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Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts.

ABSTRACT: Multiple myeloma is a fatal hematological malignancy with high rates of drug resistance and relapse. Vorinostat, a histone deacetylase inhibitor, has shown promise in enhancing efficacy when combined with current myeloma therapies. In this study, temporal changes of critical proteins and cell proliferation were measured in myeloma cells exposed to vorinostat. A model linking biomarker dynamics to cell proliferation was developed that captured vorinostat effects on signal transduction and cell viability. The model structure and parameters were fixed to describe tumor dynamics in vivo, and tumor-specific growth and death rate parameters were estimated. The signaling model captured tumor growth inhibition in murine xenografts for a range of dose levels and regimens. This model may be used as a mechanistic bridge to link vorinostat exposure to molecular events and pharmacodynamic (PD) outcomes. It may also provide a translational platform to explore vorinostat activity as a single agent and in combination regimens.

SUBMITTER: Nanavati C

PROVIDER: S-EPMC5702904 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts.

Nanavati Charvi C Ruszaj Donna D Mager Donald E DE

CPT: pharmacometrics & systems pharmacology 20171017 11

Multiple myeloma is a fatal hematological malignancy with high rates of drug resistance and relapse. Vorinostat, a histone deacetylase inhibitor, has shown promise in enhancing efficacy when combined with current myeloma therapies. In this study, temporal changes of critical proteins and cell proliferation were measured in myeloma cells exposed to vorinostat. A model linking biomarker dynamics to cell proliferation was developed that captured vorinostat effects on signal transduction and cell vi ...[more]

PMID: 29045072

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Project description:IntroductionDaratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes.MethodsFour clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure-efficacy and exposure-safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively.ResultsPharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events.ConclusionThese data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies.FundingJanssen Research & Development.

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Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts.

Publications

Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts.

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