Pharmacokinetics of a New,Once-Daily,Sustained-release Pregabalin Tablet in Healthy Male Volunteers

PurposeA new sustained-release (SR) pregabalin formulation (YHD1119) designed for once-daily dosing has recently been developed to improve patient adherence. This study aimed to compare the pharmacokinetics of pregabalin SR and immediate-release (IR) formulations after multiple oral doses and to assess the effect of food on the pharmacokinetic profile of the pregabalin SR formulation after a single dose in healthy individuals.MethodsTwo clinical trials were conducted: a randomized, open-label, multiple-dose, 2-treatment, 2-period crossover study to evaluate the steady-state pharmacokinetic properties of SR treatment (pregabalin SR 300 mg once daily for 3 days) and IR treatment (pregabalin IR 150 mg twice daily for 3 days) under fed conditions and a randomized, open-label, single-dose, 2-treatment, 2-period, crossover study to evaluate the effect of food intake on the pharmacokinetic properties of the pregabalin SR formulation. Plasma concentrations of pregabalin were measured using LC-MS/MS. The AUC and C_max for pregabalin were calculated using noncompartmental method and compared between treatments in each study.FindingsThirty-one individuals in the bioequivalence study and 23 in the food effect study completed the pharmacokinetic sampling. The geometric mean ratios of C_max,ss and AUC_0–τ between the SR and IR formulations were 1.1642 (90% CI, 1.1043–1.2272) and 0.9704 (90% CI, 0.9372–1.0047), respectively. The geometric mean ratios of C_max and AUC_0–last between the SR formulation in the fed state and in the fasted state were 1.6514 (90% CI, 1.3820-1.9732) and 1.7899 (90%CI, 1.4499-2.2097), respectively.ImplicationsThe bioavailability of the pregabalin SR 300 mg formulation is increased if taken with a high-fat meal. Once-daily pregabalin SR 300 mg is bioequivalent to twice-daily pregabalin IR 150 mg under fed conditions at steady state. The pregabalin SR formulation is expected to improve patient adherence. ClinicalTrials.gov identifiers: NCT02783183 (bioequivalence study) and NCT03191136 (food effect study).     

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.     

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.     

Bioequivalence of single and multiple doses of venlafaxine extended-release tablets and capsules in the fasted and fed states: Four open-label,randomized crossover trials in healthy volunteers

Background: Venlafaxine extended-release (ER) tablets use osmotic pressure to deliver venlafaxine hydrochloride at a controlled rate over ~24 hours.Objective: These studies were conducted to evaluate the bioequivalence of venlafaxine ER tablets and capsules based on the US Food and Drug Administration (FDA) definition.Methods: Four pharmacokinetic studies of the capsule (reference) and tablet (test) formulations were conducted in healthy adult volunteers. The first 2 were randomized, single-dose, 4-way crossover studies of either a 37.5-mg dose (study A) or a 75-mg dose (study B) of the reference and test products under fasting and fed conditions. The other 2 were randomized, 2-way crossover studies of either a single dose (study C) or multiple doses (study D) of venlafaxine ER 225 mg, delivered as one venlafaxine ER 225-mg tablet or one 150-mg + one 75-mg venlafaxine ER capsules under fed conditions. The primary outcome measures were the log-transformed C_max, AUC_0?t, and AUC_0?∞. If the 90% CIs for the ratios of the least squares means of the primary outcome measures between the reference and test formulations fell within the regulatory range (80%–125%), the 2 formulations would be considered bioequivalent according to the FDA definition.Results: Thirty–six subjects (21 men, 15 women; mean [SD] age, 28.0 [8.7] years; mean weight, 161.0 [26.0] lb) were enrolled in study A and completed all treatment periods. Thirty-six subjects were enrolled in study B, of whom 30 (22 men, 8 women; mean age, 33.5 [9.6] years; mean weight, 172.7 [23.9] lb) completed all treatment periods. Thirty-six subjects were enrolled in study C, of whom 28 (16 men, 12 women; mean age, 33.1 [12.9] years; mean weight, 160.6 [29.6] lb) completed the study. Thirty-four subjects were enrolled in study D, of whom 33 (29 men, 4 women; mean age, 26.0 [8.1] years; mean weight, 178.0 [30.3] lb) completed the study. In study A, the 90% CIs for the log-transformed ratio (test vs reference) of C_max, AUC_0?t, and AUC_0?∞ in the fasted state were 95.58 to 107.48, 97.58 to 111.09, and 100.31 to 112.85, respectively; in the fed state, the corresponding values were 84.26 to 94.86, 93.49 to 106.58, and 98.98 to 111.91. In study B, the respective values in the fasted state were 113.07 to 126.10, 111.11 to 124.57, and 106.86 and 120.71; in the fed state, the values were 90.50 to 100.90, 96.80 to 108.50, and 95.05 to 107.21. In study C, fed values were 94.15 to 109.37, 103.8 to 115.85, and 102.64 to 113.39. In study D, which involved multiple doses, fed values for C_max and AUC_0?t were 82.26 to 88.77 and 101.16 to 109.45, respectively. Adverse effects included nausea, vomiting, dizziness, syncope, and somnolence.Conclusions: In these single- and multiple-dose studies, all doses of venlafaxine ER tablets tested met the FDA criterion for bioequivalence to the equivalent doses of venlafaxine ER capsules in the fed state. In the fasted state, the bioequivalence criterion was met for venlafaxine ER 37.5-mg tablets but not venlafaxine 75-mg tablets.     

A randomized crossover study to assess the pharmacokinetics of a novel amphetamine extended-release orally disintegrating tablet in healthy adults

Objectives: In this pharmacokinetic (PK) study in healthy adults, we sought to: (1) compare the PK properties of a novel amphetamine extended-release orally disintegrating tablet formulation (Adzenys XR-ODT? [AMP XR-ODT]) to a reference extended-release mixed amphetamine salts (MAS ER) formulation and (2) assess the effect of food on AMP XR-ODT.

Methods: Forty-two adults were enrolled in a single-dose, open-label, 3-period, 3-treatment, randomized crossover study and received an 18.8-mg dose of AMP XR-ODT (fasted or fed) or equivalent dose (30 mg) of MAS ER (fasted). Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (C_max), time to maximum plasma concentration (T_max), elimination half-life (T_1/2), area under the concentration-time curve from time zero to last quantifiable concentration (AUC_last), from time zero to infinity (AUC_inf), relevant partial AUCs, and weight-normalized clearance (CL/F/kg) were assessed. The PK parameters were compared across treatments using an ANOVA. Safety was also assessed.

Results: A total of 39 adults completed this study. The geometric mean ratios (90% confidence interval [CI]) for AMP XR-ODT/MAS ER C_max, AUC_5-last, AUC_last, and AUC_inf were within 80%–125% for both d-and l-amphetamine. The 90% CIs for AUC_0-5 were slightly below the 80%–125% range. When AMP XR-ODT was administered with food, there was a slight decrease in the d-and l-amphetamine C_max and approximately a 2-hour delay in T_max. The most common adverse events reported (>5% of participants) were dry mouth, palpitations, nausea, dizziness, headache, anxiety, and nasal congestion.

Conclusions: AMP XR-ODT displayed a PK profile similar to MAS ER, and no clinically relevant food effect was observed.     

A new high-absorption-rate Paracetamol 500-mg formulation: a comparative bioavailability study in healthy volunteers

Background: Paracetamol is often the analgesic or antipyretic of choice, especially for patients for whom salicylates or other nonsteroidal anti-inflammatory drugs are contraindicated.Objective: The aim of this study was to compare the absorption rate of a new tablet formulation of paracetamol (500 mg) with a reference formulation of paracetamol at the same dose.Methods: This was a single-center, Phase I, open-label, randomized, 2-period, crossover, single-dose, comparative bioavailability clinical trial. During both study periods, healthy volunteers were given a single oral dose of a more hydrophilic test formulation of paracetamol, or a reference formulation. Fifteen plasma samples were obtained to determine paracetamol concentrations and to calculate kinetic parameters.Results: The study participants comprised 24 healthy volunteers (12 men, 12 women; mean [SD] age, 22.8 [1.5] years). The pharmacokinetic parameters calculated for the test versus the reference formulation were as follows: median time to maximum concentration (T_max), 0.42 versus 0.75 hour; mean (SD) maximum plasma drug concentration (C_max), 9.85 (2.40) μg/mL versus 8.33 (2.22) μg/mL; and mean (SD) area under the plasma concentration-time curve from time 0 to infinity (AUC_0-∞), 30.16 (8.87) μg·h/mL versus 28.49 (8.57) μg · h/mL. The 90% CIs of the ratios were as follows: base e logarithm (Ln)-transformed C_max, 105.08% to 137.59%; Ln-AUC_0-∞, 102.02% to 110.43%; and the difference in T_max, −0.375 to −0.085 hours.Conclusions: The speed of release and absorption was statistically significantly higher with the test formulation compared with the reference one (evaluated using T_max, C_max, and C_max/AUC parameters). This speed is especially important for a rapid analgesic or antipyretic effect.     

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.     

Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: Two single-dose,open-label,randomized-sequence,crossover studies

Background: Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura.Objective: The aim of these studies was to assess the effect of food and antacids on the pharmacoki-netic and safety profiles of eltrombopag.Methods: Two independent, single-dose, open-label, randomized-sequence, crossover studies of oral eltrom-bopag were conducted in healthy adult volunteers. The first study (study A) compared eltrombopag 50 mg (tablets or capsules) administered in the fasted state or tablets with a high-fat, high-calcium breakfast. The second study (study B) investigated eltrombopag tablets (75 mg) administered in the fasted state; immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminum hydroxide and magnesium carbonate. Vital signs were recorded and electrocardiogram and clinical laboratory tests were performed at screening, within 24 hours before and within 48 hours after each dose of study medication. Symptom assessment was performed and adverse events (AEs) were assessed previous to study drug administration through follow-up in terms of severity and relationship to study medication.Results: In study A, 18 male subjects (mean age, 23.0 years; weight, 70.3 kg; white race, 94.4%) who received a high-fat, high-calcium breakfast had reduced bioavailability of eltrombopag in terms of AUC_0–∞) by 59% (geometric mean ratio [GMR], 0.41; 90% CI, 0.36–0.46) and C_max by 65% (GMR, 0.35; 90% CI, 0.30–0.41) compared with subjects in a fasted state. In study B, the bioavailability in 26 subjects (14 male, 12 female; mean age, 35.6 years; weight, 76.0 kg; white race, 65.4%) was not significantly changed when administered with food that was low in calcium, despite the fat content (GMRs ranged from 0.87–1.03 for AUC_0–∞ and 0.85–1.01 for C_max across the 3 studied meals). Mean plasma AUC_0–∞) and C_max values decreased by ~70% (GMR, 0.30; 90% CI, 0.24-0.36 for AUC_0–∞) and 0.24–0.38 for C_max) when administered with a metal cation-containing antacid. No serious AEs were reported and all AEs were rated as mild to moderate in intensity. The most frequently reported AE was headache (study A, 6.3%; study B, 12.0%–29.2%).Conclusions: Concomitant administration of el-trombopag with high-calcium food or an antacid containing aluminum and magnesium was associated with significantly reduced systemic exposure, whereas low-calcium meals were not. A single dose of eltrom-bopag was generally well tolerated in these healthy volunteers.     

Relative Oral Bioavailability of an Abuse-deterrent,Extended-release Formulation of Morphine Versus Extended-release Morphine: A 2-period,Single-dose,Randomized Crossover Study in Healthy Subjects

Purpose

Morphine ARER is a novel oral, abuse-deterrent, extended-release (ER) formulation of morphine sulfate with physical and chemical properties that deter misuse and abuse by nonoral routes of administration. Here we evaluate the relative bioavailability of morphine ARER and extended-release morphine.

Effects of Food on the Pharmacokinetic Properties and Mass Balance of Henagliflozin in Healthy Male Volunteers

PurposeHenagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of meal intake on the pharmacokinetic properties of henagliflozin, and to understand the excretion pathways of henagliflozin in humans.MethodsIn this Phase I, randomized, open-label, single-dose, two-period crossover study, 12 healthy male Chinese volunteers were randomized to receive either henagliflozin 10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition, or the reverse schedule, with the two administrations separated by a washout period of at least 7 days. Samples of blood, urine, and feces were collected and analyzed for the investigation of the pharmacokinetic profile and excretion pathways in the fasted and fed conditions. Any adverse events that occurred throughout the study were recorded for tolerability assessment.FindingsAfter the administration of a single oral dose of henagliflozin, mean (SD) plasma AUC_0–∞ and C_max were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The fed/fasted ratios (90% CIs) of the geometric mean values of C_max, AUC_0–t, and AUC_0–∞ were 64% (54%–76%), 80% (76%–85%), and 80% (76%–85%), respectively. The median (range) T_max was prolonged from 1.5 (1–3) hours in the fasted condition to 2 (1.5–6) hours in the fed condition. Mass-balance testing revealed that henagliflozin was eliminated primarily as the parent drug in feces and as glucuronide metabolites in urine. In the fasted state, the cumulative excretion percentages of the parent drug and its metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values in the fed condition were changed to 50.4% and 25.5%, respectively. These findings suggest that postprandial administration decreases the absorption rate and the extent of henagliflozin exposure in humans, but has no effect on the metabolism or elimination of the drug.ImplicationsIn the present study, the consumption of a high-fat meal prior to henagliflozin administration was associated with reductions in AUC_0–∞ and C_max of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic findings on henagliflozin, this slight change may not have clinical significance. Mass balance of henagliflozin in humans was achieved with ∼75% of the administered dose recovered in excretions within 4 days after administration whether in the fasted or fed state. These findings suggest that henagliflozin tablets can be administered with or without food.     

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.     

A Pharmacokinetic Bioequivalence Study Comparing Pirfenidone Tablet and Capsule Dosage Forms in Healthy Adult Volunteers

Introduction

Pirfenidone film-coated tablets were developed to offer an alternative to the marketed capsule formulation. This study assessed the bioequivalence of the tablet and capsule formulations under fed and fasted states.

Methods

A Phase I, open-label, randomized, four-treatment-period, four-sequence, crossover pharmacokinetics study (NCT02525484) was conducted. Each subject received an 801-mg single dose of pirfenidone as three 267-mg capsules or one 801-mg tablet under fasted and fed conditions. Pirfenidone plasma C _max, AUC_0–t and AUC_0–∞ were used to assess bioequivalence.

Results

Forty-four subjects were randomized to treatment. The 801-mg tablet in the fasted state met bioequivalence criteria [90% confidence intervals (CI) 80.00–125.00%] for the GLSM ratios of natural log-transformed C _max, AUC_0–t and AUC_0–∞. Under fed conditions, the 801-mg tablet met the bioequivalence criteria for AUC_0–t and AUC_0–∞, but slightly exceeded the bioequivalence criteria for the C _max (90% CI of 108.26–125.60%). The tablet C _max was approximately 17% higher than that of the capsules. In the fed state, the tablet C _max, and both AUC_0–t and AUC_0–∞ were reduced by 39% and 17%, respectively, relative to the fasted state. The tablet and capsules had acceptable tolerability profiles.

Conclusions

The pirfenidone 801-mg tablet met bioequivalence criteria when compared with three 267-mg capsules in the fasted state. The tablet C _max was slightly higher relative to capsules in the fed state, but this is not expected to have a clinically meaningful impact on the benefit–risk profile of pirfenidone.

Funding

This work was supported by F. Hoffmann-La Roche Ltd.

     

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     

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.     

Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers: A randomized,open-label,single- and multiple-dose study

Background: Duloxetine hydrochloride is a balanced selective serotonin and norepinephrine reuptake inhibitor. Despite being widely used for the treatment of major depressive disorder in China, little information is available on the pharmacokinetic (PK) properties of duloxetine in Chinese subjects.Objectives: This study was designed to determine the concentration of duloxetine in human plasma and to compare the PK properties of duloxetine after administration of single and multiple doses of duloxetine in healthy Chinese volunteers.Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the concentration of duloxetine in human plasma was developed and applied to this single-center, open-label, single- and multiple-dose PK study. Subjects were randomized to receive a single dose of 30, 60, or 90 mg of duloxetine. Those who received the 30-mg dose continued on to the multiple-dose phase and received 30 mg twice daily for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 60 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7 to determine the Cssmin of duloxetine; on day 7, samples were collected from 0 to 60 hours after drug administration. The PK parameters that were calculated included C_max, T_max, t_1/2, AUC_0?t AUC_0?∞, CL, V_d, C_ssmax, C_ssmin, C_ssav, AUC_ss, AUC_ss(0?t), and C_max:C_min ratio. All values were expressed as mean (SD). Tolerability was assessed throughout the study.Results: The LC-MS/MS method was developed and validated. The standard calibration curve was linear in the concentration range from 0.89 to 106.8 ng/mL; the correlation coefficient was >0.995. The methodo-logic recovery and extraction recovery ranged from 87.22% to 113.75% and 72.81% to 89.96%, respectively. Both the intraday and interday relative SDs were <11%. Thirty Chinese subjects (3 groups of 10 subjects [5 men, 5 women] each) were enrolled in the single-dose phase of the PK study. The mean (SD) age of the subjects was 23.2 (1.8) years (range, 21–25 years); their mean (SD) weight was 61.0 (7.7) kg (range, 52–80 kg) and height was 169.0 (7.1) cm (range, 155–180 cm). The main PK parameters for duloxetine after administration of a single oral dose of 30, 60, and 90 mg were as follows: C_max = 22.46 (15.15), 44.40 (17.18), and 60.78 (27.84) ng/mL, respectively; AUC_0–60 = 328.64 (203.64), 696.04 (337.82), and 1219.33 (598.29) ng/mL · h^?1; AUC_0?∞) = 359.68 (201.01), 733.82 (343.40), and 1280.51 (644.81) ng/mL · h^?1; T_max = 6.83 (1.99), 6.10 (1.29), and 6.60 (1.58) hours; t1/2 = 12.95 (3.64), 12.81 (2.31), and 11.66 (2.06) hours; CL = 107.90 (53.05), 98.41 (41.98), and 109.58 (52.74) L/hour; and V_d = 2518.88 (1707.71), 1879.74 (999.09), and 1858.47 (1203.69) L. The 10 subjects who received the 30-mg dose in the single-dose phase continued on to the multiple-dose phase and received 30 mg of duloxetine twice daily for 7 days. Mean (SD) values for the main PK parameters for duloxetine after administration of multiple doses were as follows: C_ssmax = 47.33 (16.95) ng/mL; C_ssmm = 27.92 (9.46) ng/mL; AUC_ss(0?t) = 407.25 (125.94) ng/mL · h^?1; C_ssav = 33.94 (13.00) ng/mL; T_max = 6.36 (0.92) hours; t_1/2 = 11.19 (1.98) hours; CL = 83.12 (28.75) L/hour; and V_d = 1359.01 (590.06) L.Conclusions: In these healthy Chinese subjects, AUC and Cmax increased proportionally with the dose, whereas t_1/2 was independent of the dose. Linear PK properties were found at doses of 30 to 90 mg. No statistically significant differences were observed between the PK parameters for the subjects in the multiple-dose phase (t_1/2, CL, V_d) and those for subjects in the single-dose phase. The AUC and C_max were greater after administration of multiple doses than after administration of a single dose, suggesting du-loxetine accumulation with multiple-dose administration of 30 mg.     

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.     

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.     

Steady-state pharmacokinetics of once-daily cyclobenzaprine extended release: a randomized, double-blind, 2-period crossover study in healthy volunteers

BackgroundThe single-dose pharmacokinetic profile of cyclobenzaprine extended-release (CER) has been previously characterized and compared with the pharmacokinetics of cyclobenzaprine immediate-release (CIR) administered 3 times daily for 3 doses.ObjectiveThe objective of this study was to characterize the multiple-dose pharmacokinetic properties of once-daily CER 30 mg and CIR 10 mg TID formulations in healthy volunteers.MethodsIn this double-blind, single-center, 2-period crossover study, healthy subjects were randomized to dosing sequences with once-daily CER 30 mg or CIR 10 mg TID for 7 days. Subjects crossed over to the alternative regimen following a 14-day washout period. Pharmacokinetic assessments at steady state included area under the plasma cyclobenzaprine concentration–time curve over the dosing interval (AUC_0–τ,ss), peak plasma cyclobenzaprine concentration (C_max,ss), time to observed C_max (T_max,ss), observed minimum cyclobenzaprine concentration (C_min,ss), average cyclobenzaprine concentration (C_avg,ss), accumulation ratio (R_ac), and terminal elimination half-life (t_½). Tolerability and safety assessments were conducted.ResultsA total of 36 subjects were randomized; 34 completed both dosing periods (1 subject was lost to follow-up, 1 withdrew consent). Steady state was reached for CER 30 mg on day 7. Mean C_max,ss, C_min,ss, and C_avg,ss were 41.1, 21.4, and 31.4 ng/mL, respectively. The median T_max,ss for CER 30 mg was 7.0 hours, with a mean t_½ of 34.8 hours. At steady state, CER produced a sustained plasma cyclobenzaprine concentration with a single peak in plasma concentration during the 24-hour dose interval. The R_ac for CER was 2.65. Because of a protocol violation (insufficient data), no steady-state pharmacokinetic assessments could be performed for CIR. Most adverse events were mild or moderate in intensity. Somnolence was the most frequently reported adverse event (100% of subjects) in those receiving CER, followed by dry mouth (58%), dizziness (19%), and headache (17%).ConclusionsOnce-daily CER 30 mg delivered sustained plasma cyclobenzaprine levels over 24 hours at steady state. Owing to a protocol violation, steady-state pharmacokinetic properties for CIR could not be assessed.