Certolizumab Pegol Concentrations Research Articles

Exposure-Response Relationship of Certolizumab Pegol and Achievement of Low Disease Activity and Remission in Patients With Rheumatoid Arthritis.

Anti‐tumor necrosis factor (anti‐TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune‐mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti‐TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C‐reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure‒response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P < 0.05). Receiver operating characteristic (ROC) analysis showed that CZP concentrations ≥ 28.0 μg/ml at week 12, and ≥ 17.6 μg/ml at week 24, were associated with a greater likelihood of achieving LDA/remission outcomes. Although confirmatory studies are warranted to define the optimal CZP therapeutic range at weeks 12 and 24, these data indicate that CZP concentrations may be associated with improvement of disease activity.

Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease.

SummaryBackgroundTherapeutic drug monitoring may optimize therapy for Crohn's disease (CD).AimTo use a population pharmacokinetic model that accounts for the time‐varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure‐response relationship for CZP in Crohn's disease.MethodsAdults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline ≥ 100 points), remission (CDAI ≤ 150), C‐reactive protein (CRP) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 μg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 μg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations.Results CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP ≤ 5 mg/L or FC ≤ 250 μg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure‐response relationship varied among patients, approximate CZP concentrations of at least 36.1 μg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 μg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes.ConclusionsAn exposure‐response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.

Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study

BackgroundWomen with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast...

Improving the sensitivity and specificity of a bioanalytical assay for the measurement of certolizumab pegol.

In order to evaluate placental transfer of certolizumab pegol (CZP), a more sensitive and selective bioanalytical assay was required to accurately measure low CZP concentrations in infant and umbilical cord blood. Results & methodology: A new electrochemiluminescence immunoassay was developed to measure CZP levels in human plasma. Validation experiments demonstrated improved selectivity (no matrix interference observed) and a detection range of 0.032-5.0 μg/ml. Accuracy and precision met acceptance criteria (mean total error ≤20.8%). Dilution linearity and sample stability were acceptable and sufficient to support the method. The electrochemiluminescence immunoassay was validated for measuring low CZP concentrations in human plasma. The method demonstrated a more than tenfold increase in sensitivity compared with previous assays, and improved selectivity for intact CZP.

Effects of Transient and Persistent Anti-drug Antibodies to Certolizumab Pegol: Longitudinal Data from a 7-Year Study in Crohn's Disease.

Anti-drug antibodies (ADAbs) may decrease the efficacy of biologics and increase the risk of adverse events. A single positive test may not preclude further treatment because of variations in assays used, test timing, and patient variables. We evaluated the longitudinal patterns of immunogenicity during 7 years of antitumor necrosis factor-alpha drug certolizumab pegol (CZP) treatment for moderate-to-severe Crohn's disease. PRECiSE 3 patients (n = 595) received open-label CZP 400 mg every 4 weeks up to 7 years. CZP-ADAb expression, plasma CZP concentration, Harvey-Bradshaw Index, C-reactive protein, and fecal calprotectin concentrations were measured multiple times. Longitudinal data, examined for CZP-ADAb positivity and categorized as transient (with temporary/no effect on CZP concentration), persistent, or negative, were correlated with clinical and biological variables. Of the CZP-ADAb-positive patients, 40 (22.6%) had transient CZP-ADAbs and 94 (77.4%) had persistent CZP-ADAbs. Demographic characteristics were similar between groups. Median C-reactive protein and fecal calprotectin were higher (P < 0.05 at some visits) and plasma CZP concentrations were significantly lower (P < 0.0001 at all visits) in the persistent CZP-ADAb-positive group relative to the CZP-ADAb-negative group. Transient CZP-ADAb-positive and CZP-ADAb-negative patients had similar plasma CZP, C-reactive protein, and fecal calprotectin concentrations. Median Harvey-Bradshaw Index scores and rates of adverse events were similar among groups. This analysis demonstrates that persistent CZP-ADAb has negative effects on drug levels and efficacy, whereas transient expression may not. Serial measurements may be needed to characterize ADAb positivity. www.clinicaltrials.gov, Number NCT00160524.

Evaluating Transfer of Certolizumab Pegol and Polyethylene Glycol into Breast Milk [28J

INTRODUCTION: Breastfeeding women receiving anti-TNFs for chronic inflammatory disease face concerns surrounding their potential transfer into breast milk. CRADLE was the first sponsored study to evaluate certolizumab pegol (CZP) concentrations in breast milk and estimate CZP Average Daily Infant Dose. METHODS: CRADLE (NCT02154425) studied lactating mothers (≥6 weeks postpartum) receiving CZP. After ≥3 CZP doses, breast milk samples were collected across 1 dosing period (14 days for 200 mg Q2W; 28 days for 400 mg Q4W). Optimal analytical methods were developed to determine CZP and total polyethylene glycol (PEG) levels in breast milk. RESULTS: 18 CZP-treated mothers were screened, and 17 entered the sampling period: 16 on 200 mg Q2W and 1 on 400 mg Q4W. 77/137 (56%) samples had no measurable CZP in breast milk. For 4/17 mothers, all samples were below LLQ. Estimated Average Daily Infant Dose was 0‒0.0104 mg/kg/day; median relative infant dose (RID): 0.125%. PEG was undetectable in 134/137 samples (3 had indeterminate results upon retesting). Infants of CZP-exposed mothers had a safety profile consisting of events occurring in unexposed infants of similar age. CONCLUSION: CZP was undetectable in 56% of breast milk samples. When detectable, CZP concentrations were &lt; 3xLLQ (&lt; 1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was below 0.5% of maternal dose &lt; 10% is considered unlikely to be of clinical concern. No transfer of PEG was observed. CZP absorption by infants via breast milk is unlikely, due to its low oral bioavailability and Fc-free structure. These findings are reassuring and support continuation of CZP treatment during breastfeeding.

Clinical Correlates and Pharmacokinetic Parameters of Certolizumab Pegol Predicted by Modeling in Patients With Crohn’s Disease

Introduction: To characterize clinical correlates relevant for pharmacokinetics (PK) of certolizumab pegol (CZP) in patients with Crohn’s disease (CD) via a population PK analysis. Methods: Plasma CZP concentration time data were pooled from 9 clinical studies investigating subcutaneously administered CZP in patients with moderate to severe CD, and were subject to a population PK analysis using nonlinear mixed effects modeling (NONMEM). A co-variate analysis was performed to identify factors that impact the PK parameters. Results: Plasma concentration-time data were available from 2,157 patients with 13,561 quantifiable CZP plasma concentrations. The data were adequately described by a one-compartment, first-order absorption disposition model. CZP anti-drug antibodies were found to influence clearance (CL) of CZP as well as between-subject variability. The estimate of baseline concentrations was also influenced. The results of the co-variate analysis showed that body surface area (BSA), albumin concentrations, and Creactive protein (CRP) at baseline were the most clinically relevant co-variates. Furthermore, BSA influenced both CL and volume of distribution (Vd) in a linear fashion; these parameters increased by over 53% and 49% across the range of BSA measurements. Albumin was found to influence the CL of CZP in a nonlinear fashion, with a steep change in CL with increasing albumin concentrations below 41 g/L (Figure 1). Ethnicity was found to influence Vd, but not all the race categories were statistically significant or met relevant clinical criteria.Figure 1: The impact of albumin concentrations at baseline on the clearance of certolizumab pegol.Conclusion: The clinically and statistically relevant co-variates affecting CL of CZP were anti-CZP antibodies, BSA, albumin, and CRP at baseline. Vd was influenced by BSA and ethnicity. Disclosure - Janet Wade is an employee SGS Exprimo and a consultant to UCB Pharma. Ruth Oliver, Gerry Parker, and Gordana Kosutic are employees of UCB Pharma and have stocks and stock options. Brian Feagan is a Speakers Bureau Member for: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Consulting Fee/Advisory Board: Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Axcan, Baxter Healthcare Corp., Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Merck, Millennium, Nektar, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, Tillotts, UCB Pharma, Vertex Pharma, Warner-Chilcott, Wyeth, Zealand, Zyngenia. Contracted Research: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma.

FRI0201 Immunogenicity of certolizumab pegol without concomitant methotrexate and clinical response in rheumatoid arthritis patients: post-hoc analysis of the hikari study

BackgroundImmunogenicity and subsequent reduction in clinical response is an issue for biological agents in rheumatoid arthritis (RA) treatment.ObjectivesTo assess immunogenicity and clinical response to certolizumab pegol (CZP), a PEGylated Fc-free...

Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response.

Antitumor necrosis factor α (anti-TNF) agents have dramatically influenced management of refractory inflammatory bowel disease (IBD). However, not all patients respond to treatment and some lose response or become intolerant over time. Immunogenicity, a well established phenomenon with anti-TNF agents, may have important clinical implications in patients with IBD. A comprehensive review of available evidence demonstrating how drug concentrations, immunogenicity, and other factors influence outcomes with anti-TNF agents was performed. PubMed, EMBASE, Biosis, Dialog, and Conference Papers Index were searched from 1 January 1995 to 7 April 2012 to identify clinical trials in adult and pediatric patients with IBD treated with anti-TNF agents for Crohn's disease or ulcerative colitis. Data on serum drug levels and immunogenicity and their relationship with clinical efficacy and safety outcomes were extracted and examined. Serum infliximab concentrations correlated with clinical efficacy and treatment outcomes in patients with IBD; this relationship is less well characterized with adalimumab and certolizumab pegol concentrations. In multiple studies, the presence and level of antibodies to infliximab correlated with loss of clinical efficacy and increased risk of infusion reactions. The incidence and clinical impact of antibody formation with adalimumab or certolizumab in IBD is becoming evident as more data become available. Current, enzyme-linked immunosorbent assay based anti-TNF antibody assays are suboptimal in that results are often inconclusive and comparisons between agents cannot be made. Measurement of anti-TNF agent drug concentrations and assessment of immunogenicity has the potential to positively impact clinical decision making during anti-TNF therapy for IBD. As assays are optimized, it is expected that the clinical impact of these determinations will be better characterized.

Certolizumab Pegol Plasma Concentrations and Endoscopic and Clinical Outcomes in Crohnʼs Disease: A Post Hoc Analysis of the MUSIC Trial: Presidential Poster

Purpose: The MUSIC trial (NCT00297648) demonstrated that certolizumab pegol (CZP) treatment in patients (pts) with active Crohn's disease (CD) and severe endoscopic disease showed improvement in both endoscopic and clinical outcomes as early as Wk 10.1 This post hoc analysis of data from the MUSIC trial evaluates the associations between serum plasma CZP concentrations and endoscopic and clinical outcomes at Wk 10. Methods: Adult pts (N=89) with active CD for ≥3 months and significant endoscopic lesions (ulcerations in ≥2 intestinal segments with CD Endoscopic Index of Severity [CDEIS] score ≥8) received open-label subcutaneous CZP 400 mg at Wks 0, 2, and 4 (induction dose) and then every 4 wks until Wk 54. CZP plasma concentrations were collected at Wk 8 (trough level) and stratified by quartiles. Rates of endoscopic response (CDEIS decrease from baseline >5) and remission (CDEIS <6) and of clinical response (CD Activity Index [CDAI] decrease from baseline ≥100) and remission (CDAI score ≤150) were determined at Wk 10. Results: A total of 45 pts received CZP 400 mg induction at 0, 2, and 4 wks and had an available CZP trough measurement at Wk 8 and response/remission status at Wk 10. At Wk 10, there was a significant difference between the CZP concentration quartiles regarding CDEIS response and remission rates (p=0.0016 and p=0.0302, respectively) (Table). A similar trend at Wk 10 was observed in clinical efficacy with a significant difference between the CZP concentration quartiles regarding CDAI remission (p=0.0378), while CDAI response did not achieve statistical significance (p=0.2993).Table: Proportions of pts achieving endoscopic and clinical outcomes by CZP plasma concentration quartiles (Q)Conclusion: This post hoc analysis of the MUSIC study identifies an association between endoscopic response and remission and clinical remission and higher plasma concentrations of CZP following standard induction therapy. Further prospective evaluation of the correlation between CZP plasma concentration and both endoscopic and clinical outcomes is warranted.

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<h3>Background</h3> Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. <h3>Methods</h3> CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed. <h3>Results</h3> 19 CZP-treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0–0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-age infants. <h3>Conclusion</h3> When quantifiable, CZP concentrations were &lt;3× LLOQ (&lt;1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; &lt;10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc-­free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding. <h3>Trial registration number</h3> NCT02154425; Results.