Intravenous Infusion in Adults

Systemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table 3 are based on population parameter estimates from 563 adult patients who received BENLYSTA 10 mg/kg.

Lupus Nephritis: A population pharmacokinetic analysis was conducted in 224 adult patients with lupus nephritis who received belimumab 10 mg/kg intravenously (Days 0, 14, 28, and then every 28 days up to 104 weeks) plus standard therapy [see Clinical Studies (14.2)]. In patients with lupus nephritis, due to additional clearance associated with proteinuria, belimumab exposure was initially lower than observed in SLE studies and lower belimumab exposure was observed in patients with higher proteinuria. When the proteinuria was decreased to approximately ≤1 g/g after treatment, belimumab clearance and exposure were similar to that observed in patients with SLE who received belimumab 10 mg/kg intravenously. The available data do not support a dose adjustment in patients with high proteinuria.

Subcutaneous Injection in Adults

Systemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table 4 are based on population parameter estimates from 661 subjects after subcutaneous administration of belimumab 200 mg once weekly. The time to reach maximum serum concentration (Cmax) was 2.6 days (Tmax) after administration at steady state. The bioavailability of belimumab was approximately 74%. With weekly subcutaneous administration there were minor fluctuations around the average concentration (Cavg 104 mcg/mL), with Cmin (97 mcg/mL) being only slightly below Cavg.

Lupus Nephritis: Based on population pharmacokinetic modeling and simulation of the subcutaneous 400-mg weekly loading dose, the average belimumab concentration during the first 12 weeks was predicted to be 78 mcg/mL, which is similar to the estimated concentration of 89 mcg/mL for intravenous administration. The loading dose of 400 mg weekly provides steady-state concentrations from Week 2 of dosing. The steady-state average concentrations of subcutaneous administration of belimumab 200 mg once weekly in adults with lupus nephritis are predicted to be similar to those observed in adults with lupus nephritis receiving belimumab 10 mg/kg intravenously every 4 weeks.

Specific Populations

The following information is based on the population pharmacokinetic analyses of intravenous administration and subcutaneous administration of BENLYSTA.

Age: Age did not significantly influence the pharmacokinetics of belimumab, where the majority of subjects were between 18 and 45 years of age (70% with intravenous dosing; 74% with subcutaneous dosing).

Geriatric Patients: Limited pharmacokinetic data are available for elderly patients as less than 2% of the subjects included in the pharmacokinetic analysis were 65 years of age or older [see Use in Specific Populations (8.5)].

Pediatric Patients: The pharmacokinetic parameters of belimumab after intravenous administration, are based on individual parameter estimates from a population pharmacokinetic analysis of 53 pediatric patients with SLE (Trial 6). Following IV administration of 10 mg/kg on Days 0, 14, and 28, and at 4‑week intervals thereafter, belimumab exposures were similar between pediatric and adult subjects with SLE. Steady-state geometric mean Cmax, Cmin, Cavg, and AUC values were 305, 42, 92 mcg/mL, and 2,569 day•mcg/mL in the 5- to 11-year-old group, and 317, 52, 112 mcg/mL and 3,126 day•mcg/mL in the 12- to 17-year-old group. [See Use in Specific Populations (8.4).]

The pharmacokinetic parameters of belimumab, following subcutaneous administration, are based on a population pharmacokinetic analysis derived from 25 pediatric patients with SLE who received BENLYSTA subcutaneously and Trial 6 (a Phase II study in pediatric patients with SLE receiving BENLYSTA intravenously). Following subcutaneous administration of 200 mg of BENLYSTA in pediatric patients 5 to less than 18 years of age, either weekly (patients weighing ≥40 kg) or every 2 weeks (patients weighing 15 to <40 kg), the steady state average belimumab concentration is estimated to be similar to that of adult subjects with SLE following subcutaneous administration of 200 mg weekly and similar to that of pediatric subjects with SLE following intravenous administration of 10 mg/kg BENLYSTA on Days 0, 14, and 28, and at 4‑week intervals thereafter. Simulated steady-state geometric mean Cmax and AUC are estimated to be 110 mcg/mL and 1,328 day•mcg/mL for pediatric patients (weighing 15 to <40 kg) receiving BENLYSTA every 2 weeks, and 134 mcg/mL and 899 day•mcg/mL for pediatric patients (weighing ≥40 kg) receiving BENLYSTA once weekly. [See Use in Specific Populations (8.4).]

For active lupus nephritis, the pharmacokinetics of belimumab, following intravenous administration in pediatric patients, were estimated based on a population pharmacokinetic model developed from 224 adults with active lupus nephritis and validated using data from 53 pediatric patients with SLE. With IV administration of 10 mg/kg on Days 0, 14, and 28 and at 4-week intervals thereafter, the simulated belimumab exposures for both the 5- to 11-year-old group and the 12- to 17-year-old group were estimated to be comparable to adults with active lupus nephritis. [See Use in Specific Populations (8.4).]

Male and Female Patients: Gender did not significantly influence belimumab pharmacokinetics in the largely female trial population (94% with intravenous dosing; 85% with subcutaneous dosing).

Racial Groups: Race did not significantly influence belimumab pharmacokinetics. The racial distribution with intravenous administration was 53% White, 16% Asian, 16% Alaska native/American Indian, and 14% Black in Trials 1, 2, and 3. Trial 4 enrolled only Black patients. The racial distribution with subcutaneous administration (Trial 7) was 61% White, 20% Asian, 11% Black, and 6% Alaska native/American Indian.

Weight: Body weight and body mass index (BMI) had no clinically relevant effect on the pharmacokinetics of belimumab administered subcutaneously in adults. No dose adjustment is recommended in adults based on weight or BMI for subcutaneous administration.

The effects of body weight on belimumab exposure, after subcutaneous administration in pediatric patients, have been determined using a population pharmacokinetic model. Pediatric patients with lower body weight have lower belimumab clearance and volume of distribution. To ensure belimumab exposures remain within acceptable limits and are consistent across the pediatric weight range, patients with lower body weight are given BENLYSTA less frequently. [See Dosage and Administration (2.3).]

Patients with Renal Impairment: No formal trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. BENLYSTA was studied in a limited number of adult patients with SLE who had mild (CrCl ≥60 and <90 mL/min), moderate (CrCl ≥30 and <60 mL/min), or severe (CrCl ≥15 and <30 mL/min) renal impairment: 770 patients with mild renal impairment, 261 patients with moderate renal impairment, and 14 patients with severe renal impairment received belimumab intravenously; 121 patients with mild renal impairment and 30 patients with moderate renal impairment received belimumab subcutaneously. [See Use in Specific Populations (8.6).]

Patients with Hepatic Impairment: No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels did not significantly influence belimumab pharmacokinetics. [See Use in Specific Populations (8.7).]

Drug Interaction Studies

No formal drug interaction studies have been conducted with BENLYSTA. Concomitant use of mycophenolate, cyclophosphamide, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and/or HMG-CoA reductase inhibitors did not significantly influence belimumab pharmacokinetics. Coadministration of steroids and angiotensin-converting enzyme (ACE) inhibitors resulted in an increase of systemic clearance of belimumab that was not clinically significant because the magnitude was well within the range of normal variability of clearance. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated.