Translational Pharmacokinetic Model Research Articles

Abstract 4089: Quantitative prediction of human pharmacokinetics for duvortuxizumab from cynomolgus monkey data: a translational pharmacokinetic modeling approach

Abstract Duvortuxizumab (also known as JNJ-64052781 and MGD011) is a bispecific CD19 x CD3 DART® molecule designed to simultaneously target CD19-positive cells for recognition and elimination by CD3-expressing T-lymphocytes as effector cells. Duvortuxizumab is currently in clinical development for the potential treatment of B-cell malignancies. Here we report the results from a translational PK model that utilized duvortuxizumab pharmacokinetic (PK) data from cynomolgus monkeys to predict duvortuxizumab PK in humans. The PK of duvortuxizumab administered by intravenous infusion was evaluated in cynomolgus monkeys in two separate studies. Study 1 evaluated intra-animal escalating doses from 0.5 to 100 µg/kg or repeated doses from 0.005 to 0.5 µg/kg administered over a period of up to 4 weeks. Serum concentrations of duvortuxizumab above the lower limit of quantification were obtained at dose levels >0.5 µg/kg. Study 2 evaluated duvortuxizumab doses of 0.2, 2, 5, or 10 µg/kg administered once weekly for 4 weeks. Dose-proportional increases in maximum concentration (Cmax) were observed across the dose ranges evaluated, and no significant differences between male and female animals were observed. PK modeling analysis, which integrated data from both study 1 and study 2 at 0.2 to 100 µg/kg dose levels, was performed to further understand the PK behavior of duvortuxizumab in cynomolgus monkeys. Duvortuxizumab PK was reasonably characterized using a two compartment model with linear clearance (CL) from the central compartment. Model estimated parameters were CL = 0.797 mL/h/kg; volume of distribution for the central compartment (V1) = 51.7 mL/kg; intercompartmental clearance (Q) = 2.29 mL/h/kg; and volume of distribution for the peripheral compartment (V2) = 88.8 mL/kg. Assuming a body weight of 3 kg and 70 kg for a cynomolgus monkey and a human, respectively, human PK parameters were estimated using an allometric scaling factor of 0.75 for CL and 1.0 for volume in the translational PK model. Observed duvortuxizumab PK values obtained from an ongoing, first-in-human (FIH), phase 1 dose-escalation trial in patients with relapsed or refractory B-cell malignancies (NCT02454270) were used to validate the translational PK model. Comparison of the predicted and observed duvortuxizumab PK profiles suggested that the translational PK model using the allometric scaling method reasonably predicted duvortuxizumab PK profiles in humans at multiple dose levels (15 to 100 ng/kg). In conclusion, the developed translational PK model successfully predicted duvortuxizumab PK in humans and has been used to aid dose escalation of duvortuxizumab in the ongoing FIH study. This work showcases the potential of translational PK modeling in supporting the selection of a FIH dose escalation strategy utilizing preclinical PK information. Citation Format: Xiling Jiang, Hua Li, Jeff Nordstrom, Jennifer Brown, Liqin Liu, Syd Johnson, Ralph Alderson, Pamela L. Clemens, Jacintha Shenton, Imran Khan, Olivia Gardner, Yu-Nien Sun, Weirong Wang. Quantitative prediction of human pharmacokinetics for duvortuxizumab from cynomolgus monkey data: a translational pharmacokinetic modeling approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2017-4089

Translational pharmacokinetic modeling of fingolimod (FTY720) as a paradigm compound subject to sphingosine kinase-mediated phosphorylation.

A complicating factor in the translational pharmacology of sphingosine 1-phosphate agonists is that they exert their pharmacological effect through their respective phosphate metabolites, which are formed by the enzyme sphingosine kinase (S1PHK). In this investigation, we present a semimechanistic pharmacokinetic model for the interconversion of S1PHK substrates and their respective phosphates in rats and humans with the aim of investigating whether characterization of the rate of phosphorylation in blood platelets constitutes a basis for interspecies scaling using fingolimod as a model compound. Data on the time course of fingolimod and fingolimod-phosphate (fingolimod-P) blood concentrations after intravenous and oral administration of fingolimod and/or fingolimod-P in rats and after oral administration of fingolimod in doses of 0.5, 1.25, and 5 mg once daily in healthy volunteers were analyzed in conjunction with data on the ex vivo interconversion and blood-plasma distribution in rat and human blood, respectively. Integrating the data from the ex vivo and in vivo studies enabled simulation of fingolimod and fingolimod-P concentrations in plasma rather than blood, which are more relevant for characterizing drug effects. Large interspecies differences in the rate of phosphorylation between rats and humans were quantified. In human, phosphorylation of fingolimod in the platelets was four times slower compared with rat, whereas the dephosphorylation rates were comparable in both species. This partly explained the 10-12-fold overprediction of fingolimod-P exposure in human when applying a dose-by-factor approach on the developed rat model. Additionally, differences in presystemic phosphorylation should also be taken into account.