AB0553 Switching from SC to IV abatacept: Pharmacokinetic simulations to support dose regimen. (23rd January 2014) - Tagen, M.
Abstract : Background: Abatacept (ABA) is a selective T-cell co-stimulation modulator approved in the US for RA, available in both IV and SC formulations. There is a need to establish a safe and effective dosing regimen for patients (pts) who receive SC ABA (125 mg, administered weekly) to switch to IV ABA (weight-tiered dose approximating 10 mg/kg, administered every 4 weeks). Objectives: To identify a dosing regimen that allows pts to switch from SC to IV administration of ABA while maintaining serum concentrations of ABA in a safe and effective range. Methods: A population pharmacokinetic (PPK) model was used to explore different regimens for switching from SC to IV dosing. The PPK model was previously developed and qualified using IV and SC ABA concentration data from 2244 pts with RA. 1 ABA serum concentration–time (C-T) profiles were simulated for 1000 virtual subjects with body weights between 40 and 150 kg. Simulated regimens included switching to IV dosing either 7 or 14 days after the last SC dose. Exposure measures (Cmax, Cavg and Cmin ) were calculated for the last SC profile before switch and the first IV profile after switch, and were evaluated within weight groups of <60 kg, 60 to <100 kg, and ≥100 kg (corresponding to the recommended IV dosing weight-tiers). Switch regimens were evaluated in order to maintain a Cmin >10 μg/mL (associated with near maximal efficacy for ABA). Predicted exposures from the switch regimens were also compared with predicted exposures from two reference regimens for which there is clinical experience: steady-state IV dosing (every 28 days) and the standard IV dosing schedule with an IV load on days 1, 15 and 29. Results: After the last SC dose, the Day-7 switching regimen is predicted to achieve a greater proportion of subjects (92%) with a Cmin >10 μg/mL compared with 67% with the Day-14 regimen. Predicted Cmax, Cmin and Cavg distributions after the first IV dose for the Day-7 switching regimen were comparable to the distributions from IV steady-state dosing for the middle and high body-weight groups. Within the low body-weight group, distributions of ABA exposures after the first IV dose for the switch regimens were higher than the distributions from IV steady-state dosing. However, they did not exceed exposure distributions from the Day-29 dose of the standard IV loading regimen. Conclusions: With the Day-7 switch recommendation, the predicted abatacept exposures are within the range associated with the established safety and efficacy profile for IV abatacept. If a switch from SC to IV abatacept is required, these results support administration of IV abatacept at the recommended body-weight-tiered dose 7 days after administration of the last SC dose for pts of all body weights. References: Zhou Z, Gao L, Murthy B, Kaul S, Roy A. Population pharmacokinetics of subcutaneously administered abatacept in rheumatoid arthritis patients. Poster presented at AAPS National Biotechnology Conference, May, 2011, San Francisco. Disclosure of Interest: M. Tagen Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, B. Murthy Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, I. Delaet Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, C. Karyekar Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Roy Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb