Objectives To determine an optimized dosing regimen for IV golimumab in patients with active RA using population pharmacokinetic (PK) modeling and simulation.
Methods Two Phase 3 trials were performed for IV golimumab. In the first trial, IV infusions of 2 mg/kg golimumab every 12 weeks (Q12W) or 4 mg/kg Q12W with concomitant methotrexate (MTX) were investigated in RA patients. Population PK modeling was conducted using data from this first trial. Simulations were performed to identify an optimized IV regimen that would result in steady-state trough golimumab concentrations similar to the approved subcutaneous (SC) dosing regimen of 50 mg Q4W. Absolute bioavailability of 50% and Ka of 0.658 day-1 were used for simulating the SC golimumab profile. The dosing regimen for the second trial was then modified to shorten the dosing interval to Q8W.
Results In the first trial, although there were strong trends towards clinical benefit, the primary endpoint (ACR 50) was marginally missed. It was found that Q12W dosing was inadequate to maintain adequate trough golimumab concentrations at the later part of the dosing interval. Using population PK analysis, a two-compartmental IV infusion model with first-order elimination was developed. Parameter estimates for the model were: CL: 0.654 L/day; V1: 4.33 L; V2: 2.82 L and Q: 0.215 L/day. Simulations showed that IV golimumab 2 mg/kg Q8W + MTX and currently approved SC golimumab 50 mg Q4W + MTX resulted in similar steady-state trough golimumab concentrations. When the IV regimen of 2 mg/kg golimumab at Weeks 0, 4 followed by Q8W was studied in the second trial, the primary efficacy endpoint (ACR 20) was achieved.
Conclusions Population PK modeling and simulation aided in the determination of an optimized dosing regimen for IV golimumab in patients with active RA. Both observed data and population PK modeling and simulation corroborate the importance of maintaining adequate steady-state trough concentrations of golimumab for robust clinical efficacy.
Disclosure of Interest J. H. Leu Employee of: Janssen R & D, LLC, Z. Xu Employee of: Janssen R & D, LLC, C. Hu Employee of: Janssen R & D, LLC, A. Mendelsohn Employee of: Janssen R & D, LLC, J. Ford Employee of: Janssen R & D, LLC, H. M. Davis Employee of: Janssen R & D, LLC, H. Zhou Employee of: Janssen R & D, LLC