OT-101 (Trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specifically inhibiting the expression of transforming growth factor-beta 2 (TGF-b2), whose overexpression is a pivotal factor for malignant progression in solid tumors. In the clinical Phase I/II study, plasma pharmacokinetic (PK) profile of OT-101 administered intravenously was evaluated in patients with advanced tumors. A population PK model was built to further understand the factors contributing to the variability in PK of OT-101.
A total of 61 patients with pancreatic cancer (n = 37), malignant melanoma (n = 19), or colorectal carcinoma (n = 5) were treated with OT-101 with escalating doses in 2 treatment schedules (1st schedule: 7-days-on/7-days-off; 2nd schedule: 4-days-on/10-days-off; up to 10 cycles). The plasma concentration data of OT-101 were analyzed using nonlinear mixed-effect modeling (Phoenix NLME 7.0). The influence of age, gender, body mass index (BMI), body weight (BW), cancer type, treatment schedule, creatinine clearance (CrCl) and estimated glomerular filtration rate (eGFR) as covariates on PK was evaluated.
With exclusion of protocol deviations, the final analysis dataset contained 92 patient cycles and 1188 plasma samples. Twenty-six patient cycles were from 7-days-on/7-days-off schedule and 66 were from 4-days-on/10-days-off schedule. The concentration time course of OT-101 was best described by a two-compartment model with combination of additive and multiplicative error. The estimates of PK parameters were as follows: total body clearance, 41.79 mL/hr; distribution volume of the central compartment, 6.30 L; inter-compartmental clearance, 4.02 L/hr; distribution volume of the peripheral compartment, 5965.83 L. eGFR were identified as the covariates on OT-101 central compartmental clearance, with KeGFR as 11.45.
The PK profile of OT-101 was best described by a two-compartment model. The model will be used with the sparse PK samples collected from the planned phase 3 clinical trial to calculate exposure measures for use in subsequent PK-PD analysis of efficacy.
Clinical trial identification
Legal entity responsible for the study
W. Wang, V. Trieu, L. Hwang: Employee of Oncotelic Inc. K. Ng, D. Nam: Employee of Autotelic Inc.