Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clin Transl Sci. 2021 Nov;14(6):2152-2160. doi: 10.1111/cts.13069. Epub 2021 Jun 1.
Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady-state exposures (area under the concentration curve from 0 to 12-h [AUC ]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m /dose) or a pharmacokinetically guided dose targeting an AUC between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in-target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.
索拉非尼可改善成人肝细胞癌的预后；然而，手足皮肤反应（HFSR）是索拉非尼的剂量限制毒性，限制了其应用。HFSR 与索拉非尼的全身暴露有关。本研究的目的是利用建模和模拟来确定使用药代动力学指导的剂量来达到预定的索拉非尼目标范围是否可以降低 HFSR 的发生率。使用已发表的索拉非尼药代动力学数据，模拟索拉非尼稳态暴露（从 0 到 12 小时的浓度曲线下面积[AUC]），固定剂量（90mg/m2/剂量）或药代动力学指导剂量靶向 AUC 在 20 至 55 小时µg/ml 之间。剂量要么舍入到最接近四分之一片（50mg）或胶囊（10mg）。先前发表的研究中的 Cox 比例风险模型用于量化 HFSR 毒性。模拟表明，在靶向研究中，从使用片剂的固定剂量的 50%增加到使用胶囊的药代动力学指导剂量的 74%。使用片剂的固定剂量观察到至少 4 名患者在目标范围内的可能性从 33%增加到使用胶囊的药代动力学指导剂量的 80%。预期的 HFSR 毒性发生率从使用片剂的固定剂量的 22%降低到使用胶囊的药代动力学指导剂量的 16%。使用片剂的固定剂量观察到 24 项研究中有 HFSR 毒性的可能性从 51%增加到使用胶囊的药代动力学指导剂量的 88%。我们的模拟提供了使用药代动力学指导的索拉非尼剂量来维持有效暴露的理由，这可能会提高儿科临床试验的耐受性。
