A Tolerance Interval Approach to Assessing the Biosimilarity of Follow-On Biologics

<p>With many important biologic products due to lose patent protection in the next few years, the development of follow-on biologics has received much attention from both sponsors and regulatory authorities. Biologics are often produced in living systems. The living systems used to produce biologics are highly complex and could be sensitive to very minor changes in the manufacturing process. According to the guideline published by the European Medicines Agency, biosimilar products are similar, not identical, to the innovator products they seek to copy. Therefore, in developing a biosimilar, it is important to assess the similarity between it and the innovator product. In this article, we consider a two-arm, parallel design with a reference biological product and a biosimilar. Then we construct a biosimilarity index for assessing the degree of similarity based on the tolerance limits. The acceptance criterion is proposed to judge whether the biosimilar is similar to the reference product. We also address the determination of the number of subjects to ensure that the occurring probability of biosimilarity criterion is maintained at a desired level, say 80 or 90%.</p

Demography of the methadone maintenance treatment patients.

<p>Demography of the methadone maintenance treatment patients.</p

Methadone and its metabolism between the HCV antibody-positive and antibody-negative MMT subjects.

<p>N, subject number; SD, standard deviation; HCV (+), hepatitis C virus antibody-positive;</p><p>HCV (−), hepatitis C virus antibody-negative.</p><p><i>P</i>-value: Wilcoxon Rank-Sum Test, Permutation <i>P</i>-value: permutation test.</p

Missense mutation at <i>CLDN8</i> associated with a high plasma interferon gamma-inducible protein 10 level in methadone-maintained patients with urine test positive for morphine

<div><p>We previously reported a high plasma chemokine interferon gamma-inducible protein 10 (IP-10) level and prolonged electrocardiography QT-interval in methadone maintenance treatment (MMT) patients with HIV or HCV infection. The purpose of this study was to evaluate the genetic association of high plasma IP-10 level in the MMT patients. The gene-based and pathway-based association analyses were conducted using a genome-wide association study dataset in 344 MMT patients for identifying genes and pathways associated with plasma IP-10 level. We found that plasma IP-10 level was significantly associated with a pathway in the tight junction (<i>P</i> = 1.01x10^-5), where the claudin 8 (<i>CLDN8</i>) gene had the most significant association (<i>P</i> = 6.8x10^-5). A functional single nucleotide polymorphism (SNP) rs686364 at exon 1 of <i>CLDN8</i> showed strong association with plasma IP-10 levels, in the MMT subjects with positive urine test for morphine (dominant model, <i>P</i> = 0.00004). The minor allele type carriers had higher plasma IP-10 levels than the major allele type carriers. Our data support that the tight junction protein claudin 8 exon 1 is a predictor for the plasma levels of IP-10 in MMT patients with urine test positive for morphine.</p></div

The dominant model association analyses between the SNPs of <i>CLDN8</i> and IP-10 (pg/ml) in all MMT patients and urine morphine positive MMT patients.

<p>The dominant model association analyses between the SNPs of <i>CLDN8</i> and IP-10 (pg/ml) in all MMT patients and urine morphine positive MMT patients.</p

The relative CYP2B6 expression levels in EBV-transformed lymphoblastoids were compared between HCV antibody-positive (HCV(+)) and antibody-negative patients (HCV(−)).

<p>(The error bar represents the standard deviation; n, subject number).</p

Hepatitis C Virus Infection Influences the <i>S</i>-Methadone Metabolite Plasma Concentration

<div><p>Background and Objectives</p><p>Heroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan.</p><p>Methods</p><p>A total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening.</p><p>Results</p><p>Of the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, <i>P</i> = 0.02) and ALT (Wilcoxon Rank-Sum test, <i>P</i> = 0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, <i>P</i> = 0.043) and the <i>R</i>-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, <i>P</i> = 0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the <i>S</i>-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose ( = 14.65 and 14.13; <i>P</i> = 0.029 and 0.03) and the <i>S</i>-EDDP/methadone dose ratio ( = −0.41 and −0.40; <i>P</i> = 0.00084 and 0.002) in both univariate and multivariate regression analyses.</p><p>Conclusions</p><p>We conclude that HCV may influence the methadone dose and plasma <i>S</i>-EDDP/methadone dose ratio in MMT patients in this preliminary study.</p></div

Multivariate regression analyses of the methadone dose and <i>S</i>-EDDP/methadone dose ratio.

<p>HCV Ab, hepatitis C virus antibody; , regression coefficient; SE, standard error of regression coefficient; VIF, variance inflation factor.</p

Flow diagram of the study recruitment procedure for MMT patients.

<p>Flow diagram of the study recruitment procedure for MMT patients.</p

Pharmacogenomics study on cadherin 2 network with regard to HIV infection and methadone treatment outcome

<div><p>Heroin dependent patients have a high incidence of HIV infection. In contrast to the gene expression method, we developed a systemic correlation analysis method built upon the results of pharmacogenomics study in a methadone maintenance treatment (MMT) cohort consisting of 344 Taiwanese heroin dependent patients. We identified genetic variants and their encoding proteins that may be involved with HIV infection and MMT treatment outcome. Cadherin 2 (<i>CDH2</i>) genetic determinants were identified through the genome-wide pharmacogenomic study. We found significant correlations among HIV infection status, plasma levels of CDH2, cytokine IL-7, ADAM10, and the treatment responses to methadone. Two single nucleotide polymorphisms located within <i>CDH2</i> gene showed associations with blood pressure and plasma CDH2 concentration. Plasma concentration of CDH2 showed correlations with the level of cytokine IL-7, status of HIV infection, and urine morphine test result. Plasma level of IL-7 was correlated with corrected QT interval (QTc) and gooseflesh skin withdrawal symptom score, while level of ADAM10 was correlated with plasma concentrations of vitamin D metabolite, nicotine metabolite, and <i>R</i>-methadone. The results suggest a novel network involving HIV infection and methadone treatment outcome.</p></div