依从性和药物-药物相互作用，同时摄入食物，分裂摄入时刻或剂量增量)。
结果：总计，包括600名患者，其中426名患者可评估主要结果，552名患者具有≥1个PK样本，因此可评估总体分析。与历史数据相比，药代动力学指导的给药在第三次PK测量时将曝光不足患者的比例降低了39.0％（95％置信区间28.0％至49.0％）。在第三次PK测量时，426例患者中有110例（25.8%）暴露量较低。总的来说,294名患者(53.3%)在治疗期间的某个时间点具有低于预设目标的≥1个PK样本。其中166例患者（56.5%），进行了药代动力学指导的干预，在152名可评估的患者中，有113名成功（74.3%）。
结论：药代动力学指导的口服靶向治疗的剂量优化在临床实践中是可行的，并且大大降低了患者的比例。
