Healthy Chinese Male Subjects Research Articles

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

The aim of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence of 2 formulations of agomelatine, and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects. This was performed in a single-dose, randomized-sequence, open-label, four-way crossover study with a one-day washout period between doses. Healthy Chinese males were randomly assigned to receive 25mg of either the test or reference formulation. The formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios and ratio of geometric means (GMR) of AUC and Cmax of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and Cmax of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of Cmax, AUC0–t and AUC0–∞ of agomelatine (104.42–139.86, 101.33–123.83 and 97.90–117.94) were within the RSABE acceptance limits, and 3-hydroxy-agomelatine (105.55–123.03, 101.95–109.10 and 101.72–108.70) and 7-desmethyl-agomelatine (104.50–125.23, 102.36–111.50 and 101.62–110.64) were within the FDA bioequivalence definition intervals (0.80–1.25 for AUC and 0.75–1.33 for Cmax). The RSABE approach was successful in evaluating the bioequivalence of these two formulations.

Influence of genetic polymorphisms on the pharmacokinetics of celecoxib and its two main metabolites in healthy Chinese subjects

Celecoxib is a selective cyclooxygenase-2 inhibitor used extensively for the treatment of rheumatism and osteoarthritis. The aim of this study was to evaluate the influence of the genetic polymorphisms of CYP2C9, CYP2D6 and CYP3A4 on the pharmacokinetics (PK) of celecoxib and its two main metabolites, hydroxyl-celecoxib and carboxy-celecoxib, in healthy Chinese subjects, based on a bioequivalence study of celecoxib. This study was an open-label, two-period, crossover study. 52 healthy Chinese male subjects were recruited and were genotyped for CYP2C9*3, CYP2C9*13, CYP2D6*10 and CYP3A4*18 by using polymerase chain reactions (PCR). They were randomly divided into two groups and each group received either 200mg test formulation followed by reference formulation or vice versa with a one-week washout period. Safety and tolerability were monitored throughout the study and no severe adverse events were observed. Genotyping using PCR revealed that none of the subjects carried the CYP3A4*18 and CYP2C9*13. Therefore, the influence of the CYP2C9*3 and CYP2D6*10 on the PK of celecoxib and its metabolites in Chinese was studied. Compared with CYP2C9*1/*1 group, pharmacokinetic parameters of celecoxib such as AUC0–48 and Cmax was increased by 90.6% and 45.8%, the t1/2 was extended by 21.8% and the CL/F was decreased by 51.1% in CYP2C9*1/*3 group. In terms of hydroxy-celecoxib, compared with CYP2C9*1/*1 group, the Cmax was decreased by 17.2%, the t1/2 prolonged 42.1% in CYP2C9*1/*3 group. In terms of carboxy-celecoxib, the AUC0–48 was increased by 25.2%, the t1/2 prolonged 16.1% and the CL/F was decreased by 21.2% in CYP2C9*1/*3 group. Except for the t1/2 of hydroxy-celecoxib, no statistically significant difference was observed in other pharmacokinetic parameters of hydroxy-celecoxib and carboxy-celecoxib between the two CYP2C9 genotypic groups. This study revealed that there was no significant influence of CYP2D6*10 on the metabolism of celecoxib, and the expression of CYP2C9*3 led to increased drug exposure and slowed drug disposition in healthy Chinese male subjects.

The effect of food on the pharmacokinetic properties and bioequivalence of two formulations of pitavastatin calcium in healthy Chinese male subjects

1. Pitavastatin is an effective treatment for primary hyperlipidemia and mixed dyslipidemia. The aim of the present study was to investigate the effect of food on the pharmacokinetic properties and bioequivalence of the original, branded, formulation of pitavastatin calcium and a new generic formulation in healthy Chinese male subjects under fasting and fed conditions.2. Under fasting and fed conditions, 90% CIs of the geometric mean of generic/branded AUC0–48 h ratios were 92.2–102.4%, 93.1–104.5%, the ratios of ln(AUC0–∞) were 92.6–103.7%, 93.2–103.5%, and ln(Cmax) ratios were 90.7–110.3%, 84.7–100.8%, respectively. The generic and branded formulations were bioequivalent in terms of rate and extent of absorption under both the conditions. The average values of AUC0–48 h, AUC0–∞ and Cmax decreased noticeably following a high-fat breakfast. Values for AUC0–48 h were 87.69% and 83.7%, values for AUC0–∞ were 87.5% and 84.6%, and values for Cmax were 45.0% and 50.4% in subjects given the generic and branded preparations, respectively. The absorption of pitavastatin calcium tablets was delayed following a high-fat meal, with Tmax increasing by up to 2.43-fold.3. Both formulations were generally well tolerated, with no serious adverse reactions reported. The newly developed generic formulation may provide a reliable alternative to the branded tablets for patients with primary hyperlipidemia or mixed dyslipidemia.

CYP3A5*3 and MDR1 C3435T are influencing factors of inter-subject variability in rupatadine pharmacokinetics in healthy Chinese volunteers.

Rupatadine (RUP) is an oral antihistamine and platelet-activating factor antagonist and is shown as the substrate of CYP3A5 and P-gp. The significant interindividual differences of CYP3A5 and P-gp often cause bioavailability differences of some clinical drugs. The present study is aimed to evaluate the effect of genetic polymorphisms of CYP3A5 and MDR1 on RUP pharmacokinetics in healthy male Chinese volunteer subjects. Blood samples were collected from 36 subjects before and after a single, oral RUP 10 mg dose. A PCR-RFLP assay was used to genotype CYP3A5*3 and assess MDR1 C3435T variation. A validated LC-MS/MS method quantified plasma RUP concentration. The relationship between RUP plasma concentration, pharmacokinetic parameters, and polymorphic alleles (CYP3A5 and MDR1) were assessed. Plasma RUP concentrations were lower for CYP3A5*1/*1 carriers than for CYP3A5*3/*3 and CYP3A5*1/*3 carriers. Mean C(max), AUC(0-t) and AUC(0-∞) were significantly lower, and the CLz and Vd were significantly higher in the CYP3A5 wild-type group, than in the CYP3A5 mutated group. MDR1 CT and MDR1 TT carriers had lower plasma RUP concentrations than MDR1 CC carriers. The mean C(max), AUC(0-t), AUC(0-∞) and T max were significantly lower in the TT group than in the CC and CT groups. The mean CLz was higher in the TT group than in the CC and CT groups, but not significantly. These results suggest that CYP3A5 and MDR1 may play a key role in the variability of RUP metabolism and transport, respectively. CYP3A5 and MDR1 polymorphisms may be the main explanation for the differences observed in RUP pharmacokinetics, and therefore may provide a rationale for safe and effective clinical use of RUP. Our research lays down a solid theory foundation to guide the safe and effective clinical use of RUP and a route to achieve individualized therapy.

Pharmacokinetic Interaction of Finasteride With Tamsulosin Hydrochloride: An Open-label, Randomized, 3-period Crossover Study in Healthy Chinese Male Volunteers

PurposeThe primary aim of this study was to evaluate whether there was clinically significant pharmacokinetic (PK) interaction between finasteride and tamsulosin in healthy Chinese male subjects. MethodsThis was an open-label, randomized, 3-period, crossover study. Subjects received single and multiple doses of 5 mg finasteride alone, single and multiple doses of 0.2 mg tamsulosin hydrochloride sustained-release capsule alone, and single and multiple doses of 5 mg finasteride with 0.2 mg tamsulosin hydrochloride, in an order determined by a computerized randomization schedule. Blood samples were collected up to 48 hours after dosing on study day 1 and up to 24 hours after dosing on study day 9 for determination of plasma concentrations with a validated LC-MS/MS method. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECG. FindingsFifteen subjects were enrolled, and 14 completed the study. The geometric mean ratios (GMRs) (90% CIs) of AUCτ,ss and Cmax,ss values of finasteride at steady state between coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.14 (1.05–1.23) and 1.06 (0.99–1.14), respectively. The GMRs (90% CIs) for AUC0–t and Cmax values of finasteride for a single dose of coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.02 (0.94–1.11) and 1.06 (1.01–1.11), respectively. The GMRs (90% CIs) for AUCτ,ss and Cmax,ss values of tamsulosin at steady-state for coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.18 (1.05–1.33) and 1.23 (1.06–1.43), respectively. The GMRs (90% CIs) for AUC0–t and Cmax values of tamsulosin for a single dose of coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.04 (0.97–1.10) and 1.04 (0.98–1.11), respectively. Statistical analyses confirmed that the 90% CIs for these PK parameters were within the predefined not clinically significant PK drug-drug interaction effect boundaries (0.5–2.0) in this study. If comparing the findings with narrower boundaries (0.8–1.25), the conclusion may not be supportive for tamsulosin hydrochloride. During the study, a total of 4 adverse events were reported in 3 subjects including allergic reaction, abnormal findings on an ECG, a slight increase in alanine aminotransferase, and a positive result on glucose urine test. ImplicationsBoth finasteride and tamsulosin hydrochloride were well tolerated. Coadministration of finasteride and tamulosin hydrochloride seems unlikely to lead to a clinically significant PK drug-drug interaction, after a single dose and at steady state.

Evaluation of the highly variable agomelatine pharmacokinetics in Chinese healthy subjects to support bioequivalence study.

ObjectivesWe aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy.MethodsA single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples.ResultsThe intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%).ConclusionsAgomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies.Trial RegistrationChiCTR.org ChiCTR-TTRCC-13003835

Clock gene modulates roles of OXTR and AVPR1b genes in prosociality.

BackgroundThe arginine vasopressin receptor (AVPR) and oxytocin receptor (OXTR) genes have been demonstrated to contribute to prosocial behavior. Recent research has focused on the manner by which these simple receptor genes influence prosociality, particularly with regard to the AVP system, which is modulated by the clock gene. The clock gene is responsible for regulating the human biological clock, affecting sleep, emotion and behavior. The current study examined in detail whether the influences of the OXTR and AVPR1b genes on prosociality are dependent on the clock gene.Methodology/Principal FindingsThis study assessed interactions between the clock gene (rs1801260, rs6832769) and the OXTR (rs1042778, rs237887) and AVPR1b (rs28373064) genes in association with individual differences in prosociality in healthy male Chinese subjects (n = 436). The Prosocial Tendencies Measure (PTM-R) was used to assess prosociality. Participants carrying both the GG/GA variant of AVPR1b rs28373064 and the AA variant of clock rs6832769 showed the highest scores on the Emotional PTM. Carriers of both the T allele of OXTR rs1042778 and the C allele of clock rs1801260 showed the lowest total PTM scores compared with the other groups.ConclusionsThe observed interaction effects provide converging evidence that the clock gene and OXT/AVP systems are intertwined and contribute to human prosociality.

Effects of grapefruit juice on cortisol metabolism in healthy male Chinese subjects

Grapefruit juice (GFJ) inhibits intestinal CYP3A4 activity and it has been suggested that GFJ may also inhibit renal 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which converts cortisol to cortisone. This study examined the effect of GFJ on the urinary excretion of cortisol, cortisone and 6β-hydroxycortisol (6β-OHC) and their ratios to asses these effects. Healthy male Chinese subjects took single doses of GFJ (200, 400, and 600 mL, respectively) at weekly intervals. Urine was collected over 24 h the day before and following GFJ intake. Subsequently, volunteers drank 400 mL GFJ for 7 days and urine was collected from 0 to 4 h daily. GFJ had dose-dependent effects on increasing cortisol excretion (P < 0.05) and the ratio of cortisol to cortisone (P < 0.005) and reducing 6β-OHC excretion (P < 0.05) and the ratio of 6β-OHC to cortisol (P < 0.005). There was no significant effect on cortisone excretion. Maximal effects were observed within 4 h after GFJ ingestion. Repeated doses had persistent but no cumulative effects. GFJ significantly reduced the ratio of 6β-OHC to cortisol. It increased the ratio of cortisol to cortisone and this appeared largely due to increased cortisol excretion related to impaired CYP3A4-mediated cortisol metabolism although a true inhibitory effect on 11β-HSD2 in the kidney cannot be excluded.

Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult Chinese subjects.

As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the potential for increased patient compliance with the convenience of once daily dosing. The aim of the present study was to show that the FDC of saxagliptin and metformin XR is bioequivalent to co-administration of the individual components when given to Chinese subjects residing in China. This was a randomized, open-label, single-dose, two-period, cross-over pharmacokinetic study in two cohorts of healthy adult Chinese male subjects (n=32 in each cohort) under fed conditions. In cohort 1, the pharmacokinetic properties of a saxagliptin/metformin XR 5/500mg FDC tablet were compared with those of co-administration of a 5mg saxagliptin tablet and a 500mg metformin XR tablet. In cohort 2, the pharmacokinetic properties of a saxagliptin/metformin XR 5/1,000mg FDC tablet were compared with those of co-administration of a 5mg saxagliptin tablet and 2×500mg metformin XR tablets. The two cohorts were independent of each other with respect to treatment and results. The pharmacokinetic properties of the active metabolite of saxagliptin (5-hydroxy-saxagliptin), as well as the safety and tolerability of each treatment, were also evaluated. For both cohorts, saxagliptin and metformin in the FDCs were bioequivalent to the individual components, as the limits of the 90% confidence intervals of the geometric least squares mean ratios were contained within the 80-125% bioequivalence limits for the area under the plasma concentration-time curve parameters and within the 70-143% bioequivalence limits for the maximum plasma concentration. Similar exposures of 5-hydroxy-saxagliptin were observed with the two treatment regimens within each cohort. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. Saxagliptin/metformin XR 5/500mg and saxagliptin/metformin XR 5/1,000mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin XR of the same strengths and were generally well tolerated. These results in healthy Chinese subjects are consistent with those of previous assessments of saxagliptin/metformin XR FDC in the saxagliptin clinical development programme.

Quantification of strontium in human serum by ICP-MS using alternate analyte-free matrix and its application to a pilot bioequivalence study of two strontium ranelate oral formulations in healthy Chinese subjects

A rapid, sensitive and accurate ICP-MS method using alternate analyte-free matrix for calibration standards preparation and a rapid direct dilution procedure for sample preparation was developed and validated for the quantification of exogenous strontium (Sr) from the drug in human serum. Serum was prepared by direct dilution (1:29, v/v) in an acidic solution consisting of nitric acid (0.1%) and germanium (Ge) added as internal standard (IS), to obtain simple and high-throughput preparation procedure with minimized matrix effect, and good repeatability. ICP-MS analysis was performed using collision cell technology (CCT) mode. Alternate matrix method by using distilled water as an alternate analyte-free matrix for the preparation of calibration standards (CS) was used to avoid the influence of endogenous Sr in serum on the quantification. The method was validated in terms of selectivity, carry-over, matrix effects, lower limit of quantification (LLOQ), linearity, precision and accuracy, and stability. Instrumental linearity was verified in the range of 1.00–500ng/mL, corresponding to a concentration range of 0.0300–15.0μg/mL in 50μL sample of serum matrix and alternate matrix. Intra- and inter-day precision as relative standard deviation (RSD) were less than 8.0% and accuracy as relative error (RE) was within ±3.0%. The method allowed a high sample throughput, and was sensitive and accurate enough for a pilot bioequivalence study in healthy male Chinese subjects following single oral administration of two strontium ranelate formulations containing 2g strontium ranelate.

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

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. 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. 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. The DES ODF is well tolerated and better absorbed in comparison with DES-capsule.

Rapid determination of glutamine in human plasma by high-performance liquid chromatographic-tandem mass spectrometry and its application in pharmacokinetic studies.

A rapid and accurate high-performance liquid chromatographic-tandem mass spectrometric method was developed and validated for the determination of glutamine in human plasma. Phenomenex EZ: faast(TM) amino acid analysis kit was used for sample pretreatment. Chromatographic separation was conducted on an EZ: faast amino acid analysis-mass spectrometry column (250 × 3.0 mm i.d., 4 μm). A binary gradient elution of mobile phases A (0.2% formic acid containing 5 mM ammonium acetate) and B (methanol, containing 0.2% formic acid and 5 mM ammonium acetate) was programmed at 0.4 mL/min. Multiple reaction monitoring was used for quantification by monitoring ion transitions of m/z 275.3/172.1 for derivatized glutamine and 317.3/84.1 for internal standard in the electrospray positive ionization mode. The standard curve was linear (r(2) > 0.99) over the concentration range of 3.14-157.20 μg/mL. The intra- and inter-day precision values were <8.70% and the accuracy within -4.35 to 8.91% at three concentrations. The method was successfully applied to the pharmacokinetic study in Chinese healthy male subjects following oral administration of glutamine with doses of 2 and 4 g.

Abstract P423: Effects of Green Tea and Soy Isoflavones on Plasma Lipids In Healthy Subjects

Introduction: Green tea and soy products are widely consumed in daily life and are considered to have beneficial effects on reducing cardiovascular risks. The flavonoids present in soya bean and tea leaves are believed to be responsible for the proposed benefits. Hypothesis: We assessed the hypothesis that epigallocatechin gallate (EGCG), the most abundant active component of green tea and soy isoflavonoids may reduce the plasma lipid levels in healthy volunteers. Methods: Healthy Chinese male subjects were given green tea extract containing EGCG 800 mg once daily for 14 days and soy isoflavones extract 80 mg once daily for 14 days with a wash-out of at least 4-weeks between the two treatments. Sitting blood pressure and fasting plasma lipids were measured at baseline, after green tea and after soy isoflavones, respectively. Results: In 18 healthy male subjects (mean age 26.6 ± 6.0 years, weight 61.7 ± 6.3 kg), consumption of green tea extract, but not soy isoflavones, was associated with significant reductions in plasma low-density lipoprotein cholesterol (LDL-C) (8.1% [95% confidence interval: -2.0, -14.3%], P&lt;0.01) and total cholesterol (4.8 % [0.4,-10.1%], P&lt;0.05) compared to baseline (Table 1). Reduction in LDL-C with green tea was observed in 15 out of 18 subjects and the change in LDL-C was not affected by the baseline levels. Neither product influenced the plasma high-density lipoprotein cholesterol (HDL-C) or triglyceride levels or blood pressure in this normotensive group of subjects (Table 1). Conclusion: This study showed that short term treatment with a high dose of green tea extract, which is equivalent to about 7-10 cups of green tea, reduced plasma LDL-C which may be beneficial for reducing cardiovascular risk.

Association of platelet ITGA2B and ITGB3 polymorphisms with ex vivo antiplatelet effect of ticagrelor in healthy Chinese male subjects

Ticagrelor (TIC) is the first reversible P2Y12 receptor antagonist that exhibits rapid antiplatelet effect by indirect inhibition of the GPIIb/IIIa complex. Polymorphisms in genes coding GPIIb/IIIa, namely ITGA2B and ITGB3, are associated with aspirin resistance and risk for thrombotic diseases. We assessed whether ITGA2B and ITGB3 polymorphisms can influence the ex vivo antiplatelet activity of ticagrelor in Chinese population. A total of 196 healthy Chinese male individuals were recruited. ADP-induced platelet aggregation was determined using optical aggregometry at baseline and after incubation of the platelet-rich plasma with 15 and 50 μM ticagrelor, respectively. Single nucleotide polymorphisms in ITGA2B (rs5911 G>T) and ITGB3 (rs4642 A>G and rs4634 G>A) were genotyped by sequencing. TIC at both concentrations of 15 and 50 μM decreased ADP-induced platelet aggregation significantly (P < 0.05, respectively). As compared to ITGA2B rs5911 GG homozygotes, individuals with the rs5911 TG genotype showed significantly increased inhibition of platelet aggregation (IPA) by both 15 and 50 μM ticagrelor incubation (P < 0.05, respectively). Neither rs4642 nor rs4634 polymorphism affected ticagrelor-induced IPA. We suggest that the ITGA2B rs5911 GG genotype is associated with decreased ex vivo antiplatelet activity of ticagrelor in healthy Chinese male subjects.

Optimization of solid phase extraction clean up and validation of quantitative determination of carbazochrome sodium sulfonate in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry

A mixed-mode anion exchange solid phase extraction (SPE) method for extraction and clean up of carbazochrome sodium sulfonate (CSS) and (1S)-(+)-10-camphorsulfonic acid (IS) was optimized for quantification by high-performance liquid chromatography/negative electrospray ionization mass spectrometry. The analytes were extracted from 1mL of human plasma via SPE on Oasis(®) WAX cartridge. Chromatographic separation was achieved on a Zorbax SB-Aq (4.6×250mm, 5μm) column under an isocratic condition. Detection was performed using electrospray ionization in negative ion multiple reaction monitoring (MRM) mode. The deprotonated precursor to product ion transitions monitored for CSS and IS was at m/z 299.0→256.0 and m/z 230.9→79.8, respectively. The method was fully validated for its selectivity, sensitivity, precision, accuracy, recovery, matrix effect and stability. Linear range was 0.189-37.8ng/mL with a high square regression coefficient (r=0.9995). The intra-and inter-day precision (RSD, %) ranged from 0.95% to 4.17%, and the intra-and inter-day accuracy was between 95.03% and 105.9%. This method was successfully applied to a bioequivalence study of 90mg CSS formulation in 18 healthy Chinese male subjects under fasting condition.

Bioequivalence Study of Two 30 Mg Tolvaptan Tablets Formulations in Healthy Chinese under Fed Condition

Objective: The purpose of this study was to compare the bioavailability between the two 30 mg tolvaptan tablets formulations and to evaluate the bioequivalence of Reference and Test formulations of tolvaptan tablets 30 mg in healthy adult male and female subjects under fed condition. Method: 50 healthy Chinese male and female subjects were enrolled in a single-center, randomized, open-label, single-dose, two-treatment, two-sequence, two-period, crossover study. The plasma of tolvaptan were determined by a validated LC- MS/MS method. The bioequivalence of Test and Reference will be determined based on AUC0-t, AUC0A¢Â€Â‘inf and Cmax of tolvaptan in plasma. Results: All the 50 subjects completed the study and the main pharmacokinetic parameters for test and reference preparations were as follows: Cmax were 308.8 ± 108.8 and 339.9 ± 114.3 ng/mL, tmax were 2.670 (1.0–6.0) and 2.330 (1.0–6.0) h, AUC0-48 were 1832 ± 781.8 and 1702 ± 616.2 ngA¢ÂˆÂ™h/ml, AUC0-inf were 1848 ± 785.2 and 1720 ± 616.7 ngA¢ÂˆÂ™h/ml, t1/2 were 4.742 ± 1.129 and 4.608 ± 1.120 h. The 90% confidence intervals (CIs) of Cmax, AUC0-48 and AUC0-inf on the ratio of test to reference formulation were 82.83%-97.61%, 99.55%-112.91% and 99.44%-112.66%, respectively. The results of two one-side t test and variance analysis showed that there was no significant difference between the main parameters of the two preparations (P>0.05). Conclusion: This study shows that two tolvaptan tablets 30 mg preparations are bioequivalent in Chinese adult healthy volunteers under fed condition.

Pharmacokinetics and Bioequivalence Comparison of 600 mg Single-Dose Linezolid Oral Suspension and Tablet Formulation in Healthy Chinese Subjects

Study background:Linezolid is indicated for the treatment of infections caused by aerobic Gram-positive bacteria. An oral suspension formulation poses an alternative to solid oral formulations in patients with swallowing difficulties, especially pediatric and geriatric patients, or patients with feeding tubes. Methods: This randomized, open-label, two-way cross-over, clinical pharmacology study in healthy Chinese male subjects evaluated the bioequivalence of single-dose 600 mg linezolid oral suspension to single-dose 600 mg linezolid film-coated tablet under fasted conditions. Pharmacokinetic blood sampling was carried out at various time points within 48 h post-dosing and plasma samples were analyzed using a validated high-performance liquid chromatography tandem mass spectrometric method. The primary endpoints were area under plasma concentration– time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast) and maximum plasma concentration (Cmax)for linezolid. Results: All 20 enrolled male subjects completed the study (mean age 25 years, mean body mass index 22 kg/ m2). The 90% confidence intervals (CIs) for the ratios of the adjusted geometric means of the primary endpoints, AUClast(97.81% [90% CI, 93.11-102.75%])and Cmax (113.67% [90% CI, 105.26-122.75%]), for the oral suspension formulation compared with the oral tablet were fullywithin the established bioequivalence limits of 80-125%. The two linezolid formulations were well tolerated and no serious adverse event or other significant adverse event was noted. Conclusions: Based on the results of this study, linezolid 600 mg oral suspension and linezolid 600 mg tablets are anticipated to be therapeutically equivalent and could be switched in subjects without any need for dose modification. Both formulations were safe and well tolerated.

Simple and Robust Analysis of Cefuroxime in Human Plasma by LC-MS/MS: Application to a Bioequivalence Study.

A simple, robust LC-MS/MS assay for quantifying cefuroxime in human plasma was developed. Cefuroxime and tazobactam, as internal standard (IS), were extracted from human plasma by methanol to precipitate protein. Separation was achieved on a Zorbax SB-Aq (4.6 × 250 mm, 5 μm) column under isocratic conditions. The calibration curve was linear in the concentration range of 0.0525–21.0 μg/mL (r = 0.9998). The accuracy was higher than 90.92%, while the intra- and interday precision were less than 6.26%. The extraction procedure provides recovery ranged from 89.44% to 92.32%, for both analyte and IS. Finally, the method was successfully applied to a bioequivalence study of a single 500 mg dose of cefuroxime axetil in 22 healthy Chinese male subjects under fasting condition. Bioequivalence was determined by calculating 90% Cls for the ratios of C max, AUC0−t, and AUC0−∞ values for the test and reference products, using logarithmic transformed data. The 90% Cls for the ratios of C max (91.4%~104.2%), AUC0−t (97.4%~110.9%), and AUC0−∞ (97.6%~111.1%) values were within the predetermined range. It was concluded that the two formulations (test for capsule, reference for tablet) analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

A single and multiple dose study to investigate the pharmacokinetics of a prolonged release formulation of ropinirole in healthy Chinese subjects.

An open-label, single, and 7-day multiple dose study was conducted to investigate the pharmacokinetics, safety and tolerability of a prolonged release formulation of ropinirole 2 mg in healthy Chinese male (n = 12) and female (n = 12) subjects. After single doses, median tmax was 8 hours and mean t12 was 5.26 hours. After 7 days dosing, median tmax was 6 hours (t12 not determined). Systemic exposure, AUC and Cmax , following multiple and single dosing was similar (mean AUC(0-τ) (h ng/mL): 23.84 vs. AUC(0-∞) : 22.13; Cmax (ng/mL) 1.48 vs. 1.21, respectively). Systemic exposure was higher in females than males following single doses (mean AUC(0-24) (h ng/mL): 21.45 vs. 15.48; P = 0.009; Cmax (ng/mL): 1.40 vs. 0.99; P = 0.014, respectively), but similar at steady state (mean AUC(0-τ) (h ng/mL): 24.96 vs. 22.62; Cmax (ng/mL): 1.56 vs. 1.39, respectively). Estimated accumulation ratio was 1.29 (90% CI: 1.11, 1.51). Ropinirole did not display time-dependent pharmacokinetics (estimated steady state ratio: 1.09; 90% CI: 0.93, 1.27). The most common adverse events included dizziness and oral ulcer. In conclusion, Chinese subjects displayed predictable absorption, exposure and elimination following the prolonged release formulation of ropinirole 2 mg. The safety findings are consistent with the previously established safety profile for ropinirole.

Single-Dose Pharmacokinetic Properties, Bioavailability, and Tolerability of Two Lamivudine 100-mg Tablet Formulations: A Randomized Crossover Study in Healthy Chinese Male Subjects

BackgroundLamivudine is used in the treatment of HIV and chronic hepatitis B (HBV) infections. Since 1999, at least 2 million Chinese HBV patients have been treated with lamivudine, but there are limited studies on the pharmacokinetics and safety of the drug in Chinese populations. ObjectiveThis study was designed to assess the bioequivalence of a newly developed lamivudine tablet (test drug) and a branded lamivudine tablet (reference drug) in healthy Chinese male volunteers. MethodsA single-center, single-dose, randomized, open-label, 2-period crossover study was conducted in 28 healthy Chinese male volunteers. Blood samples were collected up to 24 hours after the administration of oral lamivudine 100 mg in each period. Plasma lamivudine concentrations were analyzed by a validated LC–MS/MS method. Pharmacokinetic and bioavailability parameters were calculated. Adverse events (AEs) were recorded. ResultsThere were no significant differences in mean (SD) pharmacokinetic parameters between the test and reference drugs, including Cmax (1239 [328.9] ng/mL vs 1176 [341.5] ng/mL), AUC0–t (4096 [599.1] ng · h/mL vs 4064 [678.2] ng · h/mL), and AUC0–∞ (4200 [607.7] ng · h/mL vs 4162 [672.2] ng · h/mL). The geometric mean test/reference ratios (90% CI) calculated for the log-transformed parameters were Cmax, 1.06 (96.21–116.90); AUC0–t, 1.01 (96.53–105.39); and AUC0–∞, 1.01 (96.81–105.16), all of which were within the acceptance limits for bioequivalence. No serious AEs were reported, and all mild AEs were recovered quickly without treatment. ConclusionThese findings suggest that the test formulation of lamivudine 100 mg meets the FDA regulatory standards for bioequivalence with the reference formulation. Both formulations were well tolerated.