Pharmacokinetic equivalence of CT-P17 to high-concentration (100 mg/ml) reference adalimumab: A randomized phase I study in healthy subjects.

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT-P17 to United States-licensed adalimumab (US-adalimumab) and European Union-approved adalimumab (EU-adalimumab). This double-blind, parallel-group, phase I trial (clinicaltrials.gov NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT-P17, US-adalimumab, or EU-adalimumab. Primary end points were PK equivalence in terms of: area under the concentration-time curve from time zero to infinity (AUC0-inf ); AUC from time zero to the last quantifiable concentration (AUC0-last ); and maximum serum concentration (Cmax ). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80-125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT-P17; 103 US-adalimumab; 106 EU-adalimumab), 308 subjects received study drug. AUC0-inf , AUC0-last , and Cmax were equivalent among CT-P17, US-adalimumab, and EU-adalimumab, because 90% CIs for the ratios of GLSMs were within the 80-125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single-dose administration of CT-P17, EU-adalimumab, and US-adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

Bowel preparation for colonoscopy may decrease the levels of testosterone in Korean men.

Although colonoscopy is commonly conducted for medical check-ups in Korea, investigations for the influence of bowel preparation on various health conditions are insufficient. This cross-sectional study investigated whether bowel preparation has an influence on serum levels of testosterone. A total of 1114 men were divided into the bowel preparation group and control groups. The median total and free testosterone levels were significantly lower in the bowel preparation group (14.89 and 0.26 nmol/L, respectively) than in the control groups (15.72 and 0.28 nmol/L, respectively). The level of total testosterone significantly increased with age in the bowel preparation group (r = 0.103). The differences in the levels of total and free testosterone between the 2 groups were more prominent in younger men than in older men. In multivariate regression models, bowel preparation was independently associated with the levels of total and free testosterone. In these models, the interaction between age and bowel preparation was significant for the levels of total and free testosterone. In conclusion, bowel preparation may independently decrease the serum levels of total and free testosterone. The decline in testosterone was more evident in younger men than in older men.

Reliability and Validity of the Korean Version of the Multidimensional Fatigue Inventory (MFI-20): A Multicenter, Cross-Sectional Study.

Introduction: A nonspecific symptom, fatigue accompanies a variety of diseases, including cancer, and can have a grave impact on patients' quality of life. As for multidimensional instruments, one of the most widely used is the Multidimensional Fatigue Inventory (MFI). This study aims to verify the reliability and validity of the MFI Korean (MFI-K) version. Materials and Method: This study was performed at four university hospitals in the Republic of Korea. Among outpatients visiting the Department of Family Medicine, those complaining of fatigue or visiting a chronic care clinic were enrolled in this study. A total of 595 participants were included, and the mean age was 42.2 years. Results: The Cronbach's alpha coefficient of the MFI-K was 0.88. The MFI-K had good convergent validity. Most subscales of the MFI-K were significantly correlated with the Visual Analogue Scale (VAS) and Fatigue Severity Scale (FSS). In particular, general and physical fatigue had the greatest correlation with the VAS and FSS. Although the English version of MFI had five subscales, the factor analysis led to four subscales in the Korean version. Conclusion: This study demonstrated the clinical usefulness of MFI-K instrument, particularly in assessing the degree of fatigue and performing a multidimensional assessment of fatigue.

Combined Effect of Blood Cadmium and Lead Levels on Coronary Heart Disease Prediction Risk in Korean Men.

This study was designed to investigate the combined effects of cadmium (Cd) and lead (Pb) on 10-year coronary heart disease (CHD) risk calculated using the Framingham risk score. The heavy metal data set of the Korean National Health and Nutrition Examination Survey IV and V (2008-2010) was analyzed. The 10-year CHD risk was significantly associated with the log-transformed blood Cd and Pb levels in Korean men. For the highest quartile of Cd and Pb, the odds ratio (OR) of the intermediate risk and beyond for CHD (10-year risk ≥10%) compared to the lowest quartile was 6.870 (Cd, 95% confidence interval [CI]: 4.58-10.30) and 3.127 (Pb, 95% CI: 2.09-4.69) after adjusting for confounders, respectively. The adjusted OR of the intermediate risk and beyond for CHD (10-year risk ≥10%) in the fourth quartile of both Cd and Pb was 12.2 (95% CI: 8.0-18.5) compared to the reference group (first and second quartiles of Cd and Pb). However, the association between log-transformed blood Cd and Pb and the 10-year CHD risk was not significant in Korean women.

Women with fibromyalgia have lower levels of calcium, magnesium, iron and manganese in hair mineral analysis.

Little is known about hair mineral status in fibromyalgia patients. This study evaluated the characteristics of hair minerals in female patients with fibromyalgia compared with a healthy reference group. Forty-four female patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria were enrolled as the case group. Age and body mass index-matched data were obtained from 122 control subjects enrolled during visit for a regular health check-up. Hair minerals were analyzed and compared between the two groups. The mean age was 43.7 yr. General characteristics were not different between the two groups. Fibromyalgia patients showed a significantly lower level of calcium (775 µg/g vs 1,093 µg/g), magnesium (52 µg/g vs 72 µg/g), iron (5.9 µg/g vs 7.1 µg/g), copper (28.3 µg/g vs 40.2 µg/g) and manganese (140 ng/g vs 190 ng/g). Calcium, magnesium, iron, and manganese were loaded in the same factor using factor analysis; the mean of this factor was significantly lower in fibromyalgia group in multivariate analysis with adjustment for potential confounders. In conclusion, the concentrations of calcium, magnesium, iron, and manganese in the hair of female patients with fibromyalgia are lower than of controls, even after adjustment of potential confounders.

Carcinoembryonic antigen level can be overestimated in metabolic syndrome.

Carcinoembryonic antigen (CEA) levels can be affected by many factors and metabolic syndrome is also a candidate. This study examined the relationship between CEA levels and metabolic syndrome using the data of 32,897 healthy Koreans. Fecal occult blood tests were also performed. Subjects with colorectal carcinoma were excluded. Subjects were classified by their smoking status, metabolic syndrome and its components. Prevalence of metabolic syndrome and its all components showed a significant increase according to the quartile of serum CEA concentration (P < 0.001). Increased numbers of metabolic syndrome components showed a positive association with CEA levels (P-trend < 0.001). The odds ratios for the highest CEA quartile vs the lowest serum CEA quartile significantly increased in the presence of metabolic syndrome and its components. After adjusting for age, gender and smoking status, metabolic syndrome, low high density lipoprotein cholesterol and elevated blood pressure had higher odds ratios (OR) of the highest CEA quartile compared with the lowest serum CEA quartile (OR = 1.125, 95% CI = 1.030 to 1.222, P = 0.009; OR = 1.296, 95% CI = 1.195 to 1.405, P < 0.001; OR = 1.334, 95% CI = 1.229 to 1.448, P < 0.001, respectively). These results indicate that metabolic syndrome is associated with CEA value, which may lead to a misunderstanding of the CEA levels.

Identification of P2Y12 single-nucleotide polymorphisms and their influences on the variation in ADP-induced platelet aggregation.

INTRODUCTION: Although P2Y12 has a significant role in normal hemostasis and thrombosis, no genetic study has been described about the association between P2Y12 variants and the extent of ADP-induced platelet activation in the Korean population. MATERIALS AND METHODS: The expression levels of two reference sequences of P2Y12 mRNA transcripts (variants 1 and 2) were examined in the whole blood before direct DNA sequencing. The subjects were screened for single-nucleotide polymorphisms (SNPs) in P2Y12 by direct DNA sequencing (n=50). Frequencies of P2Y12 single nucleotide polymorphisms (SNPs), linkage disequilibrium blocks, haplotype structures, and haplotype-tagging SNPs were determined. The effects of genetic variation in the P2Y12 gene on the extent of ADP-induced platelet aggregation were studied in healthy Korean men (n=40). RESULTS: Variant 2 (NM 176876.1) was the predominantly expressed form in all subjects, but variant 1 was also weakly expressed in all cases (n=10). A total of 20 SNPs were identified: 2 in exons, 5 in introns, and 8 and 5 in the 5'-untranslated regions of the known P2Y12 RNA variants 1 and 2, respectively. Genetic analysis of the P2Y12 SNPs and haplotypes revealed a statistically significant association between P2Y12 haplotype, denoted H3, and an increase in the ADP-induced platelet aggregation response relative to that for the reference haplotype H1 (P=0.01). CONCLUSIONS: Application of these findings to the development of a multivariate model might be useful in explaining the variable outcome of antiplatelet drug therapy in Asian populations.

The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15.

OBJECTIVE: This study was addressed to understand the underlying mechanism of the substrate-dependent effect of genetic variation in SLCO1B1, which encodes OATP1B1 (organic anion transporting polypeptide) transporter, on the disposition of two OATP1B1 substrates, pravastatin and pitavastatin, in relation to their transport activities. METHODS: The uptake of pravastatin, pitavastatin, and fluvastatin was measured in oocytes overexpressing SLCO1B1*1a and SLCO1B1*15 to compare the alterations of in-vitro transporting activity. After 40-mg pravastatin or 4-mg pitavastatin was administered to 11 healthy volunteers with homozygous genotypes of SLCO1B1*1a/*1a and SLCO1B1*15/*15, the pharmacokinetic parameters of pravastatin and pitavastatin were compared among participants with SLCO1B1*1a/*1a and SLCO1B1*15/*15 genotypes. RESULTS: The uptake of pravastatin and pitavastatin in SLCO1B1*15 overexpressing oocytes was decreased compared with that in SLCO1B1*15, but no change occurred with fluvastatin. The fold change of in-vitro intrinsic clearance (Clint) for pitavastatin in SLCO1B1*15 compared with SLCO1B1*1a was larger than that of pravastatin (P<0.0001). The clearance (Cl/F) of pitavastatin was decreased to a greater degree in participant with SLCO1B1*15/*15 compared with that of pravastatin in vivo (P<0.01), consistent with in-vitro study. As a result, Cmax and area under the plasma concentration-time curve of these nonmetabolized substrates were increased by SLCO1B1*15 variant. The greater decrease in the transport activity for pitavastatin in SLCO1B1*15 variant compared with SLCO1B1*1a was, however, associated with the greater effect on the pharmacokinetics of pitavastatin compared with pravastatin in relation to the SLCO1B1 genetic polymorphism. CONCLUSION: This study suggests that substrate dependency in the consequences of the SLCO1B1*15 variant could modulate the effect of SLCO1B1 polymorphism on the disposition of pitavastatin and pravastatin.

Duplex pyrosequencing assay of the 388A>G and 521T>C SLCO1B1 polymorphisms in three Asian populations.

BACKGROUND: We developed a method for detecting important SLCO1B1 polymorphisms and compared the haplotype frequencies in 3 Asian populations. METHODS: We designed a duplex pyrosequencing assay to detect simultaneously the 388A>G and 521T>C variants of SLCO1B1; this method can identify SLCO1B1*1b, SLCO1B1*5, and SLCO1B1*15. The method was validated by direct sequencing of 96 Korean subjects. In addition, duplex genotyping and the monoplex method were compared and validated with 469 Korean subjects. To characterize the haplotype frequencies based on the 2 polymorphisms, we genotyped 106 Chinese and 104 Vietnamese subjects, as well as Korean subjects, using the new method. RESULTS: The results showed 100% concordance among the monoplex and duplex pyrosequencing assays and direct sequencing method. The allele frequencies were similar in the 3 Asian populations: the most common allele was SLCO1B1*1b, while SLCO1B1*5 was rare or absent. The frequencies of functional SLCO1B1*15 alleles differed statistically between Chinese (8.2%) and Korean (14.0%) and Vietnamese (16.3%) (p<0.05, chi(2)-test). CONCLUSIONS: The duplex pyrosequencing assay appears to be an accurate, rapid, and cost-effective genotyping method to detect major SLCO1B1 important alleles in Asian populations.