First-in-Human Dose Selection for TU7710 through Pharmacokinetic and Pharmacodynamic Modeling and Simulation
Moon Hee Lee (1), InYoung Song (2), Minsun Lee (2), Ji-hyun Noh(2), Hyeong-Seok Lim (1)
(1) Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, (2) TiumBio, Seongnam, Republic of Korea
Objectives: TU7710 is a recombinant human coagulation factor VIIa, in which human transferrin is linked in order to increase half-life. Factor VIIa forms a complex with tissue factor present during bleeding, and this complex activates factor X into factor Xa. TU7710 was developed to treat bleeding in patients with hemophilia (factor VIII or IX deficiency) and factor VII deficiency. A phase 1 clinical trial of TU7710 in healthy volunteers pretreated with warfarin is planned. The maximum recommended starting dose for TU7710 calculated from no observed adverse effect level in the rat and monkey was 96.0 ug/kg. Through modeling and simulation, we aimed to predict factor Xa production at various doses of TU7710 and aid first-in-human dose selection and dose escalation.
Methods: A pharmacokinetic model of TU7710 was constructed based on the enzymatic activities observed in the mouse and rat after intravenous injection of TU7710. The animal pharmacokinetic parameters were used to estimate human pharmacokinetic parameters by allometry. A pharmacodynamic model of factor Xa production following intravenous administration of TU7710 was constructed using in vitro mechanism study data and human physiologic values from the literature[1-10]. By modeling the conversion of factor X to factor Xa using in vitro study data, enzyme kinetics parameters (association rate constant, dissociation rate constant, catalytic constant) of TU7710 and NovoSeven® were obtained. The pharmacokinetic and pharmacodynamic models were linked to complete a PK-PD model. Single intravenous doses of TU7710 at 2 to 19,200 ug/kg were simulated in three scenarios: healthy subjects with bleeding, healthy subjects without bleeding, and warfarin-pretreated healthy subjects without bleeding. Modeling and simulation were performed using NONMEM® version 7.5.
Results: A two-compartment pharmacokinetic model with proportional residual error well described the observed TU7710 activities in animals. The clearance, central and peripheral volumes of distribution of TU7710 in a 60 kg human body estimated by allometry were 0.48 L/h, 2.92 L and 0.85 L, respectively. Throughout the dose range, the 24-hour mean plasma factor Xa concentration after TU7710 administration was predicted to be significantly lower in healthy subjects without bleeding than in those with bleeding. The factor Xa production was estimated to be lower after warfarin pretreatment in healthy subjects without bleeding. The maximum increase (Emax) in 24-hour mean plasma factor Xa concentration was estimated as 570 nmole/L for healthy subjects with bleeding. The Emax values for healthy subjects without bleeding and warfarin-pretreated healthy subjects without bleeding were 4.6 nmole/L and 2.2 nmole/L, respectively. At the dose required to achieve 20 percent of response (ED20) in healthy subjects with bleeding, the efficacy was estimated to be 105.1 nmole/L.
Conclusions: Factor Xa production following TU7710 administration was successfully estimated through pharmacokinetic-pharmacodynamic modeling and simulation. The Emax in healthy subjects pretreated with warfarin was predicted to be much lower than the efficacy at ED20 in healthy subjects with bleeding. Based on these results, the first-in-human dose selection based on NOAEL is judged safe for healthy volunteers receiving warfarin pretreatment.
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