ObjectivesThis ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE).MethodsPatients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and ‘30 alternative’ definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing.ResultsNinety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL.ConclusionThe belimumab intravenous pharmacokinetics and benefit–risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate.Trial registration numberNCT01649765.

The population pharmacokinetics (PK) of belimumab were characterized in 1,603 patients with systemic lupus erythematosus receiving belimumab 1, 4, 10, or 20 mg/kg doses in Phase 1-3 trials. Belimumab PK were well described with a linear two-compartment model, with clearance from the central compartment (CL). Belimumab exposure was approximately dose-proportional. The estimated population terminal half-life was 19.4 days and steady-state volume of distribution (Vss) was 5.29 L for the currently approved 10 mg/kg dose used in the Phase 3 trials, with an estimated CL of 215 mL/day. No effects of age, sex, race, disease activity, co-medications, or baseline characteristics on belimumab PK were found to alter exposure in a manner requiring dose adjustment. An association observed between increasing baseline proteinuria and increasing CL may be clinically relevant in nephropathy with very high proteinuria levels. No evidence of target-mediated clearance was observed. Clinically relevant effects of body size (increased CL and V1 with increased body weight, and reduced V1 with increased body mass index) have been accounted for in current weight-normalized belimumab dosing.

A large-scale mathematical model, the Entelos Rheumatoid Arthritis (RA) PhysioLab platform, has been developed to describe the inflammatory and erosive processes in afflicted joints of people suffering from RA. The platform represents the life cycle of inflammatory cells, endothelium, synovial fibroblasts, and chondrocytes, as well as their products and interactions. The interplay between these processes culminates in clinically relevant measures for inflammation and erosion. The simulation model is deterministic, which allows tracing back the mechanism of action for a particular simulation result. Different patient phenotypes are represented by different virtual patients. The RA PhysioLab platform has been used to systematically and quantitatively study the predicted therapeutic effect of modulating several molecular targets, which resulted in a ranking of putative drug targets and a workflow to confirm the simulations experimentally. In addition, critical pathways were identified that drive the predicted disease outcome. Within these pathways, targets were identified from public literature that were not previously associated with arthritis. The model provides insights into the biology of RA and can be used as a platform for hypothesis-driven research. Case studies of therapies directed against IL-12 and IL-15 illustrate the approach, with emphasis on the analysis of system dynamics.

Ofatumumab is a human monoclonal antibody directed at CD20 approved for treatment of chronic lymphocytic leukemia. The population pharmacokinetics of intravenous ofatumumab were characterized in patients with relapsed/refractory chronic lymphocytic leukemia, relapsed/refractory follicular lymphoma, and rheumatoid arthritis, diseases with widely varying CD20⁺ B-cell counts in blood. Serum concentration data from a total of 477 patients who received ofatumumab doses ranging from 100 mg to 2000 mg in different dosing regimens were analyzed to determine the pharmacokinetic characteristics of ofatumumab across different patient groups and to identify factors contributing to the pharmacokinetic variability. Ofatumumab pharmacokinetics were well described by a linear two-compartment model component to represent non-specific monoclonal antibody clearance from the central compartment interacting with a model component representing the target-mediated clearance of ofatumumab by binding to CD20 expressed on B cells. The clearance (7.5 mL/h) and steady-state volume of distribution (5.3 L) for the linear, non-specific component were consistent with results obtained for other monoclonal antibodies. The target-mediated clearance component was related to the disease-specific number of circulating B cells, which will allow simulation of the contribution of target-mediated clearance to ofatumumab pharmacokinetics in untested disease states with data on B-cell counts and turnover.

The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results.

Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m 2 ) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 mg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 mg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 mg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168-78. Ó2013 AACR.

BackgroundBelimumab is a recombinant, human, IgG1λ monoclonal antibody that targets B-lymphocyte stimulator. The intravenous formulation is indicated for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Belimumab has been formulated for subcutaneous (SC) administration to improve patient convenience. This post-hoc modeling and simulation analysis characterizes the population pharmacokinetics (PK) of SC belimumab, and compares the exposure profiles of the approved belimumab IV dose—10 mg/kg every four weeks—to the 200 mg SC weekly dose in SLE patients, highlighting key pharmacological differences relevant for clinicians.MethodsData from two Phase 1 studies in US American and Japanese healthy subjects were analyzed with a non-linear mixed effects modeling approach. The resulting SC population PK model and a previously developed IV population PK model were used to conduct simulation trials in a Phase 3 IV belimumab SLE patient population, comparing chronic exposure profiles and exposure ranges stratified by body weight tertiles for IV vs SC dosing.ResultsThe PK of belimumab following SC administration was best described by a linear two-comment model. The estimates for clearance, steady-state volume of distribution, and bioavailability were 208 mL/day, 5250 mL, and 76%, respectively. After four weeks of SC dosing, simulated belimumab concentrations exceeded the steady-state trough concentrations of the IV dosing regimen. At steady state simulated serum profiles demonstrated comparable average belimumab concentrations (Cavg,ss) after IV and SC dosing. Simulated belimumab exposures demonstrated largely overlapping concentration ranges following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing.DiscussionThe predicted Cavg,ss of belimumab in SLE patients was comparable following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. The simulated belimumab accumulation following SC weekly dosing indicated that administration of a loading dose was not required. Similar Cavg,ss ranges were predicted for fixed dose SC and weight-proportional IV regimens in the simulated SLE population, albeit with a reversed body-size-to-exposure relationship for the SC regimen. These findings provide rheumatologists with a better understanding of expected differences in belimumab exposure when comparing IV and SC dosing regimens.

BackgroundIntravenous belimumab 10 mg/kg every 4 weeks is indicated in patients with active, autoantibody-positive systemic lupus erythematosus receiving standard systemic lupus erythematosus care. Subcutaneous 200-mg weekly administration, which may prove more convenient for patients and improve adherence, is currently under investigation.ObjectiveThe objective of this study was to characterize the population pharmacokinetics and exposure-efficacy response of subcutaneous belimumab in a pooled analysis of pharmacokinetic data [phase I: BEL114448 (NCT01583530) and BEL116119 (NCT01516450) in healthy subjects (n = 134); phase III: BEL112341 (NCT01484496) in adults with systemic lupus erythematosus (n = 554)] and pharmacodynamic data [BEL112341 in adults with systemic lupus erythematosus (n = 833)].MethodsNon-linear mixed-effects modeling (NONMEM®) was used to develop a population pharmacokinetic model and perform a covariate analysis. Subsequently, exploratory exposure-response analysis and logistic regression modeling was performed based on the individual parameter estimates of the population pharmacokinetic model. ResultsPopulation-pharmacokinetic parameters for subcutaneous belimumab were consistent with those for intravenous belimumab and other immunoglobulin G1 monoclonal antibodies. Pharmacokinetic parameters and subcutaneous belimumab exposure were consistent between healthy subjects and patients with systemic lupus erythematosus, and no evidence for target-mediated disposition of belimumab was found. Subcutaneous belimumab steady-state exposure was achieved after ~11 weeks; subcutaneous belimumab steady-state minimum concentration exceeded that of intravenous belimumab after <4 weeks, and average steady-state concentration was similar to that achieved following intravenous administration. In patients with moderate-to-severe systemic lupus erythematosus, subcutaneous belimumab 200 mg once weekly plus standard of care significantly improved the systemic lupus erythematosus responder index. However, at this dose, the systemic lupus erythematosus responder index response was not significantly associated with belimumab exposure concentrations.ConclusionThe analysis demonstrates that a 200-mg once-weekly dose of belimumab is appropriate for subcutaneous administration in patients with systemic lupus erythematosus and that no dose adjustments are required for adult patients to maintain efficacy and safety.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0586-5) contains supplementary material, which is available to authorized users.