Pharmacokinetics of rosuvastatin in healthy Chinese volunteers living in China: A randomized,open-label,ascending single- and multiple-dose study

Background: Cross-study comparisons suggest that systemic exposure (AUC) to rosuvastatin calcium, a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, may be ~2-fold higher in Asian subjects living in Asian countries than in white subjects living in Western countries.Objective: This study was conducted to determine the pharmacokinetic characteristics of rosuvastatin and its metabolites after single and multiple doses of rosuvastatin in healthy Chinese subjects living in China.Methods: This was an open-label, ascending singleand multiple-dose study. Subjects were randomly assigned to receive rosuvastatin 5, 10, or 20 mg. Each subject received 1 tablet of the assigned treatment on day 1 and days 4 through 10. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone were measured through 72 hours after administration of single doses and through 96 hours after administration of multiple doses. Blood samples were obtained within 30 minutes before dosing on days 7, 8, and 9 for the assessment of pharmacokinetic parameters at steady state. Noncompartmental pharmacokinetic analysis was performed to determine the C_max and AUC_0?t for rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone after single and multiple doses of rosuvastatin. Tolerability assessments were conducted throughout the study.Results: Of the 36 enrolled subjects, only 1 was female. The mean age of subjects in the rosuvastatin 5-, 10-, and 20-mg groups was 22.4, 21.3, and 22.4 years, respectively. Weight and height ranged from 54 to 85 kg and from 161 to 189 cm, respectively. Geometric mean C_max values for rosuvastatin after administration of single doses of rosuvastatin 5, 10, and 20 mg were 8.33, 10.76, and 19.17 ng/mL, respectively; the corresponding geometric mean AUC_0?t values were 57.63, 88.89, and 163.87 ng · h/mL. At steady state, values for C_max were 8.31, 8.41, and 20.73 ng/mL; the corresponding geometric mean AUC values were 64.87, 77.29, and 178.64 ng · h/mL. After administration of multiple doses of rosuvastatin 5, 10, and 20 mg, the accumulation ratios were 1.23, 0.95, and 1.23, respectively, indicating minimal accumulation of rosuvastatin. Circulating concentrations of N-desmethyl rosuvastatin and rosuvastatin lactone were well below those of rosuvastatin after administration of single and multiple doses of rosuvastatin.Conclusions: Increases in C_max, AUC_0?t, C_max,ss, and AUC_ss were observed with increasing single and multiple doses of rosuvastatin 5, 10, and 20 mg. The increase in exposure with increasing doses was lower than would be expected under conditions of strict proportionality. Rosuvastatin exhibited little accumulation on repeated administration. All rosuvastatin doses were well tolerated in these Chinese subjects.     

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized,Double-blind,Parallel-group Study

PurposeThe objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixed-dose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing.MethodsThis Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18–45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 μg, BGF MDI 160/14.4/10 μg, or GFF MDI 14.4/10 μg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC_0–12, C_max, and T_max. Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values.FindingsNinety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC_0–12 and C_max were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC_0–12, 811.8 vs 1748 h · pg/mL; C_max, 224.3 vs 459.3 pg/mL; repeated dosing: AUC_0–12, 1250 vs 2510 h · pg/mL; C_max, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC_0–12 and C_max were similar across all treatments (single dose: AUC_0–12, 27.20–29.40 h · pg/mL; C_max, 4.884–5.674 pg/mL; repeated dosing: AUC_0–12, 69.49–77.08 h · pg/mL; C_max, 11.30–13.12 pg/mL) and formoterol (single dose: AUC_0–12, 46.49–53.58 h · pg/mL; C_max 9.651–10.62 pg/mL; repeated dosing: AUC_0–12, 81.94–85.32 h · pg/mL; C_max, 16.13–17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%–56.3%). There were no new or unexpected findings on tolerability.ImplicationsOverall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267.     

Celecoxib-tramadol co-crystal: A Randomized 4-Way Crossover Comparative Bioavailability Study

PurposeCelecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure.MethodsThis was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were C_max, AUC_0–T, and AUC_0–∞, which were also calculated normalized to the dose. T_max was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the C_max, AUC_0–T, and AUC_0–∞ was based on ln-transformed data, and T_max was rank-transformed.FindingsThirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower C_max, reduced AUCs, and a faster T_max. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (C_max), respectively; 1930, 2348, and 1929 ng • h/mL (AUC_0–T); and 1.5, 3.0, and 2.5 hours (T_max). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower C_max and AUCs as well as a longer T_max. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for C_max; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC_0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for T_max. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4.ImplicationsThe aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.     

Pharmacokinetic properties and bioequivalence of two formulations of arbidol: An open-label,single-dose,randomized-sequence,two-period crossover study in healthy chinese male volunteers

Background: Arbidol is an antiviral drug indicated for the prevention and treatment of all types of influenza infection and some other kinds of acute respiratory infections, specifically against influenza groups A and B, and severe acute respiratory syndrome. It is used to help prevent influenza infection as long as necessary with little risk for influenza mutation rendering it less effective.Objective: The aim of this study was to compare the pharmacokinetic properties and tolerability, and to determine bioequivalence, of a newly developed generic dispersible tablet formulation (test) and a branded capsule formulation (reference) of arbidol 200 mg in healthy Chinese fasted male volunteers.Methods: This open-label, single-dose, randomized-sequence, 2-period crossover study was conducted in healthy native Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. After the study drug administration, serial blood samples were collected for 72 hours after administration. Plasma drug concentrations were determined using high-performance liquid chromatography coupled with tandem mass spectrometry. Several pharmacokinetic pararameters, including C_max, T_max, t_½, AUC_0-t, and AUC_0-∞, were determined from the plasma concentrations of the 2 formulations of arbidol using noncom-partmental analysis. The formulations were to be considered bioequivalent if the log-transformed ratios of C_max and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration (SFDA) of the People's Republic of China. Tolerability was assessed by monitoring vital signs (blood pressure, heart rate, temperature, and electrocardiography), laboratory analysis (hematology, blood biochemistry, hepatic function, and urinalysis), and subject interview on adverse events.Results: Twenty subjects were enrolled and completed the study (mean [SD] age, 21.1 [1.1] years; weight, 64.7 [5.1] kg; and height, 172.3 [3.1] cm). Neither period nor sequence effect was observed. The main pharmacokinetic properties with the test and reference formulations were as follows: C_max, 417.4 (107.6) and 414.8 (95.1) ng/mL, respectively (P = NS); median (range) T_max, 0.63 (0.25–1.0) and 0.75 (0.5–1.5) hours (P = 0.035); AUC_0-t, 2033.6 (564.9) and 1992.0 (483.3) ng/mL/h (P = NS); AUC_0-∞, 2285.4 (597.7) and 2215.2 (604.0) ng/mL/h (P = NS); and t_1/2, 6.9 (4.2) and 6.1 (5.2) hours (P = NS). The 90% CIs for the log-transformed ratios of C_max, AUC_0-t, and AUC_0-∞ were 91.7% to 109.7%, 91.0% to 112.8%, and 92.0% to 116.3%, respectively (all, P < 0.05), which were within the predetermined range for bioequivalence. No adverse events were found on analysis of vital signs or laboratory tests or reported by subjects in this study.Conclusion: In this study in healthy Chinese male volunteers, the dispersible tablet formulation and the 200-mg capsule formulation of arbidol met the SFDA's regulatory definition of bioequivalence based on the rate and extent of absorption.     

Bioavailability and bioequivalence of two oral formulations of alendronate sodium 70 mg: An open-label,randomized, two-period crossover comparison in healthy Korean adult male volunteers

Background: Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence.Objectives: The aims of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population.Methods: This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal interview, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC_0?t, AUC_0?∞, C_max, T_max, t_1/2, and the elimination constant (k_e), were determined using noncompart-mental analysis. The formulations were considered bioequivalent if the 90% CI ratios for C_max and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA).Results: Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19–28 years]; height, 175.9 [5.4] cm [range, 162.0–185.0 cm]; and weight, 71.2 [9.5] kg [range, 61–96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC_0?t, AUC_0?∞ and C_max were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of T_max was 1.09 hours (0.5–2.0 hours), and the mean (SD) of t_1/2 and k_e were 2.04 (0.97) hours and 0.34 (0.71) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study.Conclusions: Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC_0?t, AUC_0?∞, and C_max were found in this healthy Korean adult male population.     

A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15 mg and 30 mg: A randomized,double-blind,two-period crossover study in healthy volunteers

Objective: The purpose of this study was to compare the pharmacokinetics and tolerability of single oral doses of cyclobenzaprine extended-release (CER) 15- and 30-mg capsules.Methods: This was a randomized, double-blind, 2-period crossover study in healthy adults aged 18 to 40 years. Subjects were assigned to receive a single dose of either CER 15 mg or 30 mg on days 1 and 15, separated by a 14-day washout. Study comparisons included the plasma cyclobenzaprine AUC to 168 hours after dosing (AUC_0–168), AUC_0–∞, and C_max. Plasma cyclobenzaprine T_max, terminal elimination t_1/2, and adverse events (AEs) were also assessed.Results: Sixteen subjects (9 women, 7 men) were randomized to receive cyclobenzaprine 15 mg or 30 mg; 13 (81.3%) were white and 3 (18.8%) were black. Mean age and weight were 30.2 years and 70.7 kg, respectively. The shapes of the pharmacokinetic profiles for CER 15 and 30 mg were parallel. Mean observed values for dose-dependent pharmacokinetic parameters of CER 15 and 30 mg were as follows: AUC_0–168, 318.3 and 736.6 ng · h/mL, respectively; AUC_0–∞), 354.1 and 779.9 ng · h/mL; and C_max, 8.3 and 19.9 ng/mL. Dose-independent parameters were comparable across doses. Median observed Tmax was 6.0 hours for both CER doses; mean t_1/2 was 33.4 hours for CER 15 mg and 32.0 hours for CER 30 mg. The bioavailability of the 2 doses, as indicated by the least squares mean AUC_0–∞, was 330.3 ng · h/mL for CER 15 mg and 755.1 ng · h/mL for CER 30 mg. During the CER 15-mg treatment sequence, 5 subjects experienced 5 AEs (headache, dizziness, musculoskeletal pain, dermatitis, and glossodynia); during the CER 30-mg treatment sequence, 2 subjects experienced 2 AEs (somnolence and dysmenorrhea). All AEs were mild in intensity. No serious AEs occurred during the study.Conclusions: Once-daily CER 15 and 30 mg exhibited similarly shaped pharmacokinetic profiles. AUC_0–168, AUC_0–∞), and C_max values for the 30-mg dose were approximately double those for the 15-mg dose, a result consistent with previously reported data on the dose proportionality of cyclobenzaprine immediate release.     

Bioequivalence and tolerability of two clopidogrel salt preparations,besylate and bisulfate: A randomized,open-label,crossover study in healthy Korean male subjects

Background: Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in patients with atherothrombotic diseases. Clopidogrel is marketed primarily as a bisulfate salt. A different salt preparation of clopidogrel, clopidogrel besylate, has been developed and might provide an additional treatment option for patients.Objective: The aim of this study was to compare the pharmacokinetic, pharmacodynamic, and tolerability profiles of clopidogrel besylate with those of clopidogrel bisulfate to determine bioequivalence for the purposes of marketing approval.Methods: A randomized, open-label, 2-period, single- and multiple-dose, comparative crossover study was conducted in healthy Korean male subjects. The subjects received either clopidogrel bisulfate or clopidogrel besylate as a single 300-mg oral loading dose (day 1) followed by a 75-mg/d (once daily) maintenance dose on days 2 to 6. After a 15-day washout period, subjects were administered the alternative salt preparation according to the same protocol. The plasma concentrations of clopidogrel and its primary metabolite (SR26334) were assessed using high-performance liquid chromatography/tandem mass spectrometry after administration of the loading dose. The platelet aggregation response to 10-μmol/L adenosine diphos-phate was measured using turbidometric aggregometry during the single- and multiple-dosing periods and at steady state (day 6). Tolerability was monitored using physical examination, including vital sign measurements, and laboratory analysis.Results: Forty-four subjects were enrolled and completed the study (mean [SD] age, 24.3 [2.7] years; weight, 70.0 [8.2] kg). The mean values for C_max, T_max, and AUC_0?t with clopidogrel (parent drug) of clopidogrel besylate (5.2 ng/mL, 0.9 hour, and 10.1 ng/mL/h, respectively) were similar to those with clopidogrel bisulfate (5.4 ng/mL, 0.9 hour, and 10.3 ng/mL/h). The mean values for Cmax, AUC_0?t, and AUC_0?∞ with the SR26334 of clopidogrel besylate (10.9 μg/mL, 38.8 μg/mL/h, and 43.0 μg/mL/h, respectively) were not significantly different from those with the SR26334 of clopidogrel bisulfate (11.9 μg/mL, 40.6 μg/mL/h, and 43.8 μg/mL/h). The mean values for maximal antiplatelet effect (Emax) and area under the time-effect curve (AUEC) with the 2 clopidogrel salt preparations were as follows: clopidogrel besylate, 58.8 h · % and 4299.1 h · % inhibition, respectively; and clopidogrel bisulfate, 61.7 h · % and 4406.9 h · % inhibition; these differences were not statistically significant. The 90% CIs for the ratios of the log-transformed C_max, AUC, E_max, and AUEC values were within the predetermined bioequivalence range of 80% to 125%. Three adverse events (6.8%) were reported during the study and included abdominal discomfort (1 subject [2.3%] in the group that received clopidogrel bisulfate), easy fatigability (1 subject [2.3%] immediately before administration of loading dose of clopidogrel besylate), and thrombocytopenia (1 subject [2.3%] in the group receiving the clopidogrel bisulfate). All adverse events were transient and mild.Conclusions: In these healthy Korean male subjects, the differences in the pharmacokinetic and pharmacodynamic properties between the 2 clopidogrel salt preparations did not reach statistical significance and met the regulatory requirements for bioequivalence. Both preparations were well tolerated.     

Single- and multiple-dose pharmacokinetics of genistein capsules in healthy chinese subjects: A phase I, randomized, open-label study

Background: Genistein capsules are currently being developed to treat osteoporosis in China. Genistein is extracted from the fruit of Sophora japonica Leguminosae.Objective: The objective of this study was to assess the pharmacokinetics of genistein capsules after single and multiple oral doses in healthy Chinese subjects.Methods: This was a Phase I, randomized, open-label, single- and multiple- dose study in healthy Chinese adults (aged 19-40 years). In the single-dose study, subjects were randomly assigned in a 1:1:1 ratio to receive genistein 50, 100, or 300 mg (in 50-mg capsules). To assess the effect of food on the pharmacokinetics, subjects in the 50-mg group were equally randomized again into fasting and postprandial (genistein was administered after a high-fat breakfast) groups according to a 2-way cross-over design. A separate equal-sized group of subjects were administered genistein 50 mg on day 1 (single dose), received no treatment on days 2 and 3, and were administered genistein 50 mg QD for 6 days (days 4-9) to obtain a multiple-dose pharmacokinetic profile. Because genistein is converted so rapidly and completely to glucuronidated genistein after administration, plasma concentrations of glucuronidated genistein were determined using a validated high-performance liquid chromatography/ tandem mass spectrometry method. Drug tolerability was assessed by monitoring adverse events (AEs) and laboratory parameters.Results: The study enrolled 40 healthy subjects (24 men, 16 women; 10 each in the 50-, 100-, and 300-mg single-dose groups and 10 in the multiple-dose group). Three subjects voluntarily withdrew (2 in the 100-mg group and 1 in the 300-mg group) before study drug administration. Thirty-seven subjects (24 men, 13 women) completed the study and were included in the analysis. The mean (SD) values of the single-dose genistein 50-, 100-, and 300-mg groups were as follows: T_max, 6.0 (2.4), 7.4 (2.4), and 5.6 (1.2) hours, respectively; t_l/2, 13.0 (4.0), 12.6 (5.8), and 9.4 (1.1) hours; AUC_0−t, 3344 (1635), 8389 (5164), and 9361 (2428) ng/mL · h⁻¹; and C_max , 218.7 (68.6), 435.7 (202.1), and 553.4 (152.8) ng/mL. The plasma glucuronidated genistein concentrations were directly proportional to the administered dose over the range of 50 to 100 mg and increased nonproportionately with the 300-mg dose. No statistically significant differences in pharmacokinetic parameters were found in the fasting group compared with the postprandial group. In the multiple-dose group, the mean (SD) steady-state pharmacokinetic parameters on day 9 were similar to those following a single dose of genistein on day 1 (T_max, 6.0 [1.0] vs 5.9 [1.5] hours, respectively; t_l/2, 9.5 [1.5] vs 9.1 [1.5] hours; AUC_0−t, 2830 [1541] vs 2078 [1308] ng/mL · h⁻¹; C_max, 203.1 [130.9] vs 168.4 [105.7] ng/mL). All AEs were assessed as mild or moderate and resolved without treatment, with the exception of elevated alanine aminotransferase and aspartate aminotransferase activities in one subject that resolved with treatment.Conclusions: The pharmacokinetics of glucuronidated genistein appeared to fit the linear-dose range of genistein 50 to 100 mg, but not the 300-mg dose in these healthy Chinese volunteers. Food consumption did not significantly affect the pharmacokinetic properties. No significant differences were observed in the pharmacokinetic parameters after multiple doses of genistein compared with a single dose, suggesting that the drug did not accumulate after multiple doses.     

Pharmacokinetics and bioequivalence evaluation of two formulations of 10-mg amlodipine besylate: An open-label,single-dose,randomized, two-way crossover study in healthy chinese male volunteers

Background: Amlodipine is a third-generation dihydropyridine calcium antagonist for the treatment of angina and hypertension. The relative bioavailability of a newly developed dispersible tablet as compared with an established branded formulation has not been reported in a Chinese population.Objective: The aim of this study was to assess and compare the pharmacokinetic properties, bioavailabili-ty, and bioequivalence of a newly developed dispersi-ble tablet formulation of amlodipine besylate with those of an established branded formulation in healthy Chinese adult male volunteers.Methods: An open-label, single-dose, randomized, 2-way crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 2 tablets (5 mg each) of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Serum samples were collected over 120 hours. Amlodipine concentrations in the serum were analyzed by liquid chromatography tandem mass spectrometry with positive ion electrospray ionization using the multiple reaction monitoring mode. The visible detection of the method was in the range of 0.2 to 32.0 ng/mL, and the lower limit of quantification for amlodipine was 0.2 ng/mL. The amlodipine serum concentration-time curves were used to obtain pharmacokinetic parameters including AUC_0?t, AUC_0?∞), and C_max. The criteria for bioequivalence were 90% CIs of 80% to 125% for AUC and 70% to 143% for C_max, according to guidelines of the State Food and Drug Administration of the People's Republic of China. Tolerability was based on the recording of adverse events (AEs), monitoring vital signs, electrocardiograms, and clinical laboratory tests at baseline and completion of the study.Results: A total of 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.6] years [range, 1926 years]; weight, 61.3 [5.4] kg [range, 54.0–75.0 kg]; and height, 171.2 [3.6] cm [range, 162.0–177.0 cm) were included in the study. The mean (SD) C_max, T_max, AUC_0?t, and AUC_0?∞) values after administration of the test and reference formulations, respectively, were as follows: 5.46 (1.13) versus 5.88 (1.24) ng/mL, 7.70 (2.08) versus 9.20 (4.18) hours, 284.56 (77.59) versus 311.34 (75.97) ng/mL/h, and 331.37 (111.03) versus 358.74 (101.10) ng/mL/h. The mean (SD) t_1/2 was 38.52 (10.51) hours for the test formulation and 38.75 (7.07) hours for the reference formulation. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for C_max, AUC_0?t, and AUC_0?∞). The relative bioavaila-bility of the test formulation was 90.9% by mean AUC_0?t and 91.2% by mean AUC_0?∞. The 90% CIs for the ratios of C_max, AUC_0?t, and AUC_0?∞ were 88.4% to 97.5%, 86.4% to 95.7%, and 85.8% to 97.0%, respectively, meeting the predetermined criteria for bioequivalence. One subject (5%) reported 2 AEs. The AEs were mild, possibly associated with study drug, and resolved spontaneously by the next evaluation. No serious AEs were reported.Conclusions: In this small study in healthy Chinese adult male volunteers, a single 10-mg dose of the dispersible tablet formulation (test) of amlodipine besy-late met the regulatory criteria for bioequivalence to the established tablet formulation (reference) based on the rate and extent of absorption. Both formulations were well tolerated.     

Bioequivalence of two formulations of glucosamine sulfate 500-mg capsules in healthy male chinese volunteers: An open-label,randomized-sequence,single-dose,fasting, two-way crossover study

Background: Glucosamine sulfate is used for the treatment of arthrosis, especially osteoarthritis of the knee joint. The available evidence suggests differences in its pharmacokinetics in Chinese subjects compared with non-Chinese subjects.Objective: The aim of this study was to compare the pharmacokinetics and relative bioavailability of a test and reference formulation of glucosamine sulfate 500 mg after single oral administration in healthy Chinese volunteers.Methods: This open-label, randomized-sequence, single-dose, 2-way crossover study was performed at the First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 500-mg dose of the test or reference capsule formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Glucosamine sulfate was assayed using a liquid-chromatography tandem mass spectrometry method. For analysis of pharmacokinetic properties, including C_max, AUC_0?t, and AUC_0?∞), blood samples were obtained at intervals over a 14-hour period after study drug administration. The formulations were considered bioequivalent if the log-transformed ratios of C_max and AUC were within the predetermined equivalence range (70%–143% for C_max and 80%–125% for AUC) as established by the State Food and Drug Administration (SFDA) of China. Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events (AEs).Results: Twenty–two healthy male Chinese subjects were enrolled (mean [range] age, 24 [22–26] years; weight, 63.9 [58.5–69.3] kg; height, 172 [167–177] cm); all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of C_max, AUC_0?t, and AUC_0?∞) were 93.4 to 127.3, 92.4 to 114.5, and 92.7 to 114.6, respectively (all, P = NS). The AUC_0?∞ of the test and reference formulations was 1.83 (0.66) and 1.77 ( 0.72) μg/h/mL, respectively. No AEs were observed or reported during the study.Conclusions: In this small study in healthy male Chinese volunteers, a single 500-mg dose of the test formulation met the SFDA's regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated.     

A single-dose,three-period,six-sequence crossover study comparing the bioavailability of solution,suspension, and enteric-coated tablets of magnesium valproate in healthy Mexican volunteers under fasting conditions

Background: Valproic acid has been associated with a highly variable intersubject absorptive phase; therefore, magnesium salt (magnesium valproate [MgV]) was developed to diminish variation during enteric absorption.Objectives: The aims of this study were to assess the pharmacokinetics of single oral doses of MgV 500-mg solution, suspension, and enteric-coated tablets in a healthy Mexican population, and to compare formulation-related differences.Methods: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy Mexican volunteers aged 18 to 45 years. In each period, subjects received single oral doses of 500-mg MgV solution, suspension, and enteric-coated tablet formulations, with a 7-day washout period between each dosing period. Serial blood samples were collected at 0 hour (prior to MgV administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 hours after dosing. Valproate was measured by a new method of ultraperformance liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters of interest were C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and mean residence time (MRT). Formulation-related differences were assayed in accordance with the Mexican regulatory bioequivalence criteria. Log-transformed values of C_max and AUC were used to construct a classic 90% CI. Bioequivalence was established if the 90% CI for the mean test:reference ratio of log-transformed C_max and AUC were within the range of 0.80 to 1.25. Tolerability was assessed based on subject interview, vital sign monitoring, and clinical assessment.Results: A total of 24 healthy volunteers (12 women and 12 men; mean [SD] age, 28.79 [6.5] years; height, 164 [9.8] cm; weight, 65.42 [8.95] kg; and body mass index, 24.28 [2.11] kg/m²) were included. For the MgV solution, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0–∞, t½, V_d/F, CL/F, and MRT were 59.75 (8.24) μg/mL, 0.542 (0.14) hours, 1099.67 (241.70) μg · h/mL, 1156.30 (264.01) μg · h/mL, 16.19 (2.36) hours, 9633.68 (1892.70) mL, 418.35 (92.01) mL/h, and 18.36 (1.44) hours, respectively. For the MgV suspension, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and MRT were 55.04 (7.72) μg/mL, 0.773 (0.51) hour, 1057.76 (223.37) μg · h/mL, 1111.09 (245.07) μg · h/mL, 16.32 (2.20) hours, 1069.05 (1775.64) mL, 435.43 (99.59) mL/h,\ and 18.41 (1.43) hours, respectively. For the MgV entericcoated tablets, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and MRT were 54.88 (6.73) μg/mL, 2.79 (0.89) hours, 1100.79 (216.70) μg · h/mL, 1163.61 (238.36) μg · h/mL, 16.48 (2.10) hours, 9675.15 (1659.36) mL, 412.36 (85.24) mL/h, and 19.95 (1.53) hours, respectively. The 90% CIs for the tablets:solution ratio were 82.15 to 95.44, 94.60 to 105.39, and 95.43 to 105.95 for C_max, AUC_0–72, and AUC_0?∞, respectively. The 90% CIs for the suspension:solution ratio were 84.79 to 98.50, 88.89 to 99.02, and 89.15 to 98.97, respectively. The 90% CIs for the tablets:suspension ratio were 89.90 to 104.43, 100.84 to 112.34, and 101.60 to 112.80, respectively.Conclusion: This single-dose study found that the 3 formulations (solution, suspension, and enteric-coated tablets) of MgV met the regulatory criteria for bioequivalence in these healthy, fasting, Mexican volunteers.     

Pharmacokinetic and Pharmacodynamic Interactions Between Henagliflozin,a Novel Selective SGLT-2 Inhibitor,and Warfarin in Healthy Chinese Subjects

PurposeWhile controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects.MethodsThis single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (C_max,ss and AUC_τ,ss), the effects of henagliflozin on the PK properties of warfarin (C_max, AUC_0–t, and AUC_0–∞), and the influences of henagliflozin on the PD properties of warfarin (PT_max, PT_AUC, INR_max, and INR_AUC) were evaluated.FindingsThe geometric mean ratios (GMRs; 90% CIs) of henagliflozin C_max,ss and AUC_τ,ss were 101.75% (96.11%–107.72%) and 102.21% (100.04%–104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin C_max, AUC_0–t, and AUC_0–∞ were as follows: C_max, 114.31% (106.30%–122.91%) and 115.09% (109.46%–121.01%), respectively; AUC_0–t, 120.15% (116.71%–123.69%) and 119.01% (116.32%–121.76%); and AUC_0–∞, 120.81% (117.17%–124.58%) and 121.94% (118.90%–125.05%). The GMRs (90% CIs) of warfarin PT_max and PT_AUC were 92.73% (91.25%–94.22%) and 97.42% (96.61%–98.24%). The GMRs (90% CIs) of warfarin INR_max and INR_AUC were 92.66% (91.17%–94.17%) and 97.36% (96.52%–98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported.ImplicationsNo significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.     

A Phase I,Single- and Multiple-dose Study to Evaluate the Pharmacokinetics of Elbasvir and Grazoprevir in Healthy Chinese Participants

Purpose

This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals.

A single-dose,randomized, two-way crossover study comparing two olanzapine tablet products in healthy adult male volunteers under fasting conditions

Background: Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class.Objective: The aim of this study was to assess the bioequivalence of 2 commercial 10-mg tablet formulations of olanzapine by statistical analysis of the pharmacokinetic parameters C_max, AUC from 0 to 72 hours after dosing (AUC_0-72), and AUC_0-∞ as required by the Egyptian health authority for the marketing of a generic product.Methods: This bioequivalence study was carried out in healthy male volunteers using a single-dose, randomized, 2-way crossover design under fasting conditions. Statistical analysis of the pharmacokinetic parameters C_max, AUC_0-72, and AUC_0-∞ was conducted to determine bioequivalence (after log-transformation of data using analysis of variance and 90% CIs) and to gain marketing approval in Egypt. The formulations were considered to be bioequivalent if the log-transformed ratios of the 3 pharmacokinetic parameters were within the predetermined bioequivalence range (ie, 80%–125%), as established by the US Food and Drug Administration (FDA). Both the test product (Trademark: Integrol^® [Global Napi Pharmaceuticals, Cairo, Egypt]) and the reference product (Trademark: Zyprexa^® [Eli Lilly and Company, Basingstoke, Hampshire, United Kingdom]) were administered as 10-mg tablets with 240 mL of water after an overnight fast on 2 treatment days, separated by a 2-week washout period. After dosing, serial blood samples were collected for 72 hours. Plasma samples were analyzed using a sensitive, reproducible, and accurate liquid chromatography-tandem mass spectrometry method capable of quantitating olanzapine in the range of 0.167 to 16.7 ng/mL, with a lower limit of quantitation of 0.167 ng/mL. Adverse events were reported by the volunteers as instructed or observed by the resident physician, and were recorded, tabulated, and evaluated.Results: Twenty-four healthy adult male volunteers participated in this study. Their mean (SD) age was 24.7 (6.2) years (range, 19–41 years), mean weight was 73.4 (6.7) kg (range, 64–89 kg), and mean height was 174.25 (4.6) cm (range, 168–186 cm). Values for C_max, AUC_0-72, AUC_0-∞, T_max, t_1/2, and the terminal disposition rate constant were found to be in agreement with previously reported values. The differences between the 2 products did not reach statistical significance at P ≤ 0.05 (90% CIs: C_max, 101.82–124.79; AUC_0-72, 93.36–102.04; and AUC_0-∞, 88.57–101.77). The test/reference ratio of these parameters was within the acceptance range of the FDA criterion for bioequivalence. Both formulations were apparently well absorbed from the gastrointestinal tract (ie, no specific gastrointestinal tract-related adverse events were reported).Conclusions: In this small study in healthy male volunteers, there were no statistically significant differences in any of the calculated pharmacokinetic parameters between the 10-mg test and reference tablets of olanzapine. The 90% CIs for the ratios of mean C_max, AUC_0-72, and AUC_0-∞ were within the range of 80% to 125% (using log-transformed data), meeting the FDA regulatory criterion for bioequivalence. Both formulations were well tolerated.     

Pharmacokinetics and bioequivalence of two formulations of rebamipide 100-mg tablets: A randomized,single-dose,two-period,two-sequence crossover study in healthy Korean male volunteers

Background: Rebamipide is a quinolinone-derived gastroprotective agent approved in Korea for the treatment of gastric ulcers, acute gastritis, and exacerbated chronic gastritis.Objectives: The aims of this study were to evaluate the pharmacokinetics and bioequivalence of a reference (branded) and test (generic) formulation of rebamipide 100-mg tablets in healthy Korean male volunteers for the purposes of generic substitution and to evaluate the relationship between genetic polymorphisms in the ABCB1 gene (exons 21 and 26) and rebamipide pharmacokinetics.Methods: This study had a 2-period crossover design, with a 7-day washout between formulations. Healthy Korean male volunteers were randomly assigned to receive a single 100-mg dose of the test or reference formulation, administered with 240 mL of water after a 12-hour overnight fast. Serum concentrations of rebamipide up to 12 hours after administration were determined using a validated HPLC method with fluorescence detection. Vital signs (temperature, blood pressure, and heart rate) were measured before and after dosing in both periods. Adverse events were monitored by clinic staff on the days of study drug administration and were recorded for up to 1 week after the last dose of study medication. Pharmacokinetic parameters were determined using a noncompartmental method. The formulations were considered bioequivalent if the log-transformed ratios of AUC_0?t, AUC_0?∞), and C_max were within the predetermined bioequivalence range (80%–125%) established by the US Food and Drug Administration and Korean legislation. The in vitro dissolution profiles of the 2 formulations were examined, and the influence on rebamipide pharmacokinetics of genetic polymorphisms in the ABCB1 gene (P-glycoprotein) was investigated.Results: Thirty healthy Korean male volunteers (mean [SD] age, 22.97 [1.67] years [range, 20–27 years]; height, 174.56 [6.27] cm [range, 159.1–184.8 cm]; and weight, 69.44 [8.32] kg [range, 54.7–90.2 kg]) were enrolled in and completed the study. No adverse events were reported. The 2 formulations had comparable in vitro dissolution profiles. The mean AUC_0?t for the test and reference formulations was 831.09 (329.52) and 903.46 (419.17) ng/mL/h, respectively; the AUC_0?∞ was 851.68 (332.62) and 923.58 (423.21) ng/mL/h; the C_max was 218.12 (93.90) and 220.57 (107.48) ng/mL; the T_max was 2.05 (1.15) and 2.10 (0.76) hours; and the t_½ was 1.96 (0.52) and 1.93 (0.49) hours. No significant sequence, subject, formulation, or period effects were detected for any pharmacokinetic parameter. The point estimates for AUC_0?t, AUC_0?∞, and C_max were 0.95 (90% CI, 0.84–1.06), 0.95 (90% CI, 0.84–1.06), and 1.01 (90% CI, 0.89–1.15), respectively, satisfying the criterion for bioequivalence. There was no statistically significant difference in T_max. No significant differences in rebamipide AUC_0?t, AUC_0?∞, or C_max were found among the ABCB1 2677 GG, GT, or TT groups, or among the ABCB1 3435 CC, CT, or TT groups. There was no evidence that genetic polymorphisms in the ABCB1 gene influenced the pharmacokinetics of rebamipide.Conclusions: The results of this study in healthy Korean male volunteers suggest that the 2 rebamipide 100-mg tablet formulations administered in the fasted state met the regulatory criterion for bioequivalence. There was no evidence that rebamipide pharmacokinetic parameters were influenced by genetic polymorphisms in the ABCB1 gene (exons 21 and 26). ClinicalTrials.gov identifier: NCT00997789     

Safety,Tolerability, Pharmacokinetics,and Pharmacodynamics of SPH3127: A Phase I,Randomized, Double-Blind,Placebo-Controlled Trial

PurposeTo evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals.MethodsThis was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study.FindingsSPH3127 exposure, expressed as C_max, AUC_0–t, and AUC_0–∞, was proportionally increased with dose for a range of 25–800 mg (single ascending dose [SAD]) and 100–400 mg daily (multiple ascending doses [MADs]). In an SAD, the C_max values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC_0–t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the C_max values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC_0–t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the C_max values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC_0–24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median T_max range from 0.33 to 1.0 h and the median t_1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred.ImplicationsSPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity.Clinicaltrials.gov identifiersNCT03128138 (SAD study) and NCT03255993 (MAD study).     

Single-dose bioequivalence assessment of two formulations of polysaccharide iron complex capsules in healthy adult male Chinese volunteers: A sequence-randomized, double-blind, two-way crossover study

Background: Iron deficiency anemia (IDA) is a common nutritional disease worldwide. Iron supplementation is an efficient method for treating patients with IDA. Polysaccharide iron complex is an oral iron supplement that is associated with generally good tolerability and good bioavailability.Objective: The aim of this study was to evaluate the bioequivalence of 2 branded formulations of polysaccharide iron complex in healthy adult male Chinese volunteers by determining the pharmacokinetic parameters after single-dose oral admi ni strati on.Methods:This sequence-randomized, double-blind, 2-way crossover study was carried out in the Affiliated Hospital, Institute of Medical Sciences of Qingdao University, Qingdao, China. Healthy adult male Chinese volunteers were enrolled and evenly randomized to receive 1 of 2 formulations on day 1. Subjects received an oral dose of 150 mg (1 capsule) of polysaccharide iron complex with 150 mL of warm water in the morning. Capsules were of similar size, shape, and color to ensure blinding. Four hours after administration, the subjects were given standardized meals. After a 1-week washout period, the subjects were crossed over to receive the other formulation in a similar manner. The serum iron concentration 12 hours after study drug administration was determined using atomic-absorption spectrometry. The pharmacokinetic parameters C_max, T_max, AUC_0−t, and AUC_0−∞ were obtained and analyzed using the Schuir mann 2 one-sided t test. The 2 formulations were considered bioequi valent if the test/reference ratios of Cmax, AUC_0−t, and their 90% CIs were within the range of 70% to 143% for C_max and within 80% to 125% for AUC_0−t. Tolerability was monitored by inquiring whether the subjects had experienced adverse events (AEs), with a focus on gastrointestinal AEs, during the clinic visits during the 24-hour period after drag administration and subsequently via telephone throughout the study.Results: Thirty adult male Chinese volunteers were assessed for inclusion. Twenty healthy male volunteers (10 in each group) (mean [SD] age, 21.5 [2.9] years [range, 19-23 years]; weight, 66.2 [5-8] kg [range, 56-80 kg]; height, 172.5 [5.1] cm [range, 162-180 cm]) were enrolled and completed the study. The pharmacokinetic parameters of the test and reference formulations were as follows: AUC_O−t, 6.58 (2.09) and 6.58 (1.91) μg/mL · h⁻¹; C_max, 1.10 (0.28) and 1.07 (0.25) μg/mL; T_max, 3.93 (0.37) and 3-93 (0.37) hours; t_½, 8.33 (0.36) and 8.38 (0.41) hours; and AUC_0−∞, 6.93 (2.23) and 6.95 (2.13) μg/mL · h⁻¹, respectively. There were no statistically significant differences in AUC_0−∞ or T_max by formulation, period, or subject between the test and reference formulations. Similarly, there were no statistically significant differences in C_max by period; however, a significant difference was found in C_max by formulation (P = 0.012). No clinically significant AEs were reported with either formulation.Conclusions: In these healthy adult male Chinese volunteers, the test formulation of polysaccharide iron complex was found to be bioequivalent to the reference formulation according to the Chinese regulatory definition. A significant difference by formulation was found in Cmax. The sample size was smaller than that recommended by the US Food and Drug Administration for a bioequivalence study, and additional studies with larger sample sizes are needed.     

Pharmacokinetic comparison of a new glimepiride 1-mg + metformin 500-mg combination tablet formulation and a glimepiride 2-mg + metformin 500-mg combination tablet formulation: A single-dose,randomized, open-label,two-period,two-way crossover study in healthy,fasting Korean male volunteers

Background: Coadministration of glimepiride and metformin has been used to achieve glucose control. Because compliance with a multiple medication regimen can be difficult for some patients, combination tablets of glimepiride + metformin might be a suitable alternative for these patients.Objective: This study was conducted to compare the pharmacokinetics of test and reference formulations of glimepiride + metformin fixed-dose combination tablets under fasting conditions to meet the regulatory requirements for marketing approval of a new drug in Korea.Methods: This was a single-dose, randomized, open-label, 2-period, 2-way crossover study conducted between March 2007 and May 2007. Healthy fasting Korean men were randomized to 1 of 2 dosing sequences: a single oral administration of a fixed-dose glimepiride 1-mg + metformin 500-mg combination tablet (test) followed by single oral administration of a fixed-dose glimepiride 2 mg + metformin 500 mg combination tablet (reference), separated by a 1-week washout period between doses; or a single oral administration of a fixed-dose glimepiride 2-mg + metformin 500-mg combination tablet followed by single oral administration of a fixed-dose glimepiride 1 mg + metformin 500-mg combination tablet, separated by a 1-week washout period between doses. Serial samples of blood were collected up to 24 hours after oral administration, and drug concentrations in plasma were determined by HPLC-MS/MS. Tolerability was assessed based on adverse events and changes in clinical parameters. Serious adverse events included those that resulted in death, a life-threatening condition, congenital anomaly or birth defect, or required hospitalization or prolongation of existing hospitalization.Results: A total of 30 healthy male subjects (mean age, 25.6 years [range, 20–36 years]; weight, 69.5 kg [range, 58.2–90.7 kg]) participated in the study. After administration of the test and reference formulations, glimepiride was rapidly absorbed, reaching C_max with a median T_max of 1.75 and 2.0 hours, respectively, and then declined exponentially with an average t½ of 8.2 and 8.5 hours. The individual C_max and AUC_last of glimepiride were observed to be proportionally increased according to the administered glimepiride dose. The mean (SD) dose-normalized Cmax values of glimepiride 1 and 2 mg were 168.2 (54.9) and 149.9 (47.4) ng/mL/mg, respectively; the mean dose-normalized AUC_last values of glimepiride 1 and 2 mg were 681.5 (190.3) and 635.8 (194.1) ng · h/mL/mg. Individual plots of dose-normalized C_max and AUC_last values identified a similarity between the 2 groups but no significant between-group differences. A total of 25 adverse events (12 after the test dose and 13 after the reference dose) were reported by 13 of the 30 subjects. All adverse events were considered mild. Twenty-one adverse events were considered related to the study drug (8 after the test dose and 13 after the reference dose). Adverse events believed to be related to the test formulation were diarrhea (4 cases), dizziness (1), headache (1), tingling sensation (1), and weakness (1). Adverse events believed to be related to the reference formulation were diarrhea (6 cases), headache (3), cold sweats (1), dyspepsia (1), epigastric discomfort (1), and lethargy (1). There were no clinically significant findings in the laboratory test results or vital sign monitoring during the study. There were no serious adverse events reported.Conclusions: The C_max and AUC_last of glimepiride increased proportionally according to the administered glimepiride dose in this study of healthy, fasting Korean men. The safety profiles of the 2 combination tablets were comparable.     

Pharmacokinetic properties of lansoprazole (30-mg enteric-coated capsules) and its metabolites: A single-dose, open-label study in healthy Chinese male subjects

Background: Lansoprazole, a benzimidazole derivative, is indicated for the treatment of various peptic diseases. It is metabolized mainly in the liver, and its primary active metabolites present in plasma are 5′-hydroxy lansoprazole and lansoprazole sulfone. Few data are available on the pharmacokinetic properties of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone, which can be used to measure cytochrome P450 (CYP) 2C19 activity.Objectives: The aims of this study were to investigate the clinical plasma pharmacokinetic properties of lansoprazole and its metabolites in healthy Chinese male volunteers, and to assess the influences of CYP2C19 on the pharmacokinetics of lansoprazole.Methods: Healthy adult Chinese male volunteers were enrolled in this single-dose, open-label study. All patients received a single oral enteric capsule containing 30 mg of lansoprazole after a 12-hour overnight fast. Serial blood samples were collected immediately before (0 hour) and at 20, 40, 60, 90, 120, and 150 minutes and 3, 4, 6, 8, 10, 12, 15, and 24 hours after study drug administration. The plasma concentrations of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone were determined using a validated internal standard high-performance liquid chromatography—tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic properties (including C_max, T_max, elimination t_½ [t_½z], mean residence time [MRT], AUC_0-24, AUC_0−∞, apparent oral clearance [CL_z/F], and apparent volume of distribution [V_z/F]) were determined using the noncompartmental method.Results: Twenty volunteers (mean [SD] age, 34.9 [2.9] years; weight, 64.6 [2.2] kg; height, 171.3 [3.3] cm) were enrolled in and completed the study. The mean (SD) pharmacokinetic properties of lansoprazole were as follows: C_max, 1047 (344) ng/mL; T_max, 2.0 (0.7) hours; t_½z, 2.24 (1.43) hours; MRT, 3.62 (0.87) hours; AUC₀₋₂₄, 3388 (1484) ng/mL/h; AUC_0-∞, 3496 (1693) ng/mL/h; CL_z/F, 9.96 (3.74) L/h; and V_z/F, 32.83 (11.74) L. The findings with 5′-hydroxy lansoprazole and lansoprazole sulfone, respectively, were as follows: C_max, 111.2 (41.8) and 66.6 (52.9) ng/mL; T_max, 2.1 (0.8) and 1.9 (0.8) hours; t_½z, 2.31 (1.18) and 2.52 (1.54) hours; and AUC₀₋₂₄, 317.0 (81.2) and 231.9 (241.7) ng/mL/h. No adverse events were reported throughout the study.Conclusions: In these healthy Chinese male volunteers administered a single oral dose of lansoprazole 30 mg, absorption of lansoprazole was rapid (mean C_max, 1047 ng/mL; T_max, ~2.0 hours). Its 2 primary active metabolites, 5′-hydroxy lansoprazole and lansoprazole sulfone, were identified in measurable quantities in plasma (C_max, 111.2 and 66.6 ng/mL, respectively; and T_max, 2.1 and 1.9 hours). The plasma t_½z did not appear to reflect the duration of suppression of gastric acid secretion: the t_½z values of lansoprazole and the 2 metabolites were ~2 to 2.5 hours, while the acid-inhibitory effect lasted >24 hours. C_max, AUC, and t_½z of lansoprazole, and especially lansoprazole sulfone, varied. Differences in metabolism types and/or genotype of CYP2C19 should be taken into account when planning a lansoprazole dosing regimen.     

Pharmacokinetics and Safety of Extended-release Ranolazine in Korean and White Healthy Subjects

PurposeRanolazine, an inhibitor of late inward sodium current, is an antianginal agent. In this study, the pharmacokinetic (PK) properties and tolerability of single- and multiple-dose ranolazine were compared between healthy Korean and white subjects.MethodsAn open-label, ascending single- and multiple-dose study was conducted with healthy male Korean and white subjects. Subjects were administered 375–750 mg of ranolazine once in a single-dose and twice daily in multiple-dose based on their dose groups. Blood samples for the PK assessment were collected up to 48 h after dosing. The geometric mean ratio and its 90% confidence interval in Korean to white subjects for C_max, C_max,ss, AUC_last, and AUC_0–12h,ss of ranolazine were calculated. A population PK analysis was also performed. Safety profiles were assessed throughout the study.FindingsA total of 70 Korean and 48 white subjects completed the study. Ranolazine exposure was similar between Korean and white subjects in all dose groups; however, ranolazine exposure at 750 mg was observed to increase by up to 29% in Korean subjects compared with that in white subjects. On the basis of previous studies, these differences in ranolazine exposure between the 2 ethnic groups may not result in any clinically significant difference. Furthermore, ethnicity was not significantly correlated with the PK properties of ranolazine in the ranolazine PK model. In addition, no significant difference was found in the safety profile of ranolazine between the 2 ethnic groups.ImplicationsThe PK properties of ranolazine had no clinically significant difference, and no difference was found in the safety profiles of ranolazine between Korean and white subjects. It is anticipated that ranolazine can be administered in Korean subjects without dose adjustment. ClinicalTrials.gov identifier: NCT02817932.