Dilly Suzanne J, Morris George S, Taylor Paul C, Parmentier Frederic, Williams Coralie, Afshar Mohammad
ValiSeek Limited, 16 Upper Woburn Place, London, WC1H 0BS, UK.
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
Eur J Drug Metab Pharmacokinet. 2019 Aug;44(4):557-565. doi: 10.1007/s13318-018-00538-4.
A clinical trial was conducted to measure and analyse the pharmacokinetic parameters of a lipid formulation of risperidone, VAL401. The VAL401 formulation is designed to repurpose risperidone from an antipsychotic to an adenocarcinoma treatment, with the lipid formulation altering the cellular uptake of risperidone, thus enabling anticancer biology to be exhibited in preclinical testing.
This first human trial of VAL401 measured the concentrations of risperidone and its primary metabolite, 9-hydroxyrisperidone, in the blood of patients after treatment with a single 2-mg dose of VAL401.
The trial provided information on differences in the pharmacokinetic profile of risperidone in VAL401 that may be caused by the formulation and/or the nature of the cancer patient population. VAL401 provided the following key pharmacokinetic parameters for the risperidone plasma concentration after a single 2-mg dose of VAL401, with results normalised to a dosage of 1 mg for comparison with literature values: T, 2 h; C, 8 ng/ml; half-life, 3.5 h; area under the plasma concentration-time curve from time zero to infinity (AUC), 58.2 ng h/mL.
Further comparisons of the pharmacokinetic parameters of risperidone and 9-hydroxyrisperidone in plasma of patients administered VAL401 and the corresponding parameters obtained from published data for conventionally formulated risperidone provide evidence for altered biological processing of VAL401 as compared to risperidone. The absolute values obtained provide support for future studies of VAL401 as a cancer treatment, as the C demonstrates sufficient exposure to reach the concentrations seen during preclinical anticancer testing, yet the overall exposure to the active moiety supports the use of the safety and tolerability data from conventional risperidone during future clinical trials.
开展了一项临床试验，以测量和分析利培酮脂质制剂VAL401的药代动力学参数。VAL401制剂旨在将利培酮从抗精神病药物重新用于腺癌治疗，脂质制剂改变了利培酮的细胞摄取，从而使其在临床前试验中展现出抗癌生物学特性。
VAL401的首次人体试验测量了单次给予2毫克VAL401治疗后患者血液中利培酮及其主要代谢物9-羟基利培酮的浓度。
该试验提供了有关VAL401中利培酮药代动力学特征差异的信息，这些差异可能由制剂和/或癌症患者群体的性质引起。单次给予2毫克VAL401后，VAL401提供了利培酮血浆浓度的以下关键药代动力学参数，结果归一化为1毫克剂量以与文献值进行比较：达峰时间（T）为2小时；峰浓度（C）为8纳克/毫升；半衰期为3.5小时；从时间零至无穷大的血浆浓度-时间曲线下面积（AUC）为58.2纳克·小时/毫升。
对接受VAL401治疗患者血浆中利培酮和9-羟基利培酮的药代动力学参数与传统制剂利培酮已发表数据获得的相应参数进行进一步比较，为VAL401与利培酮相比生物过程改变提供了证据。所获得的绝对值为VAL401作为癌症治疗的未来研究提供了支持，因为峰浓度表明有足够的暴露量达到临床前抗癌试验期间所见的浓度，但活性部分的总体暴露量支持在未来临床试验中使用传统利培酮的安全性和耐受性数据。
