Chengjiao Liu

Bioequivalence and Pharmacokinetic Profiles of Agomelatine 25-mg Tablets in Healthy Chinese Subjects: A Four-Way Replicate Crossover Study Demonstrating High Intra- and Inter-individual Variations

The present study was designed to assess the bioequivalence of two agomelatine formulations (25-mg tablets) in healthy Chinese male subjects. This single-dose, open-label, randomized, four-way replicate study with a 1-week washout period was conducted in 60 healthy Chinese male volunteers under fasting conditions. Blood samples were collected over a 12-h period after a single dose of the 25-mg agomelatine test (T) formulation or a reference (R) formulation, and the drug concentrations were assayed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a non-compartmental model. Bioequivalence between the formulations was assessed. Tolerability and safety were monitored by physical examination, electrocardiogram (12-lead ECG), clinical laboratory tests, and adverse events (AEs). A total of 56 out of 60 subjects completed the study. No AEs were observed. The values of maximum plasma concentration (Cmax), maximum concentration (Tmax), area under curve (AUC)0-t and t1/2 were 12.032 ng/mL, 0.658 h, 12.637 ng·h/mL, and 0.813 h, respectively, for the test formulation, and 10.891 ng/mL, 0.709 h, 11.572 ng·h/mL, and 0.96 h, respectively, for the reference formulation. The intra-individual variability of Cmax and AUC0-t were 78.3 and 61.8%, respectively. The inter-individual coefficients of variance (CVs) of Cmax and AUC0-t were approximately 100%. The 90% confidence intervals for the ratio of means for the log-transformed Cmax (97.7-124.9%), AUC0-t (98.2-118%), and AUC0-∞ (97.8-117.2%) were within the guideline range of bioequivalence (80-125%). The test and reference formulations of agomelatine met the regulatory criteria for bioequivalence of the Chinese Food and Drug Administration. Significant intra-individual and inter-individual variations were found.

Tolerability, pharmacokinetics and antiviral activity of rHSA/IFNα2a for the treatment of chronic hepatitis B infection

Aims A recombinant human serum albumin‐interferon alpha2a fusion protein (rHSA/IFN&agr;2a) is expected to extend the half‐life of IFN&agr;2a. This study aims to evaluate the tolerability, safety and efficacy of rHSA/IFN&agr;2a. Methods This is an open, randomized, positive control, multiple‐dose ascending Phase Ib study. A panel of 32 treatment naïve and non‐cirrhotic chronic hepatitis B patients were divided into four cohorts, and each received 600, 750 or 900 &mgr;g of rHSA/IFN&agr;2a or 180 &mgr;g of PEG‐IFN&agr;2a for 3 months. Tolerability, pharmacokinetics and antiviral responses were assessed. Results Thirty‐one of 32 enrolled patients completed the treatment study. The rHSA/IFN&agr;2a treatment was better tolerated than the PEG‐IFN&agr;2a 180 &mgr;g treatment, as evidenced by blood cell counts and higher serum albumin levels. Half‐life (t1/2) of rHSA/IFN&agr;2a was estimated to be 120–140 h, and is potentially suitable for a dosing interval of 2 weeks or longer. Pharmacokinetics of the last dose between rHSA/IFN&agr;2a 750 &mgr;g and PEG‐IFN&agr;2a 180 &mgr;g, with the exception of t1/2, was comparable, and a similar kinetics of inhibiting HBV DNA replication was observed in both groups. Mean reductions in serum HBV DNA levels after treatment were −1.32, −2.13, −1.10 and −2.48 log10 IU/ml in the 600, 750 and 900 &mgr;g rHSA/IFN&agr;2a groups and PEG‐IFN&agr;2a group, respectively. Conclusions The rHSA/IFN&agr;2a treatment was well tolerated and can be administered biweekly. Similar efficacy in inhibiting HBV replication was observed in both PEG‐IFN&agr;2a and rHSA/IFN&agr;2a 750 &mgr;g groups.

Pharmacokinetics and safety profiles of novel diethylstilbestrol orally dissolving film in comparison with diethylstilbestrol capsules in healthy Chinese male subjects.

OBJECTIVE We compared the pharmacokinetic (PK) profiles of diethylstilbestrol orally dissolving film (DES ODF) and DES-capsule as well as assessing the safety, local tolerability, taste, and disintegration time of DES ODF. MATERIALS AND METHODS Twelve healthy male volunteers receiving a single administration of 2.0 mg of DES ODF or DES-capsule were included in the study. The tolerability, taste, and time to dissolution of DES ODF were assessed after dosing. Safety assessments included adverse events, hematology and biochemistry tests, urinalysis, vital signs, and electrocardiography. RESULTS The PK parameters of DES ODF were all greater than those of DEScapsule. The Cmax values were 5.64 ± 1.1 and 3.4 ± 1.93 ng/mL for DES ODF and DES-capsule, respectively. Assessment of bioequivalence was based on the 90% CIs of the treatment ratios of the log-transformed Cmax, AUC0-t, and AUC0-∞ (DES ODF to DES-capsule), with the mean values being 1.93 (141 - 264), 1.24 (98 - 156), and 1.59 (121 - 207), respectively, indicating that DES ODF had a significantly high bioavailability. The mean DES ODF disintegration time was 14 ± 5 minutes. DES ODF was well tolerated and no serious adverse events or clinically relevant changes were observed. CONCLUSIONS The DES ODF is well tolerated and better absorbed in comparison with DES-capsule.

Association of immune response parameters with virological response in hepatitis C virus patients treated with pegylated consensus interferon.

BACKGROUND A new, potent, long lasting recombinant interferon variant (pegylated consensus interferon, PEGCIFN) was expressed by Escherichia coli. The aim of this study was to test safety and antiviral activity of the new type of interferon in adults with hepatitis C virus (HCV) infection and to determine the relationship between immune response markers and virological response. METHOD 40 naive HCV patients (1 : 1 : 1 : 1) were injected subcutaneously with PEG-CIFN 1.0, 1.5, 2.0 μg/kg and peginterferon-α 180 μg once per week for 12 weeks. Serum HCV RNA, cytokines, chemokines levels were tested, and clinical data were collected at this course. RESULTS PEG-CIFN is safety/tolerability. The serum HCV RNA levels were markedly decreased after therapy. 20% (2/10), 70% (7/10), 70% (7/10), and 60% (6/10) exhibited early virologic responses (EVR (+)) during PEGCIFN 1.0, 1.5, and 2.0 μg/kg treatment and peginterferon-α 180 μg treatment, respectively. Interleukin-4, interferon induced protein 10 (IP-10), and macrophage inflammatory protein 1β (MIP-1β) levels were lower, and granulocyte colony-stimulating factor levels were higher in EVR (+) than in the group not having an EVR (EVR (-)) (p < 0.05) after PEG-CIFN treatment. IP-10 and MIP-1β levels were associated with HCV RNA values, alanine aminotransferase, and aspartate aminotransferase levels after PEG-CIFN treatment. CONCLUSION PEGCIFN was well tolerated and effective at inhibiting HCV RNA, which is associated with changes in markers of immune response. PEG-CIFN 1.5 μg/kg has been selected for further hepatitis C clinical development.

Clinical evaluation of efficacy, tolerability and pharmacokinetics of yimitasvir phosphate in patients infected with hepatitis C virus

Yimitasvir phosphate, an inhibitor of nonstructural protein 5A (NS5A) replication complex of hepatitis C virus (HCV), was evaluated in a double‐blind, placebo‐controlled, parallel, multiple‐dose study.

Association of Variability and Pharmacogenomics With Bioequivalence of Gefitinib in Healthy Male Subjects

Objective: The aim of the study was to explore the association of pharmacokinetic variability and pharmacogenomics with the bioequivalence of orally administered gefitinib (Iressa®, AstraZeneca) provided by three sponsors in healthy subjects. Methods: The study designs were randomized, open-label, and two-period crossover studies in both fasting and fed healthy subjects. In one fasting study, the sample size was enlarged from 30 to 60 for the failing study. Each study subject received a 250-mg gefitinib tablet with a 21-day washout. The plasma concentrations were measured using LC-MS/MS, and pharmacokinetic parameters were determined by noncompartmental methods. Genetic analyses of CYP3A4, CYP3A5, and CYP2D6 alleles were carried out by the polymerase chain reaction (PCR). Results: Two hundred and sixty healthy male subjects were enrolled. The median maximum plasma concentration (Tmax) was 4–5 h, and the mean elimination half-life (t1/2) was 18–26 h. The maximum plasma concentration (Cmax) and area under the curve (AUC) increased but Tmax and t1/2 were unaffected by the intake of high-fat food. Three fed and two fasting studies achieved a plausible bioequivalence. The intake of high-fat food decreased the intra-subject variability significantly. In addition, CYP2D6 was associated with gefitinib exposure and may contribute to the high inter-subject variability, but it did not influence the bioequivalence result. Conclusions: Gefitinib is well tolerated, and the bioequivalence is easier to achieve under fed conditions compared to fasting conditions. The 90% confidence interval (CI) of geometric mean ratio (GMR) can be narrowed when the sample size is enlarged without changing the formulation-related technology.

Bioequivalence of Sarpogrelate in Healthy Chinese Subjects Under Fasting and Fed Conditions: A 4-Way Replicate Crossover Investigation by a Reference-Scaled Average Bioequivalence Approach

Sarpogrelate is widely used to treat peripheral vascular disorders. However, it has been demonstrated to have a poor pharmacokinetic (PK) profile and marked within‐subject variability. Here, the bioequivalence of 2 formulations of sarpogrelate (100‐mg tablets) was assessed by using the reference‐scaled average bioequivalence (RSABE) method, and the PK parameters were quantified in healthy Chinese subjects under fasting (n = 38) and fed (n = 35) conditions. In this open and randomized 4‐way replicate study, a single dose of sarpogrelate was administered followed by a 3‐day washout period. The sarpogrelate concentration in blood samples was measured by liquid chromatography‐tandem mass spectrometry within 6 hours (fasting) or 10 hours (fed) of drug administration, and the PK parameters were determined by a noncompartmental model. The bioequivalence of the 2 formulations under both conditions was assessed using the ratios of ln(peak concentration [Cmax]) and ln(area under the concentration‐time curve [AUC]) within the limits based on the RSABE method. The 90% CIs for the ratios of lnCmax, lnAUC0‐t, and lnAUC0‐∞ were 0.8531–1.1100, 0.9616–1.0737, and 0.9550–1.0684, respectively, under fasting conditions and 0.8918–1.1076, 0.9818–1.0694, and 0.9818–1.0686, respectively, under fed conditions, which were within the RSABE acceptance limits. Food intake decreased the systemic exposure and the Cmax of sarpogrelate by 0.9‐fold and 0.5‐fold, respectively.