Clinical Pharmacokinetics of a Lipid-Based Formulation of Risperidone, VAL401: Analysis of a Single Dose in an Open-Label Trial of Late-Stage Cancer Patients

Abstract

Background and Objectives 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. Methods 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. Results 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 max , 2 h; C max , 8 ng/ml; half-life, 3.5 h; area under the plasma concentration–time curve from time zero to infinity (AUC 0–∞ ), 58.2 ng h 2 /mL. Conclusions 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 max 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. Electronic supplementary material The online version of this article (10.1007/s13318-018-00538-4) contains supplementary material, which is available to authorized users.

Comparison of COPD and Lung Cancer Mechanisms for Identifying MicroRNA Biomarkers By The Reconstruction of miRNA-mRNA Co-Expression Network

“…In addition, veli apon, imetit, iloperidone, bo apon, and bo apon sodium are identi ed as candidate drugs for target genes of common miRNAs in each disease, extraced from our drug-target interaction network, and among these candidate drugs, iloperidone could be considered as drug in treatment for both of diseases. It is reported a substantial increase in the oral bioavailability of iloperidone in rats and the presence of the lipid alters its absorption characteristics and has anti proliferative activities in cancers [55]. Moreover, iloperidone is currently under investigation for the treatment of some in ammatory diseases.…”

Friend or enemy? Review of 17β‐HSD10 and its role in human health or disease

“…In searching for anti‐cancer drugs targeting 17β‐HSD10, an FDA approved atypical antipsychotic risperidone was identified. It is now being evaluated in clinical trials to treat adenocarcinoma and prostate cancer (Dilly et al., 2019).…”

“…The novel combination of risperidone with rumenic acid, called VAL401, was tested and shown a significant slowdown of PC3 cell (prostate cancer cell line) proliferation in vitro and PC3‐induced tumor growth xenografts in vivo in mice (Dilly, Clark, et al., 2017a; Dilly et al. 2017b). Based on these data, VAL401 was assumed to be a repurposed drug for adenocarcinomas or prostate cancer and there has been a completed clinical trial stage II for lung cancer treatment using it in 2018 (Dilly et al., 2019).…”

“…2017b). Based on these data, VAL401 was assumed to be a repurposed drug for adenocarcinomas or prostate cancer and there has been a completed clinical trial stage II for lung cancer treatment using it in 2018 (Dilly et al., 2019).…”

“…Based on these findings, human 17β‐HSD10 is considered to be a potential drug target for certain cancer types (Ayan et al., 2012; He et al., 2001). However, there are no new findings in this area in recent years, except of profiling of risperidone (discussed further in section of inhibitors) as an anti‐cancer drug in clinical trials (Dilly et al., 2019). The role of 17β‐HSD10 in cancer is not thoroughly determined and further studies have to be performed to better understand its involvement.…”