Quantitative comparison of the neutralizing capacity, immunogenicity and cross-reactivity of anti-TNF-α biologicals and an Infliximab-biosimilar.

INTRODUCTION: TNF-α-neutralizing antibodies, such as infliximab (IFX) and adalimumab (ADA), are effective in the treatment of inflammatory bowel diseases (IBD), but they are expensive and become ineffective when patients develop anti-IFX or anti-ADA antibodies (ATI and ATA, respectively). Second-generation anti-TNF-α antibodies, such as Golimumab, Etanercept, Certolizumab-pegol and IFX biosimilars, may solve these issues. AIM: To determine the neutralizing capacity of first- and second generation anti-TNF-α antibodies and to determine whether ATI show cross-reactivity with the IFX biosimilar CT-P13 (Inflectra). METHODS: TNF-α neutralization was measured using a quantitative TNF-α sensor assay consisting of HeLa 8D8 cells that express the Green Fluorescence Protein (GFP) under control of a NF-кB response element. All available anti-TNF-α drugs and the IFX biosimilar CT-P13 (Inflectra) were tested for their TNF-α-neutralizing capacity. In addition, patient sera with ATI were tested for their potential to block the activity of IFX, IFX (F)ab2-fragment, biosimilar CT-P13 (Inflectra) and ADA. RESULTS: TNF-α strongly induced GFP expression in Hela 8D8 cells. Higher concentrations of first-generation anti-TNF-α drugs were required to neutralize TNF-α compared to the second-generation anti-TNF-α drugs. Serum of IBD patients with proven ATI blocked TNF-α-neutralizing properties of IFX biosimilar CT-P13 (Inflectra), whereas such sera did not block the effect of ADA. CONCLUSION: The second-generation anti-TNF-α drugs show increased TNF-α-neutralizing potential compared to first-generation variants. ATI show cross-reactivity toward IFX biosimilar CT-P13 (Inflectra), consequently patients with ATI are unlikely to benefit from treatment with this IFX biosimilar.

Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice.

BACKGROUND: Infliximab (IFX) is effective in the treatment of inflammatory bowel diseases (IBD). Currently, IFX is administered at fixed doses and intervals; however, costs are high and optimisation is necessary. Several publications indicate that IFX should be dosed on trough levels ≥3.0 mg/L. For optimising IFX dosing, the use of a pharmacokinetic model is important. Population pharmacokinetics of IFX have been described earlier; however, these models were not used for dose optimising. AIMS: To develop a pharmacokinetic model for IFX in IBD patients that can be used for dose-optimisation of IFX and to predict serum trough levels in this population. METHODS: An observational retrospective study was performed in 42 IFX-treated IBD patients. Serum samples were drawn before infusion at T = 0, 2, 6, 14, 22 and 54 weeks and analysed for IFX and antibodies against IFX (ATI). Relevant covariates were recorded and a population pharmacokinetic model was developed. RESULTS: Individual plots created using the final model showed good correspondence between observed and model predicted values. Serum levels were influenced by ATI, disease activity, sex and albumin. Our results show that in patients without ATI target trough levels ≥3.0 mg/L can be achieved by increasing dosing intervals from 8 to 12 weeks combined with a dose increase. This results in a reduction of 33% in concomitant costs. CONCLUSIONS: In IBD patients without ATI, trough level dosing based on longer intervals can reduce IFX therapy-related visits to the hospital with one-third. Trough level based dose intensification should always be justified by disease activity parameters.

ColoPulse tablets perform comparably in healthy volunteers and Crohn's patients and show no influence of food and time of food intake on bioavailability.

ColoPulse tablets are an innovative development in the field of oral drug delivery and are characterized by a colon-specific release. Until now ColoPulse dosage forms (only capsules) have been studied in healthy volunteers having a standardized breakfast three hours after administration but not in specific patient groups and not with a shorter interval between administration and breakfast. Information on bioavailability and release characteristics of ColoPulse tablets in Crohn's patients and the influence of food and time of food intake is a prerequisite to properly design future clinical studies with active substances in these patients. In the current cross-over study bioavailability and drug release characteristics of ColoPulse tablets were compared in healthy volunteers and in Crohn's patients in remission. Furthermore the influence of food and time of food intake on the in vivo drug release behavior of ColoPulse tablets was investigated. In this study the dual label isotope strategy was used which means that a ColoPulse tablet containing (13)C-urea and an uncoated, immediate release tablet containing (15)N2-urea were taken simultaneously. Breath and urine samples were collected during the test day for isotope analysis. The appearance of the stable isotopes in breath and/or urine provides information on the site of release from the dosage form, release characteristics and bioavailability. Both tablets were administered on two different days in a cross-over design: the first day with a breakfast (non-standardized) one hour after administration and the second day with a standardized breakfast three hours after administration of the tablets. There was no difference in instructions for administration between both days. Results of 16 healthy volunteers and 14 Crohn's patients were evaluated. At least 86% (51 out of 59) of all ColoPulse tablets administered in this study released their contents at the desired intestinal region. There was no significant difference in bioavailability between healthy volunteers and Crohn's patients on both days (day 1 75.8% vs 90.2%, p=0.070 and day 2 83.4% vs 91.4%, p=0.265). There was also no significant influence of food and time of food intake on bioavailability in healthy volunteers (75.8% and 83.4%, p=0.077) and in Crohn's patients (90.2% and 91.4%, p=0.618) when day 1 and day 2 were compared. Release characteristics did not significantly differ between healthy volunteers and Crohn's patients. However, food and time of food intake had some, clinically non-relevant, influence on the release characteristics within both groups which is in line with the fact that food affects gastro-intestinal transit times. This study shows that ColoPulse tablets enable the site-specific delivery of drugs or other compounds (e.g. diagnostics) deep in the ileo-colonic region of the intestine of Crohn's patients in a comparable amount and rate as in healthy volunteers. Food and time of food intake had no relevant influence on bioavailability. In conclusion ColoPulse delivery systems are promising and deserve further research for local therapy with immunosuppressive drugs in Crohn's patients in the near future.

Locally advanced verrucous carcinoma of the oral cavity: treatment using customized mold HDR brachytherapy instead of hemi-maxillectomy.

BACKGROUND: Oral verrucous carcinomas are locally invasive but rarely metastasize. Current treatment options include surgery and external beam radiotherapy (EBRT). In medical inoperable patients or irresectable tumors, high-dose-rate (HDR) brachytherapy is a valid alternative. CASE: We present an 85-year-old man with functionally irresectable cT3N0M0 verrucous carcinoma superficially spreading along the upper alveolar ridge to the retro-alveolar triangle, with infiltration of the left soft and hard palate and buccal mucosa. Using a customized intraoral mold, this patient was treated with HDR brachytherapy delivering a dose of 48 Gy in 12 fractions three times per week. Treatment was well tolerated, and after prolonged confluent mucositis the tumor is in complete remission. REVIEW OF LITERATURE AND CONCLUSION: The scarce literature on customized mold HDR brachytherapy in maxillary tumors is reviewed and recommendations for other head and neck tumors are given.

Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays.

BACKGROUND: Formation of antibodies to infliximab (ATI) inversely correlates with functional drug levels and clinical outcome. Comparison of drug levels and anti-drug antibody monitoring is hampered by lack of standardisation. AIM: To determine the correlation between three different assays for measuring infliximab and ATI. METHODS: Serum samples and spiked controls (total 62) were evaluated in a blinded way in infliximab and ATI assays developed by Sanquin Amsterdam, Netherlands (A), Laboratory for Pharmaceutical Biology, KU Leuven, Belgium (B) and a commercially available kit from Biomedical Diagnostics (BMD), Paris, France (C) performed by the University Medical Center Groningen (UMCG), Netherlands. RESULTS: All infliximab assays showed a linear quantitative correlation (Pearson r = 0.91 for A vs. B, 0.83 for A vs. C and 0.73 for B vs. C). Assay C detected infliximab in 11 samples (18%) not detected by A and B, including samples containing only ATI. All ATI assays showed a good linear correlation (Pearson r = 0.95 for A vs. B, 0.99 for A vs. C and 0.97 for B vs. C). Assay A detected ATI in five samples with low ATI that were not detected by assays B and C. Assay B did not detect ATI in three patient samples with low ATI according to assays A and C. CONCLUSIONS: There is a good correlation of infliximab and antibodies to infliximab measurements between these assays. Nevertheless, the Biomedical Diagnostics kit detected false positive infliximab levels in 18% of the samples.