Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects.

OBJECTIVE: Sirukumab (CNTO 136) is a human mAb with high affinity and specificity for binding to interleukin-6. This Phase 1 study evaluated the pharmacokinetics, immunogenicity, safety, and tolerability of sirukumab following a single subcutaneous (s.c.) administration in healthy male Japanese and Caucasian subjects. METHODS: Japanese and Caucasian subjects were randomized to placebo or 25, 50, or 100 mg sirukumab. Blood samples were collected to measure serum sirukumab concentration and antibodies to sirukumab. Noncompartmental analysis and population pharmacokinetic modeling were conducted to characterize sirukumab pharmacokinetics. Adverse events were monitored at each visit. RESULTS: 25 Japanese and 24 Caucasian subjects received sirukumab and were included in the pharmacokinetic evaluation. Mean Cmax and AUC0-∞of sirukumab increased in an approximately dose-proportional manner in both Japanese and Caucasian subjects. Median tmax was 3 -5 days after s.c. administration of sirukumab. Mean t1/2 was 15 -16 days in Japanese and 15 -18 days in Caucasian subjects. A one-compartment population pharmacokinetic model adequately described sirukumab pharmacokinetics following s.c. administration. The estimated population means for CL/F, V/F, and Ka were 0.54 ±0.03 l/day, 12.2 ±0.55 l, and 0.77 ±0.07 day-1, respectively. Race was not a significant covariate on CL/F or V/F. No subject was positive for antibodies to sirukumab. Adverse events were generally mild and did not appear to be dose-related or lead to study discontinuation. CONCLUSIONS: Sirukumab pharmacokinetics following subcutaneous administration was linear at doses ranging 25 -100 mg and was comparable between Japanese and Caucasian subjects. A single subcutaneous administration of 25, 50, or 100 mg sirukumab appeared to be well tolerated by both Japanese and Caucasian healthy male subjects.

Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn's disease before and after delivery.

GOALS: The objective of this study was to determine whether infliximab, an antitumor necrosis factor monoclonal antibody, is transferred in utero or through breast milk from nursing Crohn's disease patients to their newborns. BACKGROUND: Crohn's disease most often occurs in women of childbearing age. Many of these women receive treatment for their disease, but are advised to terminate therapy while pregnant or nursing. STUDY: Three patients diagnosed with Crohn's disease who had a history of infliximab use during and after pregnancy were followed prospectively. Patients received 5-mg/kg infliximab at regular intervals until approximately gestational week 30, and resumed infliximab treatment within 3 to 14 days after giving birth. Serum samples from patients and children and breast milk samples were collected postpartum. The concentration of infliximab in the serum and milk samples was measured using an enzyme-linked immmunosorbent assay. RESULTS: The levels of infliximab detected in the mothers' serum samples postpartum were 74.27, 62.62, and 59.97 microg/mL, respectively. However, infliximab was undetectable (<0.10 microg/mL) in the sera of the newborn children. Likewise, infliximab was undetectable in the breast milk of the nursing mothers. CONCLUSIONS: Infliximab was detected in the mothers' sera, but not in the breast milk of nursing mothers or in the sera of the breast-fed newborns. Data from this small series of patients suggest that infliximab was not transferred from mother to child, either in utero or through breast milk. These data suggest that mothers receiving infliximab should not be discouraged from nursing their children.

Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis.

PURPOSE: Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population. METHODS: Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM. RESULTS: A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value +/- standard error), based on the final covariate model, were clearance (CL: 0.407 +/- 0.0103 L/day), apparent volumes of distribution in the central (V(1): 3.29 +/- 0.0679 L) and peripheral (V(2): 4.13 +/- 0.16 L) compartments, and intercompartment clearance (Q: 7.14 +/- 0.489 L/day). Infliximab exhibited interindividual variability for CL and V(1) of 37.7% and 22.1%, respectively. Infliximab t(1/2) is approximately 14 days. Covariate analysis showed that V(1) increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population. CONCLUSIONS: The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels.

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 (V(1): 3.06 +/- 0.057 L), intercompartment clearance (Q: 1.72 +/- 0.48 L/day), and volume of distribution in the peripheral compartment (V(2): 2.94 +/- 0.17 L). Interindividual variability for CL and V(1) 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 V(1). 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.

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.

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 µg/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 µg/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 µg/mL) versus q12w (0.8 µg/mL) and with infliximab 10 mg/kg (2.9 µg/mL) versus 5 mg/kg (1.1 µg/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.

Pharmacokinetics and safety of golimumab in healthy Chinese subjects following a single subcutaneous administration in a randomized phase I trial.

BACKGROUND AND OBJECTIVES: Golimumab is an anti-tumor necrosis factor-α human immunoglobulin G1κ monoclonal antibody that is efficacious for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in adults. The objective of this study was to assess the pharmacokinetic characteristics of golimumab in healthy male Chinese subjects following a single subcutaneous (SC) administration of golimumab 50 or 100 mg. The safety, tolerability, and immunogenicity of a single SC administration of golimumab in Chinese subjects were also evaluated. METHODS: This was a phase I, randomized, open-label, single-dose, single-period, single-center study. Twenty-four healthy male Chinese subjects were randomized (1:1) to receive a single SC administration of golimumab 50 or 100 mg. Serial blood samples for the measurement of serum golimumab concentrations were collected and analyzed using a validated electrochemiluminescent immunoassay method. The pharmacokinetic parameters [maximum observed serum concentration (C(max)), time to reach C(max) (t(max)), area under the serum concentration-time curve from time zero to infinity (AUC∞), and terminal half-life (t(½))] of golimumab were derived using a noncompartmental analysis. RESULTS: Following a single SC administration of golimumab 50 or 100 mg in Chinese male subjects (age 19-41 years, body weight 60-76 kg), mean ± standard deviation C(max) (3.6 ± 1.6 and 7.5 ± 1.4 µg/mL, respectively) and AUC∞ (59.8 ± 19.8 and 132.8 ± 27.0 µg·day/mL, respectively) increased in a dose-proportional manner. The median t(max) was in the range of 4.5-5.0 days, and the mean t(½) was in the range of 10.8-11.9 days. Among 24 subjects, 23 had appropriate samples for evaluation of antibodies to golimumab, and one subject (1/23, 4.3%) in the 100-mg group tested positive. Three mild adverse events were reported (infected sebaceous cyst, upper respiratory tract infection, and headache), all in the 50-mg group; none were considered to be related to the study agent. CONCLUSIONS: Golimumab exhibited linear pharmacokinetics at dose levels of 50 and 100 mg following a single SC administration in healthy Chinese subjects. Single SC administrations of golimumab 50 or 100 mg were considered to be generally well tolerated. The results from this study indicate that there are no apparent ethnic differences in the pharmacokinetics of golimumab between Chinese and Caucasian subjects.

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.

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-alpha 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/m(2). 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 approximately 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 pilot study on safety and pharmacokinetics of infliximab for the cancer anorexia/weight loss syndrome in non-small-cell lung cancer patients.

BACKGROUND: Weight loss predicts a poor prognosis for patients with non-small-cell lung cancer. Tumor necrosis factor alpha (TNFalpha) is a mediator of this weight loss, yet no studies have tested infliximab, an IgG monoclonal antibody that blocks the binding of TNFalpha to its p55 and p75 receptors, for this indication. The safety and pharmacokinetics of infliximab in combination with docetaxel, a commonly used chemotherapy agent for non-small-cell lung cancer, were explored in this pilot study. METHODS/RESULTS: Four patients with metastatic non-small-cell lung cancer were treated initially with infliximab 5 mg/kg per day intravenously once a week on weeks 1, 3 and 5, and docetaxel 36 mg/m2 per day intravenously once a week on weeks 1, 2, 3, 4, 5 and 6 of an 8-week treatment cycle. Therapy was well tolerated with no grade 4 or 5 adverse events. Maximal serum concentrations of infliximab at 1, 3 and 5 weeks were (mean+/-SD) 108+/-11, 135+/-19, and 139+/-6 microg/ml, respectively, and appeared similar to historical concentrations from non-cancer patients not receiving concomitant chemotherapy (144+/-68 microg/ml). One patient manifested weight stability. One patient manifested a partial tumor response, one stable disease, and two disease progression. Median survival within the cohort was 203 days (range 111 to 324 days). CONCLUSIONS: The above combination appears safe, and docetaxel does not appear to increase serum concentrations of infliximab. A larger study testing the role of this combination for weight loss in non-small-cell lung cancer patients is ongoing and utilizes the doses described above.