Comparison of Pharmacokinetics of Two Fenofibrate Tablet Formulations in Healthy Human Subjects

Background

Fenofibrate is a serum lipid-lowering agent used as an adjunct to diet in patients with hypercholesterolemia and hypertriglyceridemia. The new fenofibrate tablet formulation was developed as a pharmaceutical equivalent to the marketed tablet formulation containing 145 mg.

Objective

The objective of this study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects.

Methods

The study was a randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study in healthy human subjects under fasting conditions. Eligible subjects received each treatment in a crossover manner according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. The predose blood sample was taken within 1 hour before dosing, and serial blood sampling was performed up to 72.0 hours’ postdose. The analysis of plasma samples for concentrations of fenofibric acid, the active metabolite of fenofibrate, was conducted by using a validated LC-MS/MS method. Bioequivalence was to be concluded if the 90% CIs as constructed were within the range of 80% to 125% for C_max, AUC_0–t, and AUC_0–∞ for fenofibric acid. Subjects were monitored for safety and tolerability throughout the study.

Results

15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m² were recruited into the study. The 90% CIs for the test/reference mean ratios of the ln-transformed pharmacokinetic variables C_max, AUC_0–t, and AUC_0–∞ were within the conventional bioequivalence range of 80% to 125%. Both formulations were well tolerated after a single oral dose in these healthy male subjects.

Conclusions

Both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic absorption, and hence were considered bioequivalent.     

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.     

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.     

Pharmacokinetic Properties and Bioequivalence of 2 Formulations of Valsartan 160-mg Tablets: A Randomized,Single-Dose, 2-Period Crossover Study in Healthy Korean Male Volunteers

Background

The solubility of valsartan is dependent on pH and thus may cause patient variability in drug absorption and failure in bioequivalence studies; thus, increasing the solubility and release of valsartan at low pH has been suggested for a more favorable pharmacokinetic profile. However, due to this pH dependence, the change in the formulation process could alter the disintegration and/or dissolution profile of the drug, possibly making the results of bioequivalence studies misleading.

Objective

The aim of this study was to assess the bioavailability and tolerability of a newly developed oral formulation of valsartan 160 mg (wet-granulation tablet) in healthy Korean male volunteers.

Method

This study was performed with the subjects under fasted conditions, using a randomized, single-dose, 2-period crossover design. Subjects were assigned to receive, in randomized order, a single dose of the test formulation and a reference formulation (valsartan 160-mg dry-granulation tablet), with a washout period of 7 days between the administrations. Blood samples were collected up to 24 hours after dosing, and pharmacokinetic parameters were determined after the plasma valsartan concentration was analyzed using UPLC-MS/MS. The dissolution studies of both formulations were conducted using USP apparatus 2 at 50 rpm with 1000 mL of phosphate buffer solution (pH, 6.8) at 37°C ± 0.5°C. Bioequivalence was defined per Korean Food and Drug Administration’s regulatory criteria as 90% CIs of the geometric mean test/reference ratios of AUC_0–t and C_max within the range of 0.8 to 1.25. Tolerability was assessed using physical examination and subject interviews.

Results

Sixty subjects were enrolled (mean [SD] age [range], 23.6 [2.4] years [21–31]; height, 173.7 [6.6] cm [161–190]; and weight, 68.0 [8.7] kg [54–85]). The mean AUC_0–∞ values with the test and reference tablets were 31,784 (13,844) and 32,714 (14,512) ng·h/mL, respectively; C_max, 5094 (2061) and 5064 (1864) ng/mL; T_max, 2.92 (1.04) and 3.08 (1.01) hours. The 90% CIs for the geometric mean test/reference ratios of AUC_0–t and C_max were 0.9295 to 1.0546 and 0.9190 to 1.0848, respectively, which met the criteria for bioequivalence. The most frequently reported adverse event was dizziness after blank blood sampling, recorded in 4 subjects, 2 cases each with the test and reference formulations.

Conclusions

In this study in healthy Korean male volunteers, the test and reference formulations of 160-mg valsartan met the Korean Food and Drug Administration’s regulatory criteria for bioequivalence despite the difference in formulation (wet granulation vs dry granulation). Both formulations were well tolerated, with no serious adverse events reported.     

Microsatellite polymorphism of the human leptin gene and risk of obesity

Background

Leptin is a hormone mainly produced by adipose tissue. It acts on both energy intake and expenditure to maintain relative stability of body weight and energy storage over long period of time. Variation in size of the tetranucleotide repeat located at the 3′ end of leptin gene (LEP3′HVR) can influence leptin expression.

Objectives

To predict the association of LEP3′HVR and obesity.

Materials and Methods

A case control study consisting of 40 individuals with normal BMI (control group) and 35 individuals with abnormal BMI. LEP3′HVR polymorphic region was amplified by polymerase chain reaction, and fragments were analyzed by agarose gel electrophoresis. Statistical analysis was done using SPSS (SPSS, Chicago, Ill).

Results

The frequency of LEP3′HVR class I was 52.8% in individuals with abnormal BMI versus 42.5% in the individuals with normal BMI. The homozygous class I (I/I) genotype was identified in 40% of the individuals with abnormal BMI vs 25% of the control group. Individuals with I/I genotypes showed a higher prevalence of obesity when compared with homozygous class II/II genotype (odds ratio, 1.9; 95% confidence interval, 0.6-5.6).

Conclusion

Class (I/I) genotype of LEP3′HVR was associated with increase risk of obesity.     

Comparative Bioavailability Study of Single-Dose Film-Coated and Sugar-Coated Ethionamide Tablets in Healthy Volunteers

Background

Ethionamide sugar-coated tablets have been reformulated to film-coated tablets to improve dissolution and stability.

Objective

The study objective was to compare the bioavailability of the film-coated (test) and sugar-coated (reference) formulations of ethionamide.

Methods

After providing informed consent and undergoing screening procedures, 40 healthy subjects were assigned to receive a single dose of ethionamide 250-mg film- or sugar-coated tablets, in randomized order, in the fasted state. Serial blood samples were collected before and from 0.5 to 24 hours after dosing. After a 7-day washout, procedures were repeated for the other formulation. The blood samples were processed to provide plasma samples, which were frozen until assay. Plasma ethionamide concentrations were measured using a validated LC-MS/MS method, with a lower limit of quantitation of 20 ng/mL. Pharmacokinetic parameters were determined using noncompartmental methods, with subsequent evaluation for bioequivalence.

Results

All 40 subjects (37 men, 3 women; mean age, 28 years; mean weight, 74 kg) completed the study. Seven subjects reported a total of 10 adverse events (5 with each formulation), all of which were mild and considered possibly related to drug treatment. None of the events resulted in discontinuation from the study. Mean (SD) pharmacokinetic properties observed with the film- and sugar-coated tablets, respectively, were as follows: C_max, 2160 (614) and 1484 (636) ng/mL; T_max, 1.0 (0.5) and 1.5 (0.9) hours; k_e, 0.369 (0.053) and 0.232 (0.114) h^–1; t_½, 1.92 (0.27) and 4.06 (2.52) hours; and AUC, 7668 (1688) and 6594 (1764) ng · h/mL.

Conclusions

Comparing AUC values, the formulations were bioequivalent. The maximum concentrations observed with the film-coated product were higher but were more consistent (%CV, 28%) compared with those of the sugar-coated formulation (%CV, 43%).     

The Pharmacokinetics and Safety of a Fixed-Dose Combination of Acetylsalicylic Acid and Clopidogrel Compared With the Concurrent Administration of Acetylsalicylic Acid and Clopidogrel in Healthy Subjects: A Randomized,Open-Label, 2-Sequence, 2-Period,Single-Dose Crossover Study

Background

Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is used for the treatment of acute coronary syndrome. A combined formulation of ASA and clopidogrel has been developed to provide dosing convenience and improve adherence.

Objective

This study was designed to compare the pharmacokinetic properties and safety profile of a fixed-dose combination formulation of ASA and clopidogrel with concurrent administration of each agent in healthy male Korean volunteers.

Methods

This single-dose, randomized, open-label, 2-period crossover study was conducted in 64 healthy Korean volunteers. Equal numbers of eligible participants were randomly assigned to receive either the fixed-dose combination of ASA 100 mg and clopidogrel 75 mg or the free combination of each agent followed by a 7-day washout period and then administration of the alternate formulation. Serial blood samples were collected immediately before and after dosing for 24 hours. The safety profile was evaluated by using adverse events (AEs), which were assessed by physical examination, vital signs, ECGs, clinical laboratory tests, and interviews. The 2 formulations were considered to be bioequivalent if the 90% CIs for the log-transformed C_max and AUC_0–last values were within the predetermined range of 0.8 to 1.25.

Results

Sixty-four volunteers (mean [SD] age, 27.51 [8.15] years; weight, 68.55 [7.86] kg; height, 173.80 [5.94] cm) were enrolled, and 63 completed the study. For ASA, the 90% CIs for the geometric mean ratios of C_max and AUC_0–last were 0.9483 to 1.1717 and 0.9946 to 1.1020, respectively. For salicylic acid, the 90% CIs were 0.9614 to 1.0396 for C_max and 0.9778 to 1.0163 for AUC_0–last. For clopidogrel, the 90% CIs were 0.9809 to 1.2562 for C_max and 0.9674 to 1.2073 for AUC_0–last. Six of the 20 AEs reported were drug related: decreased hemoglobin levels (n = 2), fever (n = 1), and headache (n = 1) with the test formulation and increased alanine aminotransferase levels (n = 1) and dyspepsia (n = 1) with the reference formulation. All of the drug-related AEs were transient and mild in severity.

Conclusions

The fixed-dose combination of ASA and clopidogrel 100 mg/75 mg did not meet the regulatory criteria for bioequivalence as defined by the Korea Food and Drug Administration. Both formulations were well tolerated in these healthy male Korean subjects. ClinicalTrials.gov Identifier: NCT01448330     

Pharmacokinetic Comparison of 2 Fixed-Dose Combination Tablets of Amlodipine and Valsartan in Healthy Male Korean Volunteers: A Randomized,Open-Label, 2-Period,Single-Dose,Crossover Study

Background

Amlodipine and valsartan have different mechanisms of action, and it is known that the combination therapy with the 2 drugs increases treatment effects compared with the monotherapy with each drug. A fixed-dose combination (FDC) drug is a formulation including fixed amounts of active drug ingredients combined in a single dosage form that is expected to improve medication compliance.

Objective

The goal of this study was to compare the pharmacokinetic profiles of single administration of a newly developed FDC tablet containing amlodipine orotate 10 mg and valsartan 160 mg (test formulation) with the conventional FDC tablet of amlodipine besylate 10 mg and valsartan 160 mg (reference formulation) in healthy male Korean volunteers.

Methods

This was a randomized, open-label, single-dose, 2-way crossover study. Eligible subjects were between the ages of 20 and 50 years and within 20% of their ideal weight. Each subject received a single dose of the reference and the test formulations, with a 14-day washout period between formulations. Blood samples were collected up to 144 hours after the dose, and pharmacokinetic parameters were determined for amlodipine and valsartan. Adverse events were evaluated based on subject interviews and physical examinations.

Results

Forty-eight of the 50 enrolled subjects completed the study. For both amlodipine and valsartan, the primary pharmacokinetic parameters were included in the range for assumed bioequivalence, yielding 90% CI ratios of 0.9277 to 0.9903 for AUC_0–last and 0.9357 to 1.0068 for C_max in amlodipine, and 0.9784 to 1.1817 for AUC_0–last and 0.9738 to 1.2145 for C_max in valsartan. Dizziness was the most frequently noted adverse event, occurring in 4 subjects with the test formulation, followed by oropharyngeal pain occurring in 1 subject with the test formulation and 3 subjects with the reference formulation. All other adverse events occurred in <3 subjects.

Conclusions

These findings suggest that the pharmacokinetics of the newly developed FDC tablet of amlodipine and valsartan did not differ significantly from the conventional FDC tablet in these healthy Korean male subjects. Both formulations were well tolerated, with no serious adverse events observed. ClinicalTrials.gov identifier: NCT01823913.     

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).     

Bioequivalence of Two Intravenous Formulations of Antithrombin III: A Two-Way Crossover Study in Healthy Korean Subjects

Background

Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency.

Objective

The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes.

Methods

A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG.

Results

Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) C_max, AUC_last, and AUC_0–∞ of AT-III activity were, respectively, 279.24% (35.92), 14,364.10 (2325.25) %·h, and 17,526.38 (3150.81) %·h with the test formulation and 249.75% (31.96), 12,962.95 (1897.52) %·h, and 15,957.67 (3189.21) %·h with the reference formulation. The observed mean (SD) C_max, AUC_last, and AUC_0–∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90% CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994–1.14053) for C_max, 1.11305 (1.05435–1.17503) for AUC_last, and 1.11527 (1.03754–1.19889) for AUC_0–∞; corresponding values for AT-III Ag were 1.08802 (1.06258–1.11405), 1.10905 (1.05804–1.16242), and 1.11460 (1.02058–1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period.

Conclusion

The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.     

Pharmacokinetics of Rosuvastatin/Olmesartan Fixed-Dose Combination: A Single-Dose,Randomized, Open-Label, 2-Period Crossover Study in Healthy Korean Subjects

Background

Rosuvastatin, a lipid-lowering agent, has been widely used with olmesartan, a long-acting angiotensin II receptor blocker, indicated for the treatment of dyslipidemia accompanied by hypertension. A fixed-dose combination (FDC) tablet of these 2 drugs was recently developed to enhance the dosing convenience and to increase patient compliance while yielding pharmacokinetic profiles comparable to coadministration of each drug as individual tablets.

Objective

The goal of present study was to compare the pharmacokinetic profiles of single-dose administration of an FDC tablet containing rosuvastatin/olmesartan 20/40 mg (test formulation) with coadministration of a rosuvastatin 20-mg tablet and a olmesartan 40-mg tablet (reference formulation) in healthy Korean male volunteers, for the purpose of determining bioequivalence.

Methods

This single-dose, randomized, open-label, 2-period crossover study enrolled subjects aged 20 to 50 years and within 20% of ideal body weight. Each subject received a single dose of the test and reference formulations orally in a fasted state, with a 7-day washout period between the administrations. Blood samples were collected up to 72 hours after dosing, and pharmacokinetic parameters were determined for rosuvastatin, its active metabolite (N-desmethyl rosuvastatin), and olmesartan. Bioequivalence was concluded if the 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters were within the predetermined range of 80% to 125%. Adverse events (AEs) were evaluated based on subject interviews and physical examinations.

Results

Among the 58 enrolled subjects, 54 completed the study. The 90% CIs of the geometric mean ratios of the primary pharmacokinetic parameters were as follows: rosuvastatin: AUC_last, 85.60% to 97.40% and C_max, 83.16% to 98.21%; N-desmethyl rosuvastatin: AUC_last, 82.08% to 93.45% and C_max, 79.23% to 93.41%; and olmesartan: AUC_last, 97.69% to 105.69% and C_max, 100.35% to 109.42%. The most frequently noted AE was headache, occurring in 3 and 6 patients with the test and reference formulations, respectively. All of the AEs were expected, and there was no significant difference in the prevalences of AEs between the 2 formulations.

Conclusions

The pharmacokinetic properties of the newly developed FDC tablet of rosuvastatin/olmesartan 20/40 mg suggest that it is bioequivalent to co-administration of each drug as individual tablets in these healthy Korean male subjects. The two formulations were well tolerated, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01823900.     

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.

     

Single-Dose Comparative Pharmacokinetics of Two Formulations of Lenalidomide 25 mg in Healthy Subjects: A Randomized Crossover Study

Background

Lenalidomide is used for the treatment of multiple myeloma in combination with dexamethasone. The purpose of this study was to compare the pharmacokinetics (PKs) and assess the bioequivalence of two formulations of lenalidomide 25 mg: Lenalid^® 25 mg tablet (test formulation) and Revlimid^® 25 mg capsule (reference formulation).

Methods

A randomized, single-dose, two-treatment, two-period, two-sequence crossover study was conducted in 42 healthy subjects. All subjects were randomly assigned to one of the two sequences, and they received a single dose of test or reference formulation in the first period and the alternative formulation during the next period under fasting conditions. Serial blood samples for PK evaluation were collected up to 24 h post-dose and the PK parameters were estimated by non-compartmental methods. Throughout the study, tolerability was assessed on the basis of adverse events, vital signs, and clinical laboratory tests.

Results

The test formulation showed similar PK profiles to those of the reference formulation. The geometric mean ratio and 90% confidence interval (CI) of the test formulation to the reference formulation for maximum plasma concentration (C_max) was 0.9995 (0.9250–1.0799) and the corresponding value for the area under the concentration–time curve from time zero to time of last quantifiable concentration (AUC_t) was 0.9648 (0.9451–0.9850). Both CIs were within the conventional bioequivalence range of 0.8–1.25. The tolerability profile was not significantly different between the two formulations.

Conclusion

This study found that the PKs of the two formulations of lenalidomide 25 mg were similar and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation.

Funding

Samyang Biopharmaceutical Corp.

     

Cardiopulmonary Exercise Testing Is Well Tolerated in People With Alzheimer-Related Cognitive Impairment

Objective

To retrospectively assess whether cardiopulmonary exercise testing would be well tolerated in individuals with Alzheimer disease (AD) compared with a nondemented peer group.

Design

We retrospectively reviewed 575 cardiopulmonary exercise tests (CPETs) in individuals with and without cognitive impairment caused by AD.

Setting

University medical center.

Participants

Exercise tests (N=575) were reviewed for nondemented individuals (n=340) and those with AD-related cognitive impairment (n=235).

Interventions

Not applicable.

Main Outcome Measures

The main outcome measure for this study was reporting the reason for CPET termination. The hypothesis reported was formulated after data collection.

Results

We found that in cognitively impaired individuals, CPETs were terminated because of fall risk more often, but that overall test termination was infrequent—5.5% versus 2.1% (P=.04) in peers without cognitive impairment. We recorded 6 cardiovascular and 7 fall risk events in those with AD, compared with 7 cardiovascular and 0 fall risk events in those without cognitive impairment.

Conclusions

Our findings support using CPETs to assess peak oxygen consumption in older adults with cognitive impairment caused by AD.     

Setipiprant,a Selective Oral Antagonist of Human CRTH2: Relative Bioavailability of a Capsule and a Tablet Formulation in Healthy Female and Male Subjects

Background

CRTH2 is a prostaglandin D₂ receptor that plays an important role in allergic inflammation. Setipiprant is a potent CRTH2 antagonist under development for the treatment of allergic diseases.

Objective

The aim of this study was to evaluate the tolerability and pharmacokinetics of a single oral dose of a setipiprant capsule (reference) and a tablet formulation.

Methods

This was an open-label, 2-period, 2-way crossover, randomized study in which 20 healthy women and men (1:1 ratio) received either 2 250-mg capsules or a 500-mg tablet of setipiprant. Subjects were between 18 and 45 years old, with a body mass index of 18.0 to 28.0 kg/m². Differences in pharmacokinetics of setipiprant formulations were explored overall and by sex.

Results

All subjects completed the study. Both formulations were well tolerated, with headache the most frequently reported adverse event (25% of subjects), followed by flatulence (15%) and somnolence and fatigue (10%). The adverse event profile in men and women and between formulations was similar. The ratios of geometric means for C_max (0.94; 95% CI, 0.79–1.12) and AUC_0–∞ (1.01; 95% CI, 0.92–1.12) were mostly within the limits of 0.80 to 1.25. When corrected for weight, the differences observed between sexes, within each treatment, for C_max (capsules: 1.01; 95% CI, 0.71–1.44; tablet: 0.89; 95% CI, 0.62–1.26) and AUC_0–∞ (capsules: 1.12; 95% CI, 0.86–1.47; tablet: 0.96; 95% CI, 0.73–1.25) were minor.

Conclusion

Both the setipiprant formulations were well tolerated. Setipiprant pharmacokinetics were similar between formulations, overall, and between sexes. The new tablet formulation may constitute a valid alternative to the capsule formulation for later clinical development phases. ClinicalTrials.gov identifier: NCT01877629.     

Pivotal Bioequivalence Study of Clopacin<Superscript>®</Superscript>, a Generic Formulation of Clopidogrel 75 mg Film-Coated Tablets

Introduction

Clopacin^® (Acino Pharma AG) is a proprietary, besylate salt and lactose-free formulation of the widely-used anti-platelet treatment, clopidogrel. This study aimed to evaluate the bioequivalence of Clopacin^® with the originator as reference drug, using a guideline-compliant trial design: open-labeled, randomized, single-dose (clopidogrel 75 mg tablet), two-period, crossover trial in 48 healthy male volunteers, with a 7 day wash-out period.

Methods

Plasma samples were collected at intervals and extracted before quantifying clopidogrel concentrations using a fully validated LC–MS/MS method. Bioequivalence of Clopacin^® and the reference drug was established by comparison of the primary pharmacokinetic parameters, C _max, AUC_0–t, and AUC_0–∞.

Results

The parameter values were similar for the two products (analysis of variance) and provided Clopacin/reference ratios (least squares means) of >90% and 90% confidence intervals (CIs 84.64–105.50%, 90.43–111.22%, 88.75–110.71%, respectively) that were well within the limits set for defining bioequivalence, according to international guidelines. The respective Clopacin^® and reference drug values for mean time to maximal plasma clopidogrel concentration (t _max) were 0.83 and 0.91 h, and for terminal elimination half-life were 3.99 and 3.51 h. The intra-subject coefficients of variability for maximal plasma clopidogrel concentration (C _max), area under the plasma clopidogrel concentration versus time curve, at 48 h (AUC_0–t) and extrapolated to infinity (AUC_0–∞) were 32.2%, 30.2%, and 28.9% (least square means), respectively, and the respective power values were 99.5%, 97.1%, and 95.3%.

Conclusion

This bioequivalence study provided robust clopidogrel pharmacokinetic data that established the bioequivalence of Clopacin^® and the reference originator drug.

Funding

Acino Pharma AG (formerly Cimex AG)

     

Changes in Gross Motor Function and Health-Related Quality of Life in Adults With Cerebral Palsy: An 8-Year Follow-Up Study

Objective

To describe changes in gross motor function and health-related quality of life (HRQOL) in adults with cerebral palsy (CP).

Design

An 8-year follow-up survey.

Setting

Participants who completed the baseline survey in 2003 were invited.

Participants

The sample of adults with CP (N=54; response rate=37%) included a “younger group” (group 1; n=31; age, 23–27y; 15 women) and an “older group” (group 2; n=23; age, 33–42y; 10 women).

Interventions

Not applicable.

Main Outcome Measures

The Gross Motor Function Classification System (GMFCS), Self-Rated Health (SRH), the Health Utility Index Mark III (HUI₃), and the Assessment of Quality of Life (AQoL).

Results

Eight years after the initial survey, 27% of the participants in the combined group had deteriorations on the GMFCS, 52% on the SRH, 44% on the HUI₃, and 25% on the AQoL. Members of group 1 reported stable scores as they made the transition to adulthood, while many of the group 2 members experienced declines, with relative risk of 1.47 (95% confidence interval [CI], 0.16–2.24) on the GMFCS, 1.36 (95% CI, 0.83–2.23) on the SRH, 1.19 (95% CI, 0.66–2.15) on the HUI₃, and 3.17 (95% CI, 1.12–9.00) on the AQoL.

Conclusions

Although much attention has focused on the transitions of persons with CP during their late teens and early 20s, this research found that deteriorations in the GMFCS levels and the HRQOL were most evident in adults in their late 20s and 30s. More detailed longitudinal studies are required to evaluate the longer-term health outcomes among persons with CP into their 30s and beyond.     

Evaluating the need for two incremental shuttle walk tests during a maintenance exercise program in people with COPD

Objective

To determine if there was an increase in walk distance when two incremental shuttle walk tests (ISWTs) were performed at the commencement of a maintenance exercise program (0 month) and at three, six and 12-month assessments.

Design

A prospective, longitudinal, repeated measures study in COPD.

Setting

Single site, hospital outpatient physiotherapy department.

Participants

Forty-eight participants (22 males) with COPD participated in the study: [baseline characteristics: mean (SD): FEV₁ 59 (19) % predicted; age 65 (8) years; BMI 26 (6) (kg/m²)].

Intervention

Participants completed two ISWTs at zero, three, six and twelve months.

Outcomes

Incremental shuttle walk distance (ISWD).

Results

There was a significant increase in walk distance between two ISWTs at zero month (17 metres (95% CI: 7 to 26) and three months (18 metres (95% CI: 6 to 30), but not at six or 12 months.

Conclusion

The increase in walk distance when a second ISWT was performed at zero and three months indicates the need to perform two ISWTs when participants are naïve to the test and at the three-month reassessment during a 12-month maintenance exercise program.     

Changes in Pulmonary Function During the Early Years After Inpatient Rehabilitation in Persons With Spinal Cord Injury: A Prospective Cohort Study

Objective

To describe changes in pulmonary function (PF) during the 5 years after inpatient rehabilitation in persons with spinal cord injury (SCI) and to study potential determinants of change.

Design

Prospective cohort study.

Setting

Eight rehabilitation centers with specialized SCI units.

Participants

Persons with SCI (N=180).

Interventions

Not applicable.

Main Outcome Measures

PF was determined by forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) as a percentage of the predicted value, at the start of rehabilitation, at discharge, and 1 and 5 years after discharge from inpatient rehabilitation. The population was divided into 3 subgroups on the basis of whether their PF declined, stabilized, or improved.

Results

FVC improved on average 5.1% over the whole period between discharge of inpatient rehabilitation and 5 years thereafter, but changes differed largely between persons. FVC declined in 14.9% of the population during the first year after discharge. During this year, body mass index, inspiratory muscle strength, change in peak power output, and change in peak oxygen uptake differed significantly between subgroups. FVC declined in 28.3% of the population during the following 4 years, but no differences were found between the subgroups for this period. Subgroups based on changes in FEV₁ differed only with respect to change in peak oxygen uptake the first year after discharge.

Conclusions

In our study, many persons with SCI showed a decline in PF, larger than the normal age-related decline, during the 5 years after inpatient rehabilitation. Results suggest that a decline in PF during the first year after inpatient rehabilitation is associated with higher body mass index, lower inspiratory muscle strength, and declined physical fitness.     

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.