A Practical Guide to Therapeutic Drug Monitoring of Biologic Medications for Inflammatory Bowel Disease

Therapeutic drug monitoring (TDM) is a useful strategy to optimize biologic medications for inflammatory bowel disease not responsive to standard dosing regimens. TDM is cost effective for anti-tumor necrosis factor agents in the setting of loss of response (reactive TDM). Optimizing drug dosing when patients are in remission (proactive TDM) may be beneficial in certain circumstances. However, frequently the serum drug concentration in isolation becomes the focus TDM. Additionally, the lines of reactive and proactive TDM can quickly blur in many common clinical settings. Physicians employing a TDM based strategy need to place the drug concentration in context with the inflammatory status of the patient, the underlying pharmacokinetics and pharmacodynamics of the drug, the risk of immunogenicity, and the therapeutic goals for the patient. Physicians should understand the limits of TDM and feel comfortable making therapeutic decisions with imperfect information. The goal of this narrative review is to provide a framework of questions that physicians can use to employ TDM effectively in practice.

A phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX04 to reference bevacizumab sourced from the United States, the European Union, and China in healthy Chinese male volunteers

Purpose To compare the pharmacokinetic profiles, safety and immunogenicity of proposed bevacizumab biosimilar HLX04 with reference bevacizumab in healthy Chinese males. Methods In this double-blind Phase 1 study, healthy volunteers (N = 208) were randomized 1:1:1:1 to a single 3 mg/kg intravenous infusion of HLX04 or reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) or China (bevacizumab-CN). Co-primary endpoints were area under the serum concentration–time profile (AUC) from time zero extrapolated to infinity (AUC0–inf) and from zero to last quantifiable concentration (AUClast). Secondary endpoint was the maximum serum drug concentration (Cmax). Study participants were monitored for treatment-emergent adverse events (TEAEs) and samples were collected for anti-drug antibody (ADA) testing throughout the study. Results Pharmacokinetic parameters were similar across groups. The respective geometric least-squares mean ratios (GLSMR) of AUC0–inf, AUClast and Cmax were: 95.7%, 96.0% and 101.8% for HLX04 versus bevacizumab-US; 94.3%, 94.6% and 100.5% for HLX04 versus bevacizumab-EU; and 90.0%, 90.4% and 98.2% for HLX04 versus bevacizumab-CN. For all test-to-reference comparisons, two-sided 90% confidence intervals of GLSMR for AUC0–inf, AUClast and Cmax fell in the pre-specified bioequivalence range (80–125%). There were no notable differences in the frequency, nature and/or grade of TEAEs. No deaths were reported and no ADAs were detected during the study. Conclusion HLX04 had similar safety and pharmacokinetic profiles to reference bevacizumab in healthy Chinese males, supporting the confirmatory Phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with metastatic colorectal cancer (NCT03511963). Clinical trial registration The study was registered with Clinicaltrials.gov, NCT03483649.

Effect of ethnicity and chemotherapy (mFOLFOX6) on zolbetuximab pharmacokinetics in patients with claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ).

e16078 Background: Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets Claudin 18.2 (CLDN18.2), a tight junction protein that is normally confined to gastric mucosa but is retained in G/GEJ. A phase 2 (NCT01630083, FAST) trial demonstrated significantly prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. Two global phase 3 studies are ongoing, comparing zolbetuximab + chemotherapy vs chemotherapy as first-line treatment in CLDN18.2-positive G/GEJ. This study assessed the influence of ethnic differences and chemotherapy on the pharmacokinetics (PK) of zolbetuximab in patients (pts) with G/GEJ and the potential effect of zolbetuximab on chemotherapy PK. Methods: In the Japanese phase 1 and global phase 2 studies, adult pts with CLDN18.2-postitive G/GEJ received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 1 (Cycle 1 Day 3 in Cohort 2 of phase 2) then 600 mg/m2 Q3W. Phase 1 and Cohort 1A of the phase 2 study assessed zolbetuximab monotherapy in 21-day cycles. Cohort 2 of the phase 2 study assessed zolbetuximab + mFOLFOX (5-FU, folinic acid, oxaliplatin; 4 cycles) in 42-day cycles (Q2W from Cycle 1 Day 1). Blood samples for zolbetuximab PK following single and multiple doses, and for chemotherapy (5-FU and oxaliplatin) PK alone or with zolbetuximab were collected. Maximum serum drug concentration (Cmax) and area under the concentration-time curve from 0-21 days (AUC0-21) were assessed. Potential ethnic differences in zolbetuximab exposures across Japanese, other Asian (Korean and Taiwanese), and Western pts, and the potential drug-drug interaction between zolbetuximab and chemotherapy were evaluated. Results: Zolbetuximab concentration profiles and PK parameters were generally comparable across Japanese, other Asian, and Western populations (Table). Zolbetuximab PK properties were similar between monotherapy and combination therapy cohorts (Table). Chemotherapy PK was comparable with and without zolbetuximab. Conclusions: The analyses suggest no apparent ethnic differences in zolbetuximab PK across Japanese/Asian and Western pts and no PK interactions between zolbetuximab and mFOLFOX6. These results support the use of zolbetuximab and mFOLFOX without the need for dose adjustment in global phase 3 trials. Clinical trial information: NCT03505320, NCT03528629. [Table: see text]

Effect of the dose regimen on the serum amisulpride concentration and simulation of concentration reference ranges based on population pharmacokinetics

Aims This study aims to determine the factors associated the large variability and provided the concentrations reference ranges for different dose ranges. Methods A retrospective study was conducted in a psychiatric hospital. The factors associated with the serum amisulpride concentration were examined using multiple linear regression analysis. A comparison of serum amisulpride concentrations among different dose regimens was conducted via analysis of covariance. The amisulpride concentration range for different dosing regimens was simulated using the population pharmacokinetics of Chinese patients with schizophrenia using the Monte Carlo method. Results In total, 472 samples from 291 patients were examined to determine the factors associated with amisulpride concentrations. Multiple linear regression analysis indicated that age and the daily dose were positively correlated with the serum drug concentration, whereas male gender and sampling time before the last administration were negative correlated with its concentration. The serum amisulpride concentration significantly differed among the dose regimens. Using an established amisulpride population pharmacokinetic model, the simulated trough concentrations exceeded 320 ng/mL for most regimens with daily doses greater than 600 mg/day. Conclusion Differences in dose regimens and daily doses contributed to the large variation of the serum amisulpride concentration. The currently recommended reference does not ensure the attainment of appropriate therapeutic concentrations.

Study on the relationship between adverse drug reactions of carbamazepine and HLA-B*1502 genetic polymorphism and blood concentration

Objective： To study the relationship between genetic polymorphism，blood concentration and adverse drug reactions（ADRs） of carbamazepine（CBZ），so as to promote clinical safety and reasonable use of CBZ.Methods： Clinical medical data of the inpatients treated in Ruijin Hospital Affiliated to School of Medicine，Shanghai Jiao Tong University from 2017 to 2019 were collected retrospectively.Data concerning HLA-B*1502 gene detection and serum concentration of CBZ were collected to analyze the relationship between HLA-B*1502 genotype and ADRs of CBZ in the patients.Results： A total of 148 patients were enrolled for study，of whom 101 patients received HLA-B*1502 genotypes detection，with the genotype of 34 patients being positive，accounting for 33.66%.In the 148 patients，78 were treated with CBZ（53.79%），among whom 60 patients（86 case times） received serum drug concentration detection of CBZ.The serum drug concentration in 53 case times was within the recommended concentration range，accounting for 61.63% of the detected case times，and the serum drug concentration in 32 case times（37.21%） was lower than that of the recommended data.CBZ-related ADRs occurred in 12 cases（15.38%），of which one patient with HLA-B*1502 homozygous mutation developed severe skin ADRs after taking CBZ.Conclusion： There is close association between HLA-B*1502 genotype and skin ADRs induced by CBZ.The treatment window of CBZ is narrow，and the rate of ADRs might be associated with blood concentration of CBZ.Gene detection and blood concentration detection are of great significance to the improvement of the safety of CBZ in clinical practice.

Influence Of UGT1A3 Gene Polymorphism In Pediatric Epileptics on Valproate: A Protocol (Preprint)

BACKGROUND Epilepsy is a chronic neurological disease characterized by recurrent unprovoked seizures. Therapeutic drug monitoring (TDM) has often been performed during the pharmacological treatment of epilepsy, but the plasma levels of some AEDs do not correlate well with the doses and/or the therapeutic or toxic effects of the drugs. OBJECTIVE Objective of the study is to evaluate the pattern of polymorphism in UGT1A3 in pediatric epileptics on valproate. It also aims to find the association between gene polymorphism and plasma concentration of valproate, its clinical effectiveness and its adverse effect profile. METHODS One hundred children aged 2-18 years with a diagnosis of epilepsy and treated with sodium valproate mono therapy will be included in the study. Their demographic profile, type of seizure, dose and frequency of sodium valproate will be recorded. Five ml of venous blood will be collected after 30 days of starting the regimen,3ml EDTA blood will be utilized for genotyping by PCR-RFLP method and for platelet count, 2 ml plain blood will be used for estimating serum drug concentration by HPLC and for biochemical tests. The patient will be followed up quarterly or more frequently (as deemed by the clinician) for clinical evaluation. Statistical analysis: Hardy-Weinberg equilibrium (HWE) analysis will be performed on UGT1A3 polymorphisms. ANOVA will be used to investigate the association between genotypes distribution and serum concentration of VPA. A p-value <0.05 was regarded as statistically significant. RESULTS The study is funded by Indian council of Medical research, sanction letter dated 19.08.2019 No.5/4-5/187/Neuro/2019-NCD-I. The university ethical approval was obtained, ref NU/CEC/2019/0223.A total of thirty samples are collected at the end of six months.PCR-RFLP and HPLC methods are standardized and results will be available on completion of the study. CONCLUSIONS Genetic polymorphisms of UGTs may influence VPA metabolism and hence the steady-state concentration of the drug in plasma may be altered. This may demand an increased or reduced dose of VPA in epileptics so as to maintain the therapeutic levels. The study may be useful in optimizing the anti-epileptic dosage. CLINICALTRIAL NOt applicable.

Transfer of monoclonal antibodies into breastmilk in neurologic and non-neurologic diseases

ObjectiveTo review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases.MethodsWe systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and “breastmilk,” “breast milk,” “breastfeeding,” or “lactation.” From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women.ResultsDrug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated). Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.ConclusionsThe current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.

P465 Therapeutic drug monitoring in Crohn’s disease patients, a comparison between homogeneous mobility shift assay and point of care method

Background Therapeutic Drug Monitoring (TDM) is a useful tool to help physicians managing patients with Inflammatory Bowel Disease treated with anti-tumour necrosis factor (TNF) drugs. Different techniques are available to evaluate serum drug concentration (TL), However, these techniques are time-consuming. A point-of-care (POC) method has been proposed to evaluate drug TL and overcome the limitations inherent to other methodologies. Our aim was to evaluate the capability of POC to discriminate between IBD relapse and remission and to evaluate the concordance of drug TL measured with POC and HMSA Methods We analysed with Quantum BlueÒ (Buhlmann Laboratories AG, Schonenbuch, Switzerland) (POC) 200 Adalimumab (ADA) and 200 Infliximab serum samples of 46 Crohn’s disease (CD) patients previously assessed with HMSA. Blood samples were drawn at standardised time points during anti-TNF treatment (2, 6, and every 8 weeks), before anti-TNF administration. Disease activity was assessed by the Harvey–Bradshaw Index (HBI, remission defined by HBI&lt;5). Results We evaluated 46 CD patients responders to anti-TNF induction with ADA (n = 25, 54.3%) and IFX (n = 21, 45.6%) with a median follow-up of 83 weeks (range 16–144 weeks). At week 16, median ADA TL of patients in remission were significantly higher as compared with patients in disease relapse using both HMSA [12.7 μg/ml (range, 8.9–23.6 μg/ml) vs. 6.6 μg/ml (range, 0.7–9.6 μg/ml), p = 0.0001] and POC [17.8 μg/ml (range 7.6–35.0 μg/ml) vs. 9.8 μg/ml (range 5.8–11.4 μg/ml), p = 0.0003]. The concordance between the two different techniques has been assessed as 0.76 by Choen Kappa. Considering IFX TL, patients in remission had higher serum drug concentration using both HMSA [7.0 μg/ml (range, 0.0–21.8 μg/ml)] and POC [6.2 μg/ml (range 0.4–14.3 μg/ml)] as compared with patients who experienced disease relapse [HMSA, 0.1 μg/ml (range, 0.0–4.1 μg/ml), p = 0.019; POC, 0.45 μg/ml (range 0.4–3.3 μg/ml), p = 0.0072]. The concordance between the two different test for IFX TL was 0.81. We obtained similar results at the end of follow-up: median ADA TL was higher in remission than in disease relapse patients using both HMSA and POC [p = 0.001 and p = 0.0012] with a concordance of 0.75. Median IFX TL was higher in remission than in disease relapse patients using both HMSA and POC (p = 0.13 and p = 0.25) with a concordance of 0.70. Conclusion Both POC and HMSA are TL tests able to differentiate relapse and remission in IBD patients. The association between anti-TNF TL and disease status (remission/relapse) was better in ADA-treated patients rather than patients treated with IFX. Finally, we demonstrated a good concordance between HMSA and POC. Anti-drug antibody concentrations while available on HMSA were not available on POC

Individualized medication of digoxin based on the serum drug concentration and blood biochemical indexes

Aim: The dose of digoxin is often difficult to be determined precisely. The aim of this study was to retrospectively investigate the effect of blood biochemical indexes on the serum concentration of digoxin. Materials & methods: We collected the data of hospitalized patients treated orally with digoxin in Nanjing Drum Tower Hospital (Nanjing, China) from 2016 to 2018. Descriptive statistics was used to analyze the patients’ comprehensive condition. Results: A total of 425 patients were included in the study. Through analysis, nine factors were included in the regression model of the serum concentration of digoxin, and this regression model showed good predictive performance (r2 = 0.83138; p < 0.001). Conclusion: The regression model for the prediction of serum concentration of digoxin has clinical significance, and can provide research basis for individualized medication of digoxin.