Joyce Ford

Population Pharmacokinetics of Infliximab in Patients With Ankylosing Spondylitis

The population pharmacokinetics of infliximab were characterized in patients with active ankylosing spondylitis (n =274). Serum infliximab concentration data, from a 2‐year period, were analyzed using NONMEM. A 2‐compartment linear pharmacokinetic model was chosen to describe the pharmacokinetic characteristics of infliximab in serum. Population estimates (typical value ± standard error) were obtained from the final covariate model: clearance (CL: 0.273 ± 0.007 L/day), volume of distribution in the central compartment (V1: 3.06 ± 0.057 L), intercompartment clearance (Q: 1.72 ± 0.48 L/day), and volume of distribution in the peripheral compartment (V2:2.94 ± 0.17 L). Interindividual variability for CL and V1 was 34.1% and 17.5%, respectively. White blood cell count at baseline and the antibody‐to‐infliximab status were significant covariates to CL; body surface area and sex were significant covariates to V1. The CL for patients with a positive antibody‐to‐infliximab status was estimated to be 41.9% to 76.7% higher than for the remaining patients. Other covariates (baseline disease activity and the concomitant medication use of prednisolone, omeprazole, nonsteroidal anti‐inflammatory drugs, or analgesics) did not affect infliximab pharmacokinetics. The development of antibodies to infliximab was associated with accelerated infliximab clearance and may represent a potential underlying mechanism for an inadequate response, or loss of response, to infliximab treatment.

Golimumab Pharmacokinetics After Repeated Subcutaneous and Intravenous Administrations in Patients with Rheumatoid Arthritis and the Effect of Concomitant Methotrexate: An Open-Label, Randomized Study

BACKGROUND The pharmacokinetics of golimumab, a human monoclonal antibody that inhibits the activity of tumor necrosis factor α, after a single subcutaneous (SC) or intravenous (IV) administration have been previously studied. OBJECTIVES The purpose of this study was to assess the pharmacokinetics of golimumab after multiple SC or IV administrations in patients with active rheumatoid arthritis (RA). The effect of concomitant methotrexate (MTX) use on golimumab pharmacokinetics was evaluated. METHODS In this open-label, randomized, Phase I study, 49 adult patients with RA received SC golimumab 100 mg (n = 33) every 4 weeks through week 20 or IV golimumab 2 mg/kg (n = 16) at weeks 0 and 12. Serial blood samples were collected, and serum golimumab concentration was measured with an electrochemiluminescent immunoassay. Golimumab pharmacokinetic parameters were derived with the use of a noncompartmental analysis. Adverse events were monitored at every visit. RESULTS The population was predominantly Caucasian (84%) and female (76%), and the median age was 57 years. After SC golimumab administration, the serum golimumab concentration achieved steady state by ∼12 weeks with mean trough serum concentrations ranging from 1.15 to 1.24 μg/mL. After the final 30-minute IV infusion of golimumab 2 mg/kg, the mean (SD) clearance (CL) was 7.5 (2.6) mL/d/kg. The mean terminal half-life after SC and IV administrations was ∼13 days. The mean absolute bioavailability for SC golimumab was estimated to be 53%. The geometric mean of golimumab CL/F in patients with and without concomitant MTX use was 13.9 and 21.2 mL/d/kg, respectively, and the geometric mean ratio of CL/F was 65.5% (90% CI: 45.2%-94.9%, P = 0.06). Golimumab was generally well tolerated. No malignancies or deaths occurred during the study. CONCLUSIONS Pharmacokinetics of golimumab were consistent after SC or IV administration in this population of patients with RA. Golimumab was well tolerated and no unexpected adverse events were observed in this trial.

Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase 3 study.

Background:To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). Methods:This phase 3, randomized, open-label multicenter study enrolled 60 children (6–17 yr) with moderate-to-severely active UC (Mayo score, 6–12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every 8 weeks (q8w) through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. Results:Infliximab pharmacokinetics were not influenced by age (6–11 yr versus 12–17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 &mgr;g/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 &mgr;g/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 &mgr;g/mL) versus q12w (0.8 &mgr;g/mL) and with infliximab 10 mg/kg (2.9 &mgr;g/mL) versus 5 mg/kg (1.1 &mgr;g/mL) among patients who are regimen adjusted. Conclusions:Infliximab pharmacokinetics/exposure–response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.

Lack of Racial Differences in the Pharmacokinetics of Subcutaneous Golimumab in Healthy Japanese and Caucasian Male Subjects

This phase 1 study evaluated the single‐dose pharmacokinetics and safety of subcutaneous golimumab, a human anti—tumor necrosis factor‐α monoclonal antibody, in healthy Japanese and Caucasian subjects. Eligible subjects were males, aged 20 to 45 years, weighing 50 to 90 kg with a body mass index of 19 to 30 kg/m2. Japanese and Caucasian subjects were matched by body weight and dose group. Blood samples were collected through day 50 following a single subcutaneous injection of golimumab 50 or 100 mg. The pharmacokinetic parameters were determined using a noncompartmental method. All 51 subjects (24 Japanese, 27 Caucasian) were included in the safety analysis; 47 completed the study and were included in the pharmacokinetic analysis. The pharmacokinetics of golimumab were comparable in both race groups. Peak concentrations were observed ∼4 to 6 days after administration. No significant differences in exposure or mean half‐life (range, 11–13 days) were observed between Japanese and Caucasian subjects at the same dose level. Regardless of race, serum golimumab exposure increased with increasing dose. Mean apparent clearance ranged from 12 to 19 mL/kg/d. Mean apparent volume of distribution (224–262 mL/kg) remained constant with an increase in dose. No antibodies to golimumab were detected. Single subcutaneous injections of golimumab 50 mg or 100 mg were generally well tolerated in these healthy male Japanese and Caucasian subjects.

A phase 1, randomized study to assess the pharmacokinetic comparability of siltuximab derived from two different cell lines in healthy subjects

Siltuximab, a monoclonal antibody (mAb) against interleukin (IL‐6), is under development by Janssen Research & Development, LLC. During early clinical development, siltuximab was produced in a murine Sp2/0 myeloma cell line. The production cell line was switched to stably transfected Chinese hamster ovary (CHO) cell line for subsequent clinical development. A two‐part, parallel‐group, phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of a single IV administration of Sp2/0‐ and CHO‐derived siltuximab in healthy subjects. The results from this study demonstrated PK comparability of siltuximab produced from Sp2/0 and CHO cell lines. The 90% confidence interval of the ratios of geometric means of Cmax and AUC0–84day following 1.4 mg/kg doses was (99.4%, 111.3%) and (98.1%, 109.6%), respectively, both within the pre‐specified comparability range of 80–125%. Siltuximab derived from either the Sp2/0 or CHO cell lines was in general well tolerated and was not found to be immunogenic in this study.

A36: Long‐term Pharmacokinetics of Body Surface Area‐Adjusted Doses of Golimumab Following Repeated Subcutaneous Administrations in Pediatric Patients With Polyarticular Juvenile Idiopathic Arthritis

To assess the pharmacokinetics (PK) and PK‐efficacy correlations of body surface area (BSA)‐adjusted dosing of 30 mg/m2 golimumab administered subcutaneously (SC) every 4 weeks (q4w) + methotrexate (MTX) through Week 48 in pediatric patients (ages 2 to <18 years) with juvenile idiopathic arthritis (JIA).

AB0269 Importance of steady-state trough concentrations after intravenous golimumab with concomitant methotrexate in patients with active rheumatoid arthritis

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