Pharmacokinetic Study of Enteric-Coated Sustained-Release Aspirin Tablets in Healthy Chinese Participants.

Purpose: To study and compare the pharmacokinetic characteristics of enteric-coated sustained-release (EcSr) aspirin tablets with enteric-coated (Ec) aspirin tablets (Bayer S.p.A) in healthy Chinese participants. Patients and Methods: In this open, randomized, single-dose, three-way, crossover study, 18 healthy participants randomly received 100 mg EcSr tablets pre-prandially (a.c.), EcSr tablets post-prandially (p.c.), or Ec tablets a.c. in each period. The concentrations of acetylsalicylic acid (ASA) and salicylic acid (SA) in plasma were determined by the LC-MS/MS method, and the pharmacokinetic parameters were calculated using WinNonlin (version 8.1). Results: The essential PK parameters under the three treatment conditions (ie Ec a.c., EcSr a.c. and EcSr p.c.) were as follows: Cmax, ASA: 758.38±455.34, 222.77±98.04 and 194.54±61.19 ng, Tmax, ASA: 6.75(2,16), 4.5(2,11) and 8.25(5,11) h, T1/2, ASA: 0.43±0.08, 1.44±0.59 and 4.32±10.04 h, AUC0-t, ASA: 1008.88±452.27, 918.04±238.40 and 845.55±183.25 h·ng/mL; Cmax, SA: 6409.38±2098.52, 2863.53±679.73 and 2913.75±853.27ng/mL, Tmax, SA: 7.25(2,24), 10(3.5-14) and 10(7,14) h, T1/2, SA: 2.21±0.46, 2.69±0.72 and 3.51±2.06h, AUC0-t, SA: 29,131.41±9376.23, 27,243.97±7465.16, 27,240.25±7444.67 h·ng/mL. When taking EcSr aspirin tablets, the 90% confidence intervals of the geometric mean ratios (pre-prandial/post-prandial) of AUC0-t, ASA and AUC0-∞, ASA, Cmax, SA, AUC0-t, SA and AUC0-∞, SA were within the range of 80.00%-125.00%. Conclusion: EcSr aspirin tablets showed less inter-individual variation in release and absorption than Ec aspirin tablets, which was well reflected by comparing essential PK parameters. Furthermore, meals had no significant effect on the pharmacokinetics of EcSr aspirin tablets.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Opicapone in Healthy Chinese and Caucasian Subjects: An Open-Label, Single-Center, Phase 1 Study.

INTRODUCTION: This study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of opicapone (OPC) in healthy Chinese and Caucasian subjects. METHODS: In this open-label, single-center, phase 1 study, eligible Chinese subjects received one of three OPC doses (25, 50, or 100 mg), and Caucasian subjects received either 25 or 50 mg of OPC. All subjects were administered a single dose of OPC, whereas subjects in the 50-mg OPC group continued to receive once-daily doses of 50 mg OPC for 10 days. The primary endpoint was to evaluate and compare the plasma concentrations and PK parameters of OPC and its main metabolite, and erythrocyte-soluble catechol-O-methyltransferase (S-COMT) activity in Chinese subjects with that of Caucasian subjects. The secondary endpoint was to evaluate the safety of OPC in Chinese subjects. The estimated results for geometric mean ratios (GMRs) were evaluated with the standard bioequivalence (BE) limits between 80% and 125% to evaluate the ethnic differences. All statistical analyses were performed using SAS version 9.4. RESULTS: In total, 70 subjects (45 Chinese, 25 Caucasian) were enrolled; the majority of them were male (85.7%). The plasma exposure of both OPC and BIA 9-1103 increased in an approximately dose-proportional manner in both populations. Maximum S-COMT inhibition ranged from 79% to 95% after a single dose and was about 94% after a 10-day once-daily regimen in both populations. The point estimates of GMRs (Chinese/Caucasian) and 90% CI, except Cmax in 25-mg and 50-mg OPC groups, for PK and PD parameters were within 80% to 125%. Furthermore, no new risks or safety concerns associated with OPC were identified, indicating a tolerable safety profile in healthy Chinese subjects. CONCLUSION: Ethnicity had no significant impact on PK and PD parameters after single or multiple doses of OPC, and OPC was safe and tolerable in healthy Chinese subjects. TRIAL REGISTRATION: ChiCTR number, CTR20192230.

The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects.

Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatran-related genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on Cmax and AUC0-∞.

Pharmacokinetics of Opicapone and Its Metabolites in Healthy White and Chinese Subjects.

Opicapone (OPC) is a third-generation catechol-O-methyltransferase inhibitor developed to treat Parkinson disease and motor fluctuations. This open-label, single-center, phase 1 study aimed to evaluate the pharmacokinetics (PK) of OPC and its metabolites when administered as single and multiple doses in healthy White and Chinese subjects. The study enrolled a total of 30 White and Chinese healthy subjects, equally balanced among groups. The first dose of OPC was administered orally as a single dose of 50 mg on day 1, followed by a 10-day once-daily treatment from day 5 to day 14. Plasma concentrations of OPC and its metabolites were measured at 0 to 72 and 0 to 144 hours after dosing for single dose and multiple dose, respectively. Moreover, urine concentrations of OPC and its metabolite were measured 0 to 24 hours after dosing. PK parameters were derived from noncompartmental analysis. Geometric mean ratios and 90% confidence intervals for the main PK parameters were conducted to evaluate the ethnic difference between White and Chinese subjects. The plasma and urine exposure of OPC and its metabolites in Chinese subjects were similar to those in White subjects. These results indicated that ethnicity had no significant impact on PK of OPC between White and Chinese subjects.

Host chemokine signature as a biomarker for the detection of pre-cancerous cervical lesions.

BACKGROUND: The ability to distinguish which hrHPV infections predispose to significant disease is ever more pressing as a result of the increasing move to hrHPV testing for primary cervical screening. A risk-stratifier or "triage" of infection should ideally be objective and suitable for automation given the scale of screening. RESULTS: CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL12 emerged as the strongest, candidate biomarkers to detect underlying disease [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)]. For CIN2+, CCL2 had the highest area under the curve (AUC) of 0.722 with a specificity of 82%. A combined biomarker panel of six chemokines CCL2, CCL3, CCL4, CXCL1, CXCL8, and CXCL12 provides a sensitivity of 71% and specificity of 67%. CONCLUSION: The present work demonstrates that the levels of five chemokine-proteins are indicative of underlying disease. We demonstrate technical feasibility and promising clinical performance of a chemokine-based biomarker panel, equivalent to that of other triage options. Further assessment in longitudinal series is now warranted. METHODS: A panel of 31 chemokines were investigated for expression in routinely taken archived and prospective cervical liquid based cytology (LBC) samples using Human Chemokine Proteomic Array kit. Nine chemokines were further validated using Procartaplex assay on the Luminex platform.

Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease.

High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively.