Bioequivalence and tolerability study of two brands of clopidogrel tablets, using inhibition of platelet aggregation and pharmacodynamic measures

Background

The role of platelets in acute cardiovascular atherothrombotic events has been well established and attention has focused on platelet inhibition therapy. Clopidogrel is a novel thienopyridine inhibitor of adenosine diphosphate-induced platelet activation. Recent studies have shown that in the setting of coronary angioplasty/stenting, a loading dose of 300 mg followed by 75 mg once daily is required for optimum benefit.

Objective

This study assessed the bioequivalence and tolerability of 2 oral formulations of clopidogrel 75-mg tablets.

Methods

This 10-day, open-label, randomized, parallel-group, comparative bioequivalence and tolerability study was carried out in the Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (Hyderabad, India). Young healthy male volunteers were enrolled. Subjects were randomized to receive one of two 75-mg tablet formulations of clopidogrel (Clopivas^® [test formulation] or Plavix^® [reference formulation]). Subjects first received a 300-mg loading dose (four 75-mg tablets) on day 1, followed by 75 mg (1 tablet) at 8:00 AM daily for the next 6 days. Inhibition of platelet aggregation, which is the pharmacologic basis for the therapeutic efficacy of antiplatelet agents, and the effect on bleeding time were used as the pharmacodynamic assessment criteria. Pharmacodynamic variables included mean of maximum activity of percentage of inhibition of platelet aggregation (E_max), mean time to reach E_max (t_max), and mean area under the activity-time curve from time 0 to 168 hours (AUC_0-168). Tolerability assessments included blood pressure and heart rate measurements before and at regular intervals (every hour for 12 hours and then at 24 hours) over a 24-hour period after drug administration. Clinical tolerability was assessed using adverse effects, platelet count (assessed on days 3, 6, and 10 after first-dose administration), and neutrophil count (assessed on day 10 after first-dose administration).

Results

Twenty subjects were enrolled (mean [SD] age, 26.5 [2.9] years [range, 22-32 years]). E_max, t_max, and AUC_0-168 were similar between the 2 groups, as was bleeding time. The 90% CIs were within the bioequivalence acceptance range of 80% to 125%. One subject (10%) in the Plavix group experienced mild headache; no serious adverse effects were reported, and none of the subjects dropped out due to an adverse effect. Platelet and neutrophil counts were found to be within normal limits.

Conclusions

In this study of healthy male volunteers, the 2 tablet preparations of clopidogrel showed bioequivalence. However, the sample size was smaller than that generally recommended for a bioequivalence study, and additional studies with larger sample sizes are needed.     

Comparative Fasting Bioavailability of 2 Bepotastine Formulations in Healthy Male Chinese Volunteers: An Open-Label,Randomized, Single-Dose, 2-Way Crossover Study

Background

Bepotastine is a second-generation histamine₁ receptor antagonist that is used in the treatment of allergic rhinitis, urticaria, and pruritus associated with skin disease. A new generic formulation of bepotastine has been developed in China, and information concerning bioavailability and pharmacokinetic properties in the Chinese population has not been reported.

Objective

The aim of the present study was to compare the bioavailability and pharmacokinetic properties of 2 tablet formulations of bepotastine, the 10-mg generic formulation (test) and a branded formulation (reference), in healthy male Chinese volunteers to obtain registration approval of the test formulation.

Methods

A single-center, open-label, randomized, 2-way crossover study with a 1-week washout period was conducted in 24 healthy male volunteers. Blood samples were collected for 16 hours after a single dose of the 10-mg bepotastine test formulation or the reference formulation. Plasma bepotastine concentrations were determined using a validated LC-MS/MS method. C_max, T_max, AUC_0–t, AUC_0–∞, and t_½ were determined using noncompartmental analysis. The formulations were considered bioequivalent if the 90% CIs for the log-transformed C_max and AUC values were within the predetermined interval of 75% to 133% and 80% to 125%, respectively, according to the guidelines of the China Food and Drug Administration.

Results

No significant differences were found in mean (SD) pharmacokinetic parameters between the test and reference drugs, including C_max (74.81 [9.91] ng/mL vs 78.60 [29.58] ng/mL), AUC_0–t (295.55[115.29] ng·h/mL vs 299.17[109.29] ng·h/mL), and AUC_0-∞ (305.28 [118.50] ng·h/mL vs 310.90 [112.20] ng·h/mL). The mean (SD) t_½ values of the test and reference formulations were 2.53 (0.50) hours and 2.62 (0.41) hours, respectively. The 90% CIs of the treatment ratios for the logarithmic transformed values of C_max, AUC_0–t, and AUC_0–∞ were 86.96% to 101.80%, 93.22% to 104.13%, and 92.66% to 103.30%, respectively. All values were within the predetermined bioequivalence range. Two adverse events were reported as neutropenia (1 volunteer [4.2%]) and neutrophilia (1 volunteer [4.2%]). Both adverse events were transient and considered mild by physicians.

Conclusion

The test and reference tablets met the regulatory criteria for bioequivalence as defined by the China Food and Drug Administration. Both formulations were well tolerated. Chinese Clinical Trials Registry identifier: ChiCTR-TTRCC-13003723.     

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.

Relative Bioavailability of Methylphenidate Extended-release Chewable Tablets Chewed Versus Swallowed Whole

Purpose

Methylphenidate hydrochloride extended-release chewable tablet (MPH ERCT) is approved for treatment of attention deficit hyperactivity disorder in patients aged 6 years and older. This article evaluates the pharmacokinetic parameters and relative bioavailability of MPH ERCT when chewed versus swallowed whole.

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.

     

Relative Bioavailability of a Single 4-mg Dose of Somatropin Administered by Subcutaneous Injection or by Needle-free Device and Coadministered With the Growth Hormone Inhibitor Octreotide Acetate in Healthy Adult Subjects

Purpose

Somatropin, used to treat growth hormone deficiency, has been traditionally administered by subcutaneous (SC) injection with needle and syringe. Needle-free devices offer ease of administration and may improve adherence and outcomes. This study evaluated the relative bioavailability of somatropin delivered with a needle-free device compared with traditional SC injection.

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.     

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

Background

Lamivudine is used in the treatment of HIV and chronic hepatitis B (HBV) infections. Since 1999, at least 2 million Chinese HBV patients have been treated with lamivudine, but there are limited studies on the pharmacokinetics and safety of the drug in Chinese populations.

Objective

This study was designed to assess the bioequivalence of a newly developed lamivudine tablet (test drug) and a branded lamivudine tablet (reference drug) in healthy Chinese male volunteers.

Methods

A single-center, single-dose, randomized, open-label, 2-period crossover study was conducted in 28 healthy Chinese male volunteers. Blood samples were collected up to 24 hours after the administration of oral lamivudine 100 mg in each period. Plasma lamivudine concentrations were analyzed by a validated LC–MS/MS method. Pharmacokinetic and bioavailability parameters were calculated. Adverse events (AEs) were recorded.

Results

There were no significant differences in mean (SD) pharmacokinetic parameters between the test and reference drugs, including C_max (1239 [328.9] ng/mL vs 1176 [341.5] ng/mL), AUC_0–t (4096 [599.1] ng · h/mL vs 4064 [678.2] ng · h/mL), and AUC_0–∞ (4200 [607.7] ng · h/mL vs 4162 [672.2] ng · h/mL). The geometric mean test/reference ratios (90% CI) calculated for the log-transformed parameters were C_max, 1.06 (96.21–116.90); AUC_0–t, 1.01 (96.53–105.39); and AUC_0–∞, 1.01 (96.81–105.16), all of which were within the acceptance limits for bioequivalence. No serious AEs were reported, and all mild AEs were recovered quickly without treatment.

Conclusion

These findings suggest that the test formulation of lamivudine 100 mg meets the FDA regulatory standards for bioequivalence with the reference formulation. Both formulations were well tolerated.     

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.     

Pharmacokinetics of Pilsicainide Hydrochloride for Injection in Healthy Chinese Volunteers: A Randomized,Parallel-Group,Open-Label,Single-Dose Study

Background

Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation.

Objective

The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride.

Methods

This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration–time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs.

Results

Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m²) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean C_max was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) μg/mL, respectively; AUC_0–24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h · μg/mL; and AUC_0–∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h · μg/mL. The ranges for t_½z, CL, and V_z were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC_0–24 values in the 0.50-mg/kg dose group (P = 0.044), and V_z showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters.

Conclusions

Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC_0–24 and AUC_0–∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546.     

Performance of chest compressions by laypersons during the Public Access Defibrillation Trial

Background

Increasing evidence indicates that health professionals often may not achieve guideline standards for cardiopulmonary resuscitation (CPR). Little is known about layperson CPR performance.

Methods

The investigation was a retrospective cohort study of cardiac arrest patients treated by layperson CPR and one model of automated external defibrillator (AED) as part of the Public Access Defibrillation Trial (n = 26). CPR was measured using software that integrates the event log, ECG signal, and thoracic impedance signal. We assessed chest compression fraction (proportion of attempted resuscitation spent performing chest compressions), prompted compression fraction (proportion of attempted resuscitation spent performing compressions during AED-prompted periods), compression rate, and compressions per minute.

Results

Of the 26 cases, 13 presented with ventricular fibrillation and 13 with nonshockable rhythms. Overall, during the period when patients did not have spontaneous circulation, the median chest compression fraction was 34% (IQR 17-48%), median prompted chest compression fraction was 49% (IQR 30-66%), and the median chest compression rate was 96/min (IQR 90-110/min). Taken together, the median chest compression delivered per minute among all arrests was 29 (IQR 20-42). CPR characteristics differed according to initial rhythm: median chest compression per minute was 20 (IQR 13-29) among ventricular fibrillation and 42 (IQR 28-47) among nonshockable rhythms (p = 0.003).

Conclusions

In this study of trained laypersons, CPR varied substantially and often did not achieve guideline parameters. The findings suggest a need to improve CPR training, consider changes to CPR protocols, and/or improve the AED-rescuer interface.     

Increased palpation tenderness and muscle strength deficit in the prediction of tendon hypertrophy in symptomatic unilateral shoulder tendinopathy: an ultrasonographic study

Objective

In asymptomatic, normal tendons, the difference in tendon thickness between sides is less than 15%. In this study, three tests were used to examine differences between symptomatic and asymptomatic shoulders.

Design

Cross-sectional study. The three tests were performed in sequence. The observer was blinded in the maximal pain-free isometric force test.

Setting

Outpatient physiotherapy clinic at Bergen University College, Norway.

Participants

Sixty-four patients with an exclusive, tentative diagnosis of unilateral shoulder tendinopathy.

Main outcome measures

Differences in maximal pain-free isometric force, tendon pain pressure and tendon thickness measured by ultrasonography.

Results

This paper follows the STARD recommendations for papers on diagnostic accuracy. When cut-off values for within-subject side differences were selected at ≥0.8 mm for tendon thickness (TT_diff), ≥10 N for maximal pain-free isometric force (PFF_diff) and ≥0.6 kg for tendon pain pressure (PPT_diff), positive tests were found in 92% of patients. All three tests were sensitive for the detection of within-subject side differences with the selected cut-off values (TT_diff, n = 60/64; PPT_diff, n = 59/64; PFF_diff, n = 57/64; P > 0.35). There were strong agreements between the three tests: TT_diff and PFF_diff, 0.89; TT_diff and PPT_diff, 0.83; and PFF_diff and PPT_diff, 0.84. When both clinical tests were positive (PFF_diff and PPT_diff), the positive predictive value was excellent (94%) for finding increased tendon thickness in the symptomatic side on ultrasonography.

Conclusions

Within the limitations of this partially blinded study, patients with unilateral shoulder tendinopathy exhibited significant differences between sides in all three tests. The combination of the two clinical tests seems to be valid for the detection of unilateral shoulder tendinopathy if other diagnoses have been excluded.     

Safety,Tolerability, Pharmacokinetics,and Pharmacodynamics of Recombinant Human Parathyroid Hormone (1–34) in Healthy Chinese Subjects

Background

The recombinant human parathyroid hormone (1–34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China.

Objective

The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1–34) after single and multiple subcutaneous doses in healthy Chinese subjects.

Methods

Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1–34) (10, 20, 30, 40, 50, or 60 μg) or a multiple dose of rhPTH(1–34) (10 and 20 μg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1–34) (10, 20, or 40 μg) and a multiple dose of rhPTH(1–34) (20 μg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters.

Results

Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1–34) was well tolerated during the investigated single (10–60 μg) and multiple (10–20 μg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1–34), the drug was rapidly absorbed, with a T_max of 20 to 30 minutes, and rapidly cleared from the plasma, with a t_½ of 47.2 to 60.6 minutes. The mean C_max, AUC_0–t, and AUC_0–∞ increased in proportion to the doses, whereas the t_½, total clearance, and T_max values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for T_max in the 10-μg and 20-μg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels.

Conclusions

All rhPTH(1–34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874.     

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.

Longitudinal Changes in Physical Capacity Over 20 Years in Athletes With Spinal Cord Injury

Shiba S, Okawa H, Uenishi H, Koike Y, Yamauchi K, Asayama K, Nakamura T, Tajima F. Longitudinal changes in physical capacity over 20 years in athletes with spinal cord injury.

Objective

To investigate the longitudinal changes in physical capacity over 20 years in athletes with spinal cord injury (SCI).

Design

Longitudinal study (20-y follow-up).

Setting

Laboratory setting.

Participants

Persons with SCI (N=7).

Interventions

Not applicable.

Main Outcome Measures

Maximum oxygen consumption V?o₂max) measured in 1986-1988 and in 2006.

Results

Subjects with SCI maintained stable V?o₂max in 2006. Six of the 7 continued various wheelchair sports activities, while 1 person quit sports activities 1 year after the baseline study. The latter person showed reduced V?o₂max by 53%, while 2 persons who continued strenuous wheelchair sports activities showed increased V?o₂max by 43% and 45% after 20 years.

Conclusion

The results indicated that physical capacity reflected the level of sports activity in subjects with SCI who maintained sports activities.     

Pharmacokinetics of a Novel Orodispersible Tablet of Sildenafil in Healthy Subjects

Background

Sildenafil citrate is indicated for the treatment of erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate has been developed for the benefit of patients who have difficulty swallowing solid dosage forms.

Objective

The main goal of this study was to evaluate the bioequivalence of sildenafil ODT with and without water versus marketed sildenafil oral film-coated tablets. A secondary objective was to evaluate the effects of a high-fat meal on the pharmacokinetics of sildenafil ODT.

Methods

The bioequivalence study of sildenafil ODT given with and without water versus marketed sildenafil citrate film-coated oral tablets was conducted in 36 subjects. In a food-effect study, the effect of a standard high-fat meal on the pharmacokinetics of sildenafil ODT was evaluated in 12 subjects. Both studies were randomized, open-label, crossover, single-dose (50 mg) studies in healthy men aged ≥45 years. Plasma samples were collected for 14 hours postdose, and pharmacokinetics were determined by using noncompartmental analyses.

Results

All subjects in both studies were Asian males between the ages of 45 and 69 years. Sildenafil ODT without water was bioequivalent to the marketed sildenafil film-coated oral tablet as the 90% CI for the ratio of geometric means of C_max, AUC_0–∞, and AUC_0–last were contained within equivalence limits (80%–125%). When sildenafil ODTs were given with water, the 90% CIs for sildenafil AUC_0–∞ and AUC_0–last were contained within the range of 80% to 125%; however, the 90% CI for sildenafil C_max was not (79.76–92.78). This difference in C_max is unlikely to have any clinically meaningful impact. High-fat meals reduced the rate but not the extent of absorption of sildenafil. Mean C_max was reduced by 59%, and median T_max was delayed from 0.625 hour (fasting) to 4 hours (high-fat meal). However, AUC values were comparable between fed and fasted treatments.

Conclusions

Sildenafil ODT, given with or without water, provides equivalent systemic exposure compared with marketed sildenafil film-coated oral tablets, thus offering a convenient alternative method of administration. Considering the results of the food-effect study, sildenafil ODT should be taken on an empty stomach. ClinicalTrials.gov identifiers: NCT01254383 (bioequivalence) and NCT01254396 (food effect).     

Safety,Tolerability, and Pharmacokinetics of Single and Repeat Doses of Nemiralisib Administered via the Ellipta Dry Powder Inhaler to Healthy Subjects

Purpose

Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.

Pharmacokinetics and Tolerability of Tenofovir Disoproxil Fumarate 300 mg Once Daily: An Open-Label,Single- and Multiple-Dose Study in Healthy Chinese Subjects

Background

Tenofovir disoproxil fumarate (TDF) has been approved worldwide for the treatment of adults with chronic hepatitis B and, in combination with other antiretroviral agents, HIV-1 infection. Although its use for the treatment of HIV has been approved by the Chinese State Food and Drug Administration, there are no data on the pharmacokinetic profile of TDF in Chinese individuals.

Objectives

This study aimed to investigate the pharmacokinetic properties and tolerability of TDF in healthy Chinese subjects.

Methods

This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. Subjects received TDF 300 mg once daily, administered as a single dose (day 1) and multiple doses (days 4–10). Multiple plasma samples were collected over time, and the concentrations of TDF were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs).

Results

Fourteen volunteers were enrolled (7 men, 7 women; mean age, 24.6 years). TDF was rapidly absorbed; median T_max was 0.75 hour, and t_½ was ~21 hours with single dosing. The mean ratio of AUC_0–τ steady state/AUC_0–24 single dose was 1.55. The pharmacokinetic properties of TDF were consistent between the single dose and multiple doses, and between men and women. No serious AEs were reported, and there were no discontinuations due to AEs.

Conclusions

There was an accumulation of approximately 55% in tenofovir exposure in healthy Chinese between multiple dose and single dose. TDF exhibited a pharmacokinetic profile similar to that of healthy Western subjects in a historical comparison. TDF was generally well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01480622.