van Veelen Ard, Gulikers Judith, Hendriks Lizza E L, Dursun Safiye, Ippel Juanita, Smit Egbert F, Dingemans Anne-Marie C, van Geel Robin, Croes Sander
Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Center+, P.O. BOX 5800 6202 AZ, Maastricht, the Netherlands; CARIM School for Cardiovascular Disease, Maastricht University Medical Center+, P.O. BOX 616 6200 MD, Maastricht, the Netherlands; Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, P.O. BOX 80082 3508 TB, Utrecht, the Netherlands.
Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Center+, P.O. BOX 5800 6202 AZ, Maastricht, the Netherlands; CARIM School for Cardiovascular Disease, Maastricht University Medical Center+, P.O. BOX 616 6200 MD, Maastricht, the Netherlands.
Lung Cancer. 2022 Sep;171:97-102. doi: 10.1016/j.lungcan.2022.07.012. Epub 2022 Jul 25.
Exposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor.
This was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22-26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2-4 months) of the boosting effect.
The mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC (AUC osimertinib + AUC AZ5104) was 60%, (range 19%-192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed.
Pharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.
奥希替尼是一种用于治疗非小细胞肺癌（NSCLC）的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），且存在一种敏感的EGFR突变，其血药浓度可能显著低于平均水平。我们评估了联合使用强效细胞色素P450 3A抑制剂考比司他是否能提高血浆水平。
这是一项药代动力学概念验证临床试验（OSIBOOST试验，NCT03858491）。奥希替尼治疗的NSCLC患者，若其奥希替尼血浆谷浓度较低（≤195 ng/mL）则符合入选标准。第1天，采用有限采样策略（四个样本）计算奥希替尼及其代谢产物（AZ5104）的血浆曲线下面积（AUC）。第2天开始考比司他联合治疗（150 mg，每日一次）。在第22 - 26天之间，测定第二个AUC。如果奥希替尼谷浓度仍≤195 ng/mL且无毒性，考比司他剂量可增加。主要终点是奥希替尼暴露量的增加，次要终点是毒性。在扩大准入阶段可继续使用考比司他，并对增强效果进行随访（2 - 4个月）。
11名入组患者的奥希替尼平均基线谷浓度为154 ng/mL。在所有患者中，加用考比司他导致奥希替尼暴露量增加。总AUC（AUC奥希替尼 + AUC AZ5104）的平均增加量为60%（范围19% - 192%）。增强效果随时间保持一致。未观察到≥2级毒性。
在NSCLC患者中，考比司他对奥希替尼进行药代动力学增强是可行的，且不增加毒性，尽管增强程度存在差异。
