Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNF. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown.
No formal pharmacodynamic analyses of biologic response markers have been performed in patients exposed to ORENCIA as prophylaxis for aGVHD.

Pharmacokinetic Properties

12.3 Pharmacokinetics
Healthy Adults and Adult RA - Intravenous Administration
The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions of ORENCIA (see Table 6).



Table 6:           Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg ORENCIA Intravenous Infusion(s)

Healthy Subjects                   RA Patients
(After 10 mg/kg Single        (After 10 mg/kg Multiple
PK Parameter                                   Dose)                         Dosesa) n=13                           n=14
Peak Concentration (Cmax)                  292 (175-427)                  295 (171-398) [mcg/mL]
Terminal half-life (t1/2) [days]            16.7 (12-23)                   13.1 (8-25) Systemic clearance (CL)                   0.23 (0.16-0.30)               0.22 (0.13-0.47) [mL/h/kg]
Volume of distribution (Vss)              0.09 (0.06-0.13)               0.07 (0.02-0.13) [L/kg] a
Multiple intravenous infusions of ORENCIA were administered at days 1, 15, 30, and monthly thereafter.

The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable.
In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.
Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF antagonists did not influence abatacept clearance.
No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept.
Adult RA - Subcutaneous Administration

Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration was 79%.
Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and 
terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration.
Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients [see Adverse Reactions (6.3)].In this study, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing.
Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous ORENCIA in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight [see Dosage and Administration (2.1)]. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance.
Polyarticular Juvenile Idiopathic Arthritis - Intravenous Administration In Study JIA-1 among patients 6 to 17 years of age, the mean (range) steady state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL)[see Clinical Studies (14.2)]. Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight [see Dosage and Administration (2.2)]. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender.
Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance.
Adult Psoriatic Arthritis - Intravenous and Subcutaneous Administration In Study PsA-I, a dose ranging study, intravenous ORENCIA was administered at 3 mg/kg, weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg, or doses of 30 mg/kg on Days 1 and 15 followed by weight range-based dosing [see Clinical Studies (14.3)]. Following monthly intravenous ORENCIA administration, abatacept showed linear PK over the dose range in this study. At the weight-range –based dosing (see above), the steady state of abatacept was reached by Day 57 and the geometric mean (CV%) trough concentration (Cmin) was 24.3 mcg/mL (40.8%) at Day 169. In Study PsA-II following weekly subcutaneous administration of ORENCIA at 125 mg, the steady state of abatacept was reached at Day 57 and the geometric mean (CV%) Cmin was 25.6 mcg/mL (47.7%) at Day 169.
Consistent with the RA results, population pharmacokinetic analyses for abatacept in PsA patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight [see Dosage and Administration (2.3)]. In addition, relative to the RA patients with the same body weight, abatacept clearance in PsA patients was approximately 8% lower, resulting in higher abatacept exposures in patients with PsA. This slight difference in exposures, however, is not considered to be clinically meaningful.
Prophylaxis of Acute Graft versus Host Disease – Intravenous Administration 
Table 7:               Pharmacokinetic Parameters (Mean, Range) in Subjects Undergoing HSCT from a Matched or 1 Allele-Mismatched Unrelated Donor in
Study GVHD-1
7 of 8 Cohort                        8 of 8 Cohort n=42                                 n=73
PK Parameter

Minimum Concentration (Cmin) a                      59 (26-112)                           43 (25-73) [mcg/mL]

Peak Concentration (Cmax) [mcg/mL]                 221 (163-292)                        172 (107-254) 
Terminal half-life (t1/2) [days]                     20.6 (6-43)                         20.8 (12-38) 
Systemic clearance (CL) [mL/h/kg]                 0.26 (0.15-0.65)                     0.32 (0.18-0.56) Volume of distribution (Vss) [L/kg]               0.13 (0.08-0.27)                     0.17 (0.11-0.26) a
Cmin observed on Day 5 of the treatment period; n = 18 for the 7/8 Cohort; n = 32 for the 8/8 Cohort.
Cmax, t1/2, CL, and Vss are model predicted after first 10 mg/kg ORENCIA intravenous infusion.


In a study of patients who received ORENCIA for prophylaxis of acute Graft Versus Host Disease (aGVHD) aged 6 years and older, the geometric mean (%CV) trough concentrations (C min) of abatacept on Day 63 after transplant after 4 doses utilizing weight-based dosing of 10 mg/kg (maximum dose of 1,000 mg) administered on the day before transplantation (Day -1), followed by a dose on Day 5, 14, and 28 after transplant, were 22.5 mcg/mL (243.9 %CV) for recipients of 8 of 8 Human leukocyte antigen (HLA)-matched HSCTs from unrelated donors (URD), and 31.1 mcg/mL (114.4 %CV) for recipients of 7 of 8 HLA-matched HSCTs from unrelated donors (URD), respectively.
Population pharmacokinetic analyses in patients with aGVHD demonstrated that 7 of 8 HLA- matched HSCT recipients had 29% lower clearance compared to 8 of 8 HLA-matched HSCT recipients. Consistent with previous data, increasing body weight was associated with higher clearance of abatacept, while age (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate and calcineurin inhibitors (e.g., cyclosporine and tacrolimus), did not influence abatacept clearance.