Healthy Chinese Male Subjects Research Articles

Pharmacokinetics and Safety of Golimumab in Healthy Chinese Subjects Following a Single Subcutaneous Administration in a Randomized Phase I Trial

Golimumab is an anti-tumor necrosis factor-α human immunoglobulin G1κ monoclonal antibody that is efficacious for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in adults. The objective of this study was to assess the pharmacokinetic characteristics of golimumab in healthy male Chinese subjects following a single subcutaneous (SC) administration of golimumab 50 or 100 mg. The safety, tolerability, and immunogenicity of a single SC administration of golimumab in Chinese subjects were also evaluated. This was a phase I, randomized, open-label, single-dose, single-period, single-center study. Twenty-four healthy male Chinese subjects were randomized (1:1) to receive a single SC administration of golimumab 50 or 100 mg. Serial blood samples for the measurement of serum golimumab concentrations were collected and analyzed using a validated electrochemiluminescent immunoassay method. The pharmacokinetic parameters [maximum observed serum concentration (C(max)), time to reach C(max) (t(max)), area under the serum concentration-time curve from time zero to infinity (AUC∞), and terminal half-life (t(½))] of golimumab were derived using a noncompartmental analysis. Following a single SC administration of golimumab 50 or 100 mg in Chinese male subjects (age 19-41 years, body weight 60-76 kg), mean ± standard deviation C(max) (3.6 ± 1.6 and 7.5 ± 1.4 μg/mL, respectively) and AUC∞ (59.8 ± 19.8 and 132.8 ± 27.0 μg·day/mL, respectively) increased in a dose-proportional manner. The median t(max) was in the range of 4.5-5.0 days, and the mean t(½) was in the range of 10.8-11.9 days. Among 24 subjects, 23 had appropriate samples for evaluation of antibodies to golimumab, and one subject (1/23, 4.3%) in the 100-mg group tested positive. Three mild adverse events were reported (infected sebaceous cyst, upper respiratory tract infection, and headache), all in the 50-mg group; none were considered to be related to the study agent. Golimumab exhibited linear pharmacokinetics at dose levels of 50 and 100 mg following a single SC administration in healthy Chinese subjects. Single SC administrations of golimumab 50 or 100 mg were considered to be generally well tolerated. The results from this study indicate that there are no apparent ethnic differences in the pharmacokinetics of golimumab between Chinese and Caucasian subjects.

Relative Bioequivalence Evaluation of Two Oral Atomoxetine Hydrochloride Capsules: A Single Dose, Randomized, Open-Label, 2-Period Crossover Study in Healthy Chinese Volunteers under Fasting Conditions

To evaluate the bioequivalence of a new formulation of atomoxetine hydrochloride (CAS 82248-59-7) capsules (test) and an available branded capsules (reference) after administration of a single 40 mg dose, randomized, open-label, 2-period crossover study was conducted in 22 healthy male Chinese subjects with a 1-week wash-out period. This study was designed for/the Honglin Pharmaceutical Co. Ltd and contracted to be done by the Beijing Anding Hospital in order to satisfy Chinese regulatory requirements to allow marketing of this generic product and performed according to the criteria of SFDA. Blood samples were collected before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detection. A non-compartmental method was used to calculate the pharmacokinetic parameters and evaluate bioequivalence of the 2 formulations. The 90% confidence interval (CI) of the ratios (test/reference) of atomoxetine for AUC0-24, AUC0-∞ and Cmax were 100.9% (93.6-108.8%), 103.1% (95.1-111.7%) and 105.2% (92.8-119.4%), respectively, which fell within the interval of 80-125% and 75-133%. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. From these results it can be concluded that the test formulation of atomoxetine capsules met the regulatory criterion for bioequivalence to the reference formulation.

Comparison of the Pharmacokinetics of Subcutaneous Ustekinumab between Chinese and Non-Chinese Healthy Male Subjects across Two Phase 1 Studies

Ustekinumab, a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody against interleukin-12/23p40, has been reported to be significantly efficacious in treating patients with moderate-to-severe plaque psoriasis. Although the efficacy and safety of ustekinumab have been previously studied in Asian patients with psoriasis, the pharmacokinetics of ustekinumab has not been reported for Asian patients. The objective of this analysis was to compare the pharmacokinetics of ustekinumab in Chinese and non-Chinese subjects. Two Phase 1, open-label, single-period, inpatient/outpatient studies were conducted to evaluate the pharmacokinetics of ustekinumab following a single subcutaneous (SC) injection. In Study 1, non-Chinese healthy male subjects (n = 31) received a single SC injection of ustekinumab 90 mg. In Study 2, Chinese healthy male subjects (n = 24) were randomized (1:1) to receive a single SC injection of ustekinumab 45 mg or 90 mg. Serum ustekinumab concentrations were measured using validated immunoassays. The pharmacokinetic parameters were calculated using non-compartmental analyses. After data collection, a linear mixed model approach was used to compare the log-transformed maximum observed serum concentration (Cmax) and area under the serum concentration-time curves (AUCs) generated from the 90-mg dose groups in the two studies. The ratios of the geometric means of the Cmax and AUCs in Chinese subjects (Test) to those in non-Chinese subjects (Reference) along with the 90 % confidence intervals (CIs) were calculated. The mean body weight was 80.3 kg in non-Chinese (Caucasian: 77.4 %; black: 12.9 %; Asian: 0.0 %; other: 9.7 %) and 65.7 kg in Chinese subjects, with an overall mean of 74 kg. Across studies and dose groups, the median time corresponding to the Cmax (tmax) was 4.0-8.5 days, the mean terminal half-life (t½) was approximately 3 weeks, and the mean apparent volume of distribution based on the terminal phase (Vz/F) was 80.3-97.3 mL/kg. In the 90-mg groups, mean exposure parameters of ustekinumab were 1.1- to 1.3-fold higher in Chinese versus non-Chinese subjects. However, exposure parameters were not significantly different between the two study populations when individual parameters were adjusted to a subject weighing 74 kg: the 90 % CIs of the geometric mean ratios (Chinese versus non-Chinese) for weight-adjusted Cmax, AUC from time zero to time of last measurable concentration (AUClast), and AUC from time zero to infinity (AUC∞) were (0.76-1.09), (0.85-1.16) and (0.88-1.22), respectively. Ustekinumab was generally well tolerated, with no unexpected adverse events; one subject (non-Chinese) developed anti-drug antibodies to ustekinumab. The pharmacokinetics of ustekinumab were comparable between Chinese and non-Chinese healthy male subjects when exposure parameters were adjusted by subject body weight. Study 1, conducted with non-Chinese subjects (March-July 2006), was completed before the 7th revision of the Declaration of Helsinki and was therefore exempt from registration under the existing guidelines. The clinical trial registration number for Study 2, conducted with Chinese subjects (October 2009-June 2010), is NCT01081704.

The Influence of UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4 and CYP3A5 Genetic Polymorphisms on the Pharmacokinetics of Silodosin in Healthy Chinese Volunteers

Silodosin (KMD-3213), a highly selective α1a-adrenergic receptor antagonist, was approved in Japan (2006), the United States of America (2008), and China (2011) for benign prostatic hyperplasia. Silodosin was a dual substrate for CYP3A and P-glycoprotein, and two main metabolites were generated in plasma by UDP-glucuronosyltransferase (UGT) and alcohol/aldehyde dehydrogenase. To examine the effect of genetic polymorphisms on silodosin pharmacokinetics in healthy male Chinese subjects after a single oral dose. Blood samples were collected from subjects (n = 31) at scheduled time intervals before and after an oral administration of 4 mg silodosin. A validated LC/MS/MS method was used to quantify the plasma silodosin concentration. The relationship between plasma silodosin concentration, its pharmacokinetic parameters, polymorphic alleles (UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4, and CYP3A5), and other enzymes related to silodosin metabolism were assessed for each subject. Subjects with UGT2B7*1/*2 and *2/*2 had a 27.1% and 22.7% longer terminal t(1/2) (respectively), 37.9% and 25.2% larger AUC(0-∞) (respectively), slower silodosin metabolism, and increased silodosin exposure, when compared to the subjects with UGT2B7*1/*1. The silodosin T(max) was affected by CYP3A5 (p < 0.05) with a slower time to reach C(max) for subjects with the CYP3A5*1/*1 polymorphism when compared to those with the *1/*3 or *3/*3 polymorphisms. The C(max) was affected by CYP3A4 (p < 0.05) with a lower C(max) for subject with the CYP3A4*18B/*18B compared to those with the *1/*1 and *1/*18B. UGT2B7 may play a key role in the variability observed in silodosin metabolism.

Pharmacokinetic Properties of Single-Dose Lamivudine/Adefovir Dipivoxil Fixed-Dose Combination in Healthy Chinese Male Volunteers

BackgroundBoth lamivudine and adefovir dipivoxil are approved for the treatment of chronic hepatitis B (CHB) and have established safety profiles. A fixed-dose combination (FDC) formulation of lamivudine/adefovir dipivoxil for the treatment of CHB may provide dosing convenience and improve adherence. ObjectiveThis study compared the pharmacokinetic profiles of an FDC capsule containing lamivudine/adefovir dipivoxil 100/10 mg and conventional lamivudine 100-mg + adefovir dipivoxil 10-mg tablets to determine bioequivalence. MethodsThis randomized, open-label, single-dose, 2-period crossover study was conducted in healthy male Chinese subjects. The study included a screening visit, 2 treatment sessions, and a follow-up visit. Subjects who met the inclusion/exclusion criteria were assigned to receive, in randomized order, 1 FDC capsule or 1 tablet each of lamivudine and adefovir dipivoxil. After a 7- to 10-day washout period, alternate treatment was given to the subjects during the second treatment session. Blood samples were collected immediately before and after dosing for 48 hours for plasma drug concentration measurement. Data on adverse events (AEs) were collected from the start of dosing until the follow-up visit. Tolerability assessments included physical examinations with vital sign measurements and clinical laboratory evaluations throughout the study. ResultsForty subjects were enrolled into the study (mean age, 22.4 years [range, 19–28 years]; weight, 63.8 kg [range, 54–78 kg]). The pharmacokinetic profiles of lamivudine and adefovir were similar between the FDC and reference formulations. The geometric mean ratios (GMRs) for lamivudine Cmax and AUC0–last were 1.02 (90% CI, 0.92–1.12) and 0.99 (90% CI, 0.95–1.04), respectively; adefovir, 0.94 (90% CI, 0.89–0.99) and 0.95 (90% CI, 0.91–1.00). A limited number of mild AEs were reported, with no clinically significant changes in vital signs or laboratory results. ConclusionsThe FDC capsule was bioequivalent to the concurrent administration of lamivudine + adefovir dipivoxil tablets based on the 90% CIs of the GMRs for Cmax, AUC0–∞, AUC0–last, and t12 (all were between 0.80 and 1.25). Both treatments were well-tolerated. Clinicaltrial.gov identifier: NCT01353742.

Bioequivalence and Pharmacokinetic Evaluation of Two Formulations of Risperidone 2 mg

BackgroundRisperidone is a benzisoxazole derivate and is effective in the treatment of schizophrenia and other psychiatric illnesses in adults and children. Although there are a few reports in the literature regarding the pharmacokinetic characteristics of risperidone, insufficient data on its pharmacokinetic properties in a Chinese population are available.ObjectiveTo meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic properties and bioequivalence of two 2 mg tablet formulations of risperidone: a newly developed generic formulation (test) and a branded formulation (reference) in healthy adult male Chinese volunteers.MethodsA single-dose, open-label, randomized-sequence, 2 × 2 crossover study was conducted in fasted healthy male Chinese volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 1 tablet (2 mg each) of the test formulation (Risperidone tablet; Dr. Reddy’s Laboratories Ltd., Hyderabad, India) or the reference formulation (Risperdal® tablet; Xian-Janssen Pharmaceutical Ltd., Xi-an, China), followed by a 2-week washout period and subsequent administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 96 hours. Plasma concentrations of the parent drug, risperidone, and its active metabolite, 9-hydroxy-risperidone, were analyzed by a liquid chromatography–tandem mass spectrometry method. The formulations would be considered bioequivalent if the 90% confidence intervals (CIs) of the natural log-transformed values were within the predetermined 80–125% equivalence range for the maximum plasma drug concentration (Cmax) and the area under the plasma concentration–time curve (AUC), in accordance with guidelines issued by the US Food and Drug Administration. Assessment of tolerability was based on recording of adverse events (AEs), monitoring of vital signs, electrocardiograms, and laboratory tests at baseline and at completion of the study.ResultsA total of 24 healthy male Chinese volunteers (mean age 22.9 years [standard deviation (SD) 2.7, range 19.2–27.1]; weight 63.2 kg [SD 7.0, range 52.0–78.0]; and height 171.3 cm [SD 6.1, range 162.0–187.0]) were enrolled, and all completed the study. For the parent drug, risperidone, the 90% CIs of the relative values (test vs. reference) of the Cmax, AUC from time zero to time t (AUCt), and AUC from time zero to infinity (AUC∞) were 97.0–124.0%, 92.7–115.1%, and 92.8–114.2%, respectively. For the active metabolite, 9-hydroxy-risperidone, the values were 104.4–117.7%, 101.0–113.7%, and 100.4–113.4%, respectively. The two formulations met the predetermined criteria for bioequivalence. A total of 73 AEs were observed in 24 subjects during the study. The most common AE was sedation (48 events), followed by nasal reactions (14 events), postural hypotension (3 events), hypertriglyceridemia (2 events), dizziness (4 events), nausea (1 event), and anorexia (1 event). Their severity was as follows: 16 were mild, 57 were moderate, and none were severe. The majority of the AEs were considered to be related (48 events) or probably related (23 events) to the study medication. No clinically significant abnormalities on physical examination, vital sign measurements, or electrocardiographic recordings were reported. No serious AEs were reported.ConclusionsThe data from this study in healthy adult male Chinese subjects suggest that the test formulation met the regulatory criteria for bioequivalence to the reference formulation, on the basis of the rate and extent of absorption. Both formulations were well tolerated.

Pharmacokinetics and Bioavailability Comparison of Generic and Branded Citalopram 20 mg Tablets

Citalopram is a selective serotonin reuptake inhibitor (SSRI) mainly prescribed to treat major depression. The aim of this study was to compare the pharmacokinetic characteristics of a new and a branded citalopram 20 mg formulation to support the marketing authorization of the test formulation in China. A single-dose, open-label, randomized-sequence, two-period crossover design was used in this study. Healthy Chinese male cytochrome P450 (CYP) 2C19 extensive metabolizers, aged 18-40 years, were eligible to participate. CYP2C19 poor metabolizers were excluded, based on genotyping of genomic DNA from blood samples. Twenty-four subjects were randomly assigned to receive the test formulation followed by the reference formulation, and then vice versa. A 2-week washout occurred between study periods. Blood samples were collected for up to 144 h post-dose. Quantification was carried out using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated and analysed statistically. The two formulations were considered pharmacokinetically equivalent if the 90 % confidence intervals (CIs) of the log-transformed ratios (test/reference) of the maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC(last)), and area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were within the predetermined acceptance range (70-143 % for C(max); 80-125 % for AUC(last) and AUC(∞)) according to China State Food and Drug Administration bioequivalence guidelines. Tolerability was monitored by clinical assessment, vital signs, laboratory analysis and interviews with participants about adverse events. A total of 24 participants, with a mean (SD) age of 26 (3) years (range 22-32 years), body weight of 65.2 (5.0) kg (range 53-73 kg), and height of 172.7 (4.9) cm (range 159-182 cm), were enrolled in this study. Both formulations showed similar pharmacokinetic profiles. Mean (SD) AUC(last), AUC(∞) and C(max) were 1436 (341) ng · h/mL, 1595 (381) ng · h/mL and 32.3 (5.9) ng/mL, respectively, for the test formulation, and 1444 (388) ng · h/mL, 1648 (504) ng · h/mL, 33.1 (7.4) ng/mL, respectively, for the reference formulation. Median (range) time to reach C(max) (t(max)) was 2 (1-12) hours (test) and 3 (1-6) hours (reference). The 90 % CIs of the treatment ratios for the ln-transformed values of C(max), AUC(last) and AUC(∞) were 92.5-103.6, 95.2-100.6 and 96.4-105.4, respectively. No significant difference was found between treatments with regard to pharmacokinetic parameters. Fifteen adverse events were reported during the study but none were considered serious. This single-dose study found that the test and reference citalopram 20 mg tablets met the regulatory criteria for assuming bioequivalence in the selected healthy Chinese male subjects. Both formulations were well tolerated.

CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects

The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol. The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high-performance liquid chromatographic method. Subjects were genotyped for the CYP2C19 2 and 3, UGT1A1 6, 28 and 60, UGT2B7 2 and ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms. Subjects with the CYP2C19 2/ 2 genotype had a higher peak concentration (255.5 ± 80.1 vs. 156.0 ± 66.3 ng/mL; P < 0.05) and area under the concentration-time curve (AUC0-∞; 1,473.7 ± 493.6 vs. 502.8 ± 176.1 ng[Symbol: see text]h/mL; P < 0.001) than subjects with 60 or 28, and UGT2B7 2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0-∞ and lower total clearance than the wild-types (P < 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0-∞. Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects.

Pharmacokinetics of Febuxostat in Healthy Chinese Volunteers

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase developed for the management of hyperuricemia in patients with gout. To investigate the pharmacokinetics and also evaluate the effects of gender and food on the pharmacokinetics of febuxostat in healthy Chinese volunteers. A phase I, 3-period study was performed in healthy Chinese male and female subjects. Subjects either received single 40 mg, multiple 40 mg and single 80 mg doses of febuxostat under fasted conditions, or received single 80 mg doses under fed condition. Plasma concentrations of febuxostat were collected and determined at 14 time points over 48 h. After 40 mg and 80 mg single dose administration of febuxostat, the C max were 2.308±0.812 and 4.559±1.246 μg/mL, the T max were 1.6±0.6 and 2.1±1.0 h, the t 1/2 were 6.8±1.7 and 6.7±1.9 h, and the AUC0-∞ were 7.704±1.723 and 16.34±3.87 μg∙h/mL, respectively. In the multiple-dose study at 40 mg dose for 6 consecutive days, the mean (SD) steady-state pharmacokinetic parameters on day 8 were similar to those following a single dose of febuxostat on day 1. In addition, food caused a decrease of 33% for C max and a delay of 0.3 h for T max. Gender had no significant effect on the pharmacokinetics of febuxostat. Febuxostat was well tolerated over the investigated dose range. Compared with the previous study, the pharmacokinetics of febuxostat appeared to be different between Chinese and other races.

Pharmacokinetics of Terazosin Enantiomers in Healthy Chinese Male Subjects

The purpose of this study was to elucidate the pharmacokinetics of terazosin enantiomers in healthy Chinese male subjects. After a single oral dose of 2-mg terazosin, the plasma concentrations of terazosin enantiomers were measured over the course of 48 h in 12 healthy subjects. The plasma concentrations of (+)-(R)-terazosin at all time points were higher than those of (-)-(S)-terazosin. The area under the plasma concentration-time curve (AUC(0-∞) ) and maximum plasma concentration of (+)-(R)-terazosin were significantly greater than those of the (-)-(S)-terazosin (P < 0.01, respectively). The R/S ratio of AUC(0-∞) of terazosin was 1.68. For the first time, it was proven that the pharmacokinetics of terazosin was stereoselective in healthy Chinese male subjects.

Effect of CYP2C9 and SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of nateglinide in healthy Chinese male volunteers

Nateglinide is commonly used in the treatment of patients with type 2 diabetes mellitus. Our objective was to assess the association between CYP2C9 and SLCO1B1 polymorphisms and the metabolism of nateglinide in healthy Chinese male volunteers. A total of 35 healthy Chinese male volunteers with different CYP2C9 and SLCO1B1 genotypes were given a single oral dose of 120 mg nateglinide. Plasma concentrations of nateglinide and blood glucose level were measured up to 8 h. In subjects with the CYP2C9*1/*3 & 521TT, CYP2C9*1/*1 & 521TC/CC and CYP2C9*1/*3 & 521TC genotype, AUC(0-∞) of nateglinide was 56 %, 34 % and 56 % higher (P = 0.002, P = 0.041 and P = 0.013, respectively), and the CL/F of nateglinide was 35 %, 11 % and 36 % lower (P = 0.000, P = 0.003 and P = 0.002, respectively) than that in the reference group. When only considering 521 T>C polymorphism, it had no significant association with the pharmacokinetics of nateglinide. CYP2C9*3 and 521 T>C polymorphisms were the significant predictors of the AUC(0-∞) and CL/F of nateglinide (adjusted multiple R(2) = 34 % and 43 %, respectively) according to multiple linear regression analyses, but they have no significant association with changes in the blood glucose-lowering effect of nateglinide. Both SLCO1B1 521 T>C and the CYP2C9*3 polymorphisms can significantly affect the pharmacokinetics of nateglinide, but they could only partially explain the interindividual variability of plasma concentration of nateglinide. Moreover, 521 T>C and the CYP2C9*3 polymorphisms have no effect on pharmacodynamics of nateglinide in healthy Chinese male subjects.

Bioequivalence Studies of 2 Oral Cefaclor Capsule Formulations in Chinese Healthy Subjects

An open-label, single-dose, randomized, crossover study was carried out in 20 Chinese healthy male subjects to compare the pharmacokinetics of 2 cefaclor (CAS 53994-73-3) formulations after administration of a single 250 mg dose of each drug with a 1-week wash-out period. Blood samples were collected before and with 6 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detector. 2 formulations were evaluated using the following pharmacokinetic parameters: AUC0-t, Cmax and tmax was analyzed nonparametrically. The 90% confidence interval (CI) of the ratios (teat/reference) of log-transformed AUC0-t and Cmax fell within the bioequivalence acceptance range of 80-125%. The results showed that the 90% CI of the ratios of AUC0-t and Cmax were 105.1% (101.0-109.4%) and 92.4% (82.5-103.4%), respectively, which therefore could conclude 2 oral cefaclor capsule formulations of cefaclor are bioequivalent. Both treatments showed similar tolerability and safety.

Impact of CYP2D6 polymorphisms on the pharmacokinetics of lovastatin in Chinese subjects

Although CYP3A4/5 enzymes play the predominant role in the metabolism of simvastatin and lovastatin, polymorphisms in CYP2D6 were reported to be associated with the cholesterol-lowering effect and/or tolerability of simvastatin. This study was performed to examine whether common CYP2D6 polymorphisms affect the pharmacokinetics of lovastatin, which is taken as the inactive prodrug lovastatin lactone and converted to active lovastatin acid. A single-dose pharmacokinetic study was performed with lovastatin in 23 Chinese healthy male subjects. Plasma concentrations of lovastatin lactone and acid were determined by an LC-MS-MS method in samples collected over 24h after single oral doses of 40-mg lovastatin. Compared with the CYP2D6 wt/wt group, the area under the plasma concentration-time curve (AUC(0-∞)) values for lovastatin lactone increased (P < 0.01) by average ratios (95% CI) of 1.57 (1.01-2.45), 2.11 (1.36-3.29), 2.52 (1.47-4.32), and 5.84 (3.16-10.78) in the wt/*10, *10/*10, *10/*5, and *5/*5 groups, and the values of lovastatin lactone plasma clearance (CL/F) were reduced on average (95% CI) by 40.4% (10.2-60.5%), 53.1% (29.3-68.9%), 63.8% (40.2-78.1%) and 84.2% (72.1-91.1%) in these genotype groups respectively. The pharmacokinetics of lovastatin acid did not differ among the genotype groups. This study demonstrates that CYP2D6 polymorphisms appeared to influence the disposition of lovastatin lactone in these subjects.

Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects

Although flecainide is thought to be meta-bolized predominantly by cytochrome P450 (CYP) 2D6, it shows pharmacokinetic interactions with drugs, such as verapamil and digoxin, which may suggest other CYP pathways or ATP-binding cassette (ABC) transporters might be involved. This study evaluated effects of common polymorphisms in Chinese in CYP2D6, CYP3A5, CYP1A2, and ABCB1 on flecainide pharmacokinetics. Single oral 100-mg doses of flecainide were given to 15 healthy male Chinese subjects who were genotyped for the CYP2D6*2, *5, *10, CYP3A5*3, CYP1A2*1F and ABCB1 C1236T, G2677T/A, and C3435T polymorphisms. There was no significant difference in the pharmacokinetics of flecainide among CYP2D6 (mainly involving *10) genotypes. The CYP3A5*3/*3 subjects (n=8) had a 26% higher systemic exposure (AUC0-∞) and 17% lower apparent oral clearance of flecainide than the combined group of CYP3A5*1/*1 (n=6) and CYP3A5*1/*3 (n=1) subjects (p<0.05). Subjects homozygous for CYP1A2*1F tended to have lower systemic exposure and increased clearance of flecainide compared to those with CYP1A2*1A/1F in subjects with at least one CYP2D6 variant allele. The disposition of flecainide appeared to be influenced by the CYP3A5*3 and possibly the CYP1A2*1F polymorphisms, particularly in subjects with CYP2D6 variant alleles.

Pharmacokinetics of Telmisartan in Healthy Chinese Subjects after Oral Administration of Two Dosage Levels

To study the pharmacolkinetics of telmisartan in healthy Chinese male subjects after oral administration of two dosage levels, 36 healthy subjects were divided into two groups and given a single oral dose of 40 or 80 mg telmisartan (CAS 144701-48-4, MicardisPlus). A sensitive liquid chromatography-tandem mass spectrometry method (LC-MS-MS) was used for the determination of telmisartan in plasma. Both, a non-compartmental and compartmental method were used for analysis of parameters of kinetics. The main pharmacokinetic parameters of the 40 mg and 80 mg regimen group were as follows: t(max) (1.76 +/- 1.75) h, (1.56 +/- 1.09) h, C(max) (163.2 +/- 128.4) ng/mL, (905.7 +/- 583.4) ng/mL, t1/2 (23.6 +/- 10.8) h, (23.0 +/- 6.4) h, AUC(o-t) (1456 +/- 1072) ng x h/mL, (6759 +/- 3754) ng x h/mL, AUC(o-infinity (1611 +/- 1180) ng x h/mL, (7588 +/- 4661) ng x h/mL, respectively. After dose normalization, there was significant difference for main pharmacokinetic parameters C(max) AUC(o-t) and AUC(o-infinity) between two dosage level groups. The plasma concentration-time profile of telmisartan was characterized by a high degree of inter-individual variability and the disposition of telmisartan in healthy Chinese subjects was dose-dependent. The pharmacokinetic parameters C(max) and AUC(o-inifinity) of the 80 mg regimen group increased to about 5-fold compared to that of the 40 mg regimen group, but there was no significant difference for t(max) and t1/2 between the two dose groups.

Bioequivalence of Two Tablet Formulations of Helicidum Adminstered in Single Dose to Healthy Chinese Volunteers

In this 2 x 2, randomized, crossover bioequivalence study, two tablet preparations of helicidum were compared in 20 healthy Chinese male subjects. The drug was given in a single dose of three tablets (75 mg) and blood samples were withdrawn during 12 h after drug administration. Helicidum was separated and analyzed using a validated liquid chromatography-mass spectrum method. The pharmacokinetic parameters were determined from the plasma concentration-time profiles of both formulations. The primary calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two preparations, using various statistical methods. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range (80-120%) for bioequivalence. Based on these statistical inferences it can be concluded that the two tablet preparations of helicidum are likely to be bioequivalent.

Bio equivalence of Two Formulations of Daidzein Administered in a Single Dose to Healthy Chinese Volunteers

In this two-treatment, two-period, randomized, crossover bioequivalence study of daidzein, which belongs to the isoflavone class of flavonoids and is classified as a phytoestrogen, two formulations (dripping pills, a rapidly-dissolvable formulation, and tablets) were compared in 20 healthy Chinese male subjects. The drug was given in a single dose of 50 mg and blood samples were withdrawn during 24 h after drug administration. Daidzein was separated and analyzed using a validated liquid chromatography - tandem mass spectrometry (LC-MS/MS) method. The pharmacokinetic parameters were determined from the plasma concentration-time profiles of both formulations. The primary calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two preparations, using various statistical methods. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range (80 - 120%) for bioequivalence. Based on these statistical inferences it can be concluded that the two formulations of daidzein are likely to be bioequivalent.

The Pharmacokinetics, Pharmacodynamics, and Tolerability of Liraglutide, a Once-Daily Human GLP-1 Analogue, After Multiple Subcutaneous Administration in Healthy Chinese Male Subjects

In this single-center, randomized, double-blind, within dose group, placebo-controlled, dose escalation trial, the pharmacokinetics, pharmacodynamics, tolerability, and safety of liraglutide were evaluated in 37 healthy Chinese subjects. Subjects were randomized to 1 of 3 dose groups (0.6, 1.2, or 1.8 mg), and within each group, randomized to liraglutide or placebo (3:1). All subjects started at 0.6 mg liraglutide (or placebo) once daily for 1 week, and the dose was increased for dose groups 1.2 mg and 1.8 mg in weekly steps of 0.6 mg to the predefined dose targets. Liraglutide or placebo was administered once daily by subcutaneous injection for 21 consecutive days. The dose relationships of AUC(0-24h), C(max), and C(trough) at steady state do not deviate in a relevant way from dose proportionality. t(max) and t(1/2) were 8 hours (median) and 11.2 to 12.2 hours (geometric mean), respectively. The plasma glucose levels in all liraglutide groups were decreased, while reduced serum insulin level was observed in the 1.2- and 1.8-mg groups after liraglutide treatment. The most common adverse events were of gastrointestinal origin. Other adverse events were comparable between the liraglutide and placebo groups. Liraglutide was well tolerated in healthy Chinese subjects. No major safety concerns were identified.

Comparative Bioavailability of Ferrous Succinate Tablet Formulations Without Correction for Baseline Circadian Changes in Iron Concentration in Healthy Chinese Male Subjects: A Single-Dose, Randomized, 2-Period Crossover Study

Background Ferrous succinate is used for the treatment of iron deficiency anemia. Determining the bioavailability of iron products is a challenge, because iron is naturally present in the blood and some tissues. Therefore, bioequivalence evaluation of ferrous formulations can be affected by the presence of endogenous iron species. Little information regarding the pharmacokinetics of ferrous supplements is available in the healthy Chinese population. Objectives The aim of the study was to assess the comparative bioavailability of 200-mg of a test (ferrous succinate,100 mg × 2, Hunan Huana Pharmaceutical Co., Ltd., Hunan, China) and reference (Sulifei, 100 mg × 2, Nanjing Jinling Pharmaceutical Co., Ltd., Nanjing, China) formulation in healthy Chinese male subjects. The study was conducted to meet Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of ferrous succinate. Methods This study utilized a single-dose randomized, 2-period, crossover design with alternate assignment of subjects to treatment (a single 200-mg [100 mg × 2]) or reference formulation groups. Both groups underwent a 4-day diet equilibration before 2 days of treatment and, finally, a 4-day washout period for the bioequivalence study. Blood samples were collected at 8:00 am on every diet equilibration day, 0 (baseline), 1, 2, 3, 4, 4.5, 5, 6, 9, 12, 24, and 36 hours after drug administration. Iron concentrations were determined using an inductively coupled plasma mass spectrometry. Subjects in both groups were given a standardized diet, with known amounts of iron and calories. The formulations were assumed to be bioequivalent if the 90% CI ratios for C max were within 70% to 143% and AUC 0–last were within 80% to 125%—criteria established by the Chinese Food and Drug Administration. Tolerability was monitored throughout the study by assessing clinical parameters (vital signs, chemistry laboratory) and subject reports. Results Twenty healthy Han Chinese male subjects (mean age, 26.8 years [range, 20–39 years]; weight, 61.9 kg [range, 52–72 kg]; body mass index, 21.5 kg/m 2 [range,19.1–23.8 kg/m 2]; and baseline iron values, 1271 μg/L [range 1113–1429 μg/L]) were enrolled and completed the study. Without baseline correction for endogenous iron compound, the mean C max measurements of iron for the test and reference formulations were 2981 [621.1] and 3028 [707.4] μg/L, respectively; AUC 0–last values were 48,460 [9242] and 48,390 [8420] μg/L/h, respectively; T max values were 4.3 [1.6] and 3.7 [1.3] hours. The 90% CIs for the ratios of C max and AUC 0–last were 89.9% to 109.2% and 92.5% to 107.7%. No significant difference was found between groups with regard to pharmacokinetic parameters. Both test and reference formulations were well tolerated, with only 2 (10%) subjects who received the reference formulation complaining of mild heartburn that resolved after approximately 1 hour. Another subject (5%) complained of nausea 10 minutes after the test administration, which resolved within 2 hours. The relative bioavailability of the test-reference preparations was 101.6%. Conclusion In this single-dose crossover study in healthy Chinese male subjects, the test and reference formulations of ferrous succinate 200-mg (100 mg × 2,) tablets met the criteria for assuming bioequivalence as defined by the Chinese Food and Drug Administration. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-11001646.

G-011 INFLUENCE OF PITAVASTARIN AND SLCO1B1 POLYMORPHISMS ON REPAGLINIDE PHARMACOKINETICS AND PHARMACODYNAMICS IN HEALTHY CHINESE MALE SUBJECTS

Background This study investigated the effect of pitavastatin and SLCO1B1 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide. Methods In a randomized, placebo-controlled, crossover study, twelveSLCO1B1-genotyped healthy Chinese male volunteers were given daily doses of 4 mg pitavastatin or placebo for 5 days, followed by 4 mg oral dose of repaglinide on day 5. Plasma concentrations of repaglinide and blood glucose were measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS) system and glucose oxidase method, respectively. Pharmacokinetic parameters were obtained by DAS Ver 2.0. Results Pitavastatin increased the peak plasma concentration (Cmax) of repaglinide significantly (P = 0.003), and the increase in Cmax was limited to participants with the SLCO1B1*1b/*1b genotype (P = 0.015) and carriers of the SLCO1B1*15 haplotype (P = 0.031). Pitavastatin can also increased the area under plasma concentration–time curve from 0 h to infinity (AUC0→∞) of repaglinide slightly (P = 0.091). No significant difference in the pharmacokinetic parameters and blood glucose-lowering effects of repaglinide were observed among SLCO1B1 genotype groups in either the placebo- or the pitavastatin-treatment phase. Conclusion Pitavastatin increased plasma concentrations of repaglinide in an SLCO1B1 genotype dependent manner, but had no effect on the pharmacodynamics of repaglinide in healthy volunteers.