Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuPH20

To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tocilizumab with and without rHuPH20 (a recombinant human hyaluronidase) in healthy volunteers.This was an open-label, single ascending dose study. Subjects were assigned to tocilizumab 162 mg or tocilizumab 162, 324, or 648 mg plus rHuPH20. PK and PD samples were collected after dosing and were estimated with non-compartmental methods. Geometric mean ratio (GMR) for area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and (maximum serum concentration) Cmax with and without rHuPH20 was estimated using one-way analysis of variance. Safety and tolerability were monitored throughout the study.48 subjects (12/cohort) received a single dose of tocilizumab with or without rHuPH20. For tocilizumab 162 mg, tocilizumab 162 mg/rHuPH20, tocilizumab 324 mg/rHuPH20, and tocilizumab 648 mg/rHuPH20, mean ± SD tocilizumab PK parameters were 2,510 ± 1,060, 2,860 ± 468, 10,800 ± 3,220, and 29,900 ± 5,280 μg×h/ml for AUC0-∞; 11.5 ± 3.7, 16.2 ± 2.8, 43.8 ± 12.4, and 77.8 ± 14.5 μg/ml for Cmax; and 89.1 ± 41.1, 54.0 ± 19.5, 66.0 ± 26.8, and 86.1 ± 50.6 h for tmax, respectively. Coadministration of tocilizumab 162 mg with rHuPH20 resulted in slightly increased exposure: GMR (90% confidence interval) for AUC0-∞, 1.20 (1.00 - 1.44) and Cmax, 1.45 (1.24 - 1.70). Increasing tocilizumab doses resulted in significant deviation from dose proportionality for tocilizumab Cmax (p = 0.0057) and AUC0-∞ (p < 0.0001). Changes in interleukin-6, soluble interleukin- 6 receptor, and C-reactive protein were also dose dependent and similar with and without rHuPH20.Tocilizumab in combination with rHuPH20 resulted in slightly increased tocilizumab exposure compared with tocilizumab alone, whereas PD markers were comparable. Subcutaneous administration of tocilizumab with rHuPH20 was well tolerated.