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.     

Single-Dose,Randomized Crossover Comparisons of Different-Strength Imatinib Mesylate Formulations in Healthy Korean Male Subjects

Background

Imatinib mesylate is used to treat chronic myeloid leukemia and advanced gastrointestinal stromal tumors.

Objective

The purpose of this study was to compare the pharmacokinetics of 2 different strengths of the imatinib formulation containing 100 mg (reference) and 400 mg (test) to satisfy the regulatory requirement for marketing.

Methods

A single-center, randomized, single-dose, open-label, 2-period, 2-sequence, comparative crossover study with a 14-day washout period was conducted in 30 healthy male volunteers. Plasma samples for the drug analysis were collected up to 72 hours after drug treatment. Participants received either the reference (4 tablets of 100-mg imatinib) or the test (1 tablet of 400-mg imatinib) formulation during the first period and the alternative formulation during the second period. The safety profiles and tolerability of the 2 formulations were also assessed based on physical examinations, laboratory tests, a 12-lead ECG, and vital signs.

Results

Thirty participants were initially enrolled; their mean (SD) age, height, weight, and body mass index were 24.9 (2.0) years (range, 23–30 years), 174 (5) cm (range, 164–185 cm), 69.9 (2.0) kg (range, 54.1–87.4 kg), and 23.0 (2.0) kg/m² (range, 18.5–26.9 kg/m²); 28 healthy participants completed both treatment periods. Two subjects did not complete the study because they withdrew consent for personal reasons. The observed mean (SD) C_max, AUC_0–last, and AUC_0–∞ values for the reference formulation were 1792 (357) ng/mL, 28,485 (6274) ng · h/mL, and 29,079 (6371) ng · h/mL, respectively. Corresponding values for the test formulation were 1710 (312) ng/mL, 27,222 (4624) ng · h/mL , and 27,872 (4751) ng · h/mL. The geometric mean ratios (90% CIs) between the 2 formulations at the 400-mg dose of imatinib were 0.9579 (0.9054–1.0136) for C_max, 0.9652 (0.9174–1.0155) for AUC_0–last, and 0.9679 (0.9203–1.0179) for AUC_0–∞, respectively. During the study period, 6 adverse events (3 for the reference and 3 for the test formulation) were reported; all were transient, mild, and resolved completely during the treatment period. There were 4 cases of nausea and 1 case each of dizziness and oropharyngeal pain. Four adverse events were considered related to the study drugs.

Conclusions

The results showed that despite the different strengths of the 2 imatinib formations, the test and reference formulations both met the regulatory criteria for pharmacokinetic equivalence at a dose of imatinib 400 mg in these healthy Korean male subjects. Both imatinib formulations seemed to be generally well tolerated. ClinicalTrials.gov identifier: NCT01270984.     

Bioequivalence of Two Formulations of a Single Oral Dose of 500-mg Azithromycin Granules: A Randomized, Open-Label, Two-Period Crossover Study in Healthy Han Chinese Volunteers

Background: In recent years, the use of generic drugs has been increasing due to their effectiveness and to the increasing variety of drugs that are now available in generic formulations. Although several generic oral formulations of azithromycin are available in China, information concerning the bioavailability of these formulations in the Chinese population is unavailable.Objective: The purpose of this study was to compare the bioequivalence and tolerability of a single oral dose of 2 commercial brands of 500-mg azithromycin granules in healthy Han Chinese volunteers.Methods: In a randomized, open-label, 2-period crossover study, the bioequivalence and tolerability of 2 commercial formulations of azithromycin granules (test: Dayin Ocean Biochemical Company Ltd., Shandong, China; reference: Taiyang Drug Company Ltd., Beijing, China) were compared in healthy adult Han Chinese volunteers. Both the test and the reference formulations were administered to each subject. The 2 treatment phases were separated by a 3-week washout period. Liquid chromatography-tandem mass spectrometry was used to determine plasma drug concentrations. The formulations were considered bioequivalent if the natural log-transformed ratios of C_max and AUC were within the predetermined equivalence range of 70% to 143% and 80% to 125%, respectively, and if P ≤ 0.05 for the 90% CIs.Results: Twenty-four male Han Chinese volunteers (mean [SD] age, 21.0 [2.0] years [range, 18-25 years]; mean [SD] weight, 67.6 [5.6] kg [range, 56-81 kg]; mean [SD] height, 176.0 [5.0] cm [range, 165-188 cm]) were enrolled. Twenty-two subjects completed the study, with 2 withdrawing for personal reasons. No period or sequence effect was observed. The 90% CIs for the corresponding ratios of C_max, AUC from hour 0 to time t, and AUC from hour 0 to any time point were 85.9 to 103.9, 83.6 to 106.0, and 84.7 to 105.9 (in the 2 one-sided t tests; all, P < 0.05), respectively. Similar results were found in data without a logarithmic transformation. There were no significant differences in the plasma concentration-time curves of the test and reference formulations. No adverse events were reported by the subjects or revealed by clinical or laboratory tests.Conclusions: Single oral doses of 2 commercial brands of azithromycin granules (500 mg) were equivalent with regard to the rate and extent of absorption among these healthy Han Chinese volunteers. Both formulations were well tolerated.     

Bioequivalence of 2 Azithromycin Capsule Formulations: A Randomized, Single-Dose, Open-Label, 2-Period Crossover Study in Healthy Male Pakistani Volunteers

Background

Approximately 68 brands of azithromycin capsule formulations are available in Pakistan; however, published data on their bioequivalence in the Pakistani population are not available.

Objective

Upon instructions from and approval of the Ministry of Health, Pakistan, this study was designed to evaluate the bioequivalence of a locally manufactured azithromycin capsule formulation with a reference formulation from a multinational manufacturer. This study compared dissolution profiles, relative bioavailability, and other pharmacokinetic parameters of the 2 formulations.

Methods

A single oral 500-mg dose of the 2 formulations was administered to 12 healthy adult Pakistani male volunteers under fasting conditions in a randomized, open-label, 2-period crossover study. The trial included collection of blood samples over 48 hours and a 2-week washout period. Azithromycin serum concentrations were quantified using a validated RP-HPLC/ultraviolet (UV) detection method. These results were used to determine the intended pharmacokinetic parameters. As mandated by the US Food and Drug Administration and the European Medicine Agency, the test and reference formulations were considered bioequivalent if the 90% CIs of the geometric mean ratios for the log-transformed values of their pharmacokinetic parameters were within the predetermined range of 0.8 to 1.25.

Results

When subjected to a simple model independent approach of dissolution profile comparison, f₁ (difference) and f₂ (similarity factor) were found to be 5.47 and 70.04, respectively. Similarly, the 2 azithromycin capsule formulations were well tolerated by all volunteers. Low %CV of the pharmacokinetic parameters at a sample size of 12 and significance level of 0.05 contributed to acceptable (>0.8) power of the test. The 90% CIs for the ratios of C_max, AUC_0–48, T_max, t_1/2, and mean residence time, respectively, were 0.83–0.93, 0.85–1.10, 0.86–1.08, 0.92–1.17, and 0.92–1.16.

Conclusion

This single-dose study found that test and reference formulations met the regulatory criteria for bioequivalence in these fasted, healthy male Pakistani volunteers.     

Pharmacokinetics,Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects

Purpose

The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of rotigotine in healthy Chinese men.

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.     

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.     

Pharmacokinetic Interaction Between Rosuvastatin and Olmesartan: A Randomized,Open-label, 3-period,Multiple-dose Crossover Study in Healthy Korean Male Subjects

Purpose

Rosuvastatin has been widely used in combination with olmesartan for the treatment of dyslipidemia accompanied by hypertension. With no information currently available on the interaction between the 2 drugs, a pharmacokinetic study was conducted to investigate the influence of rosuvastatin on olmesartan and vice versa when the 2 drugs were coadministered. The purpose of this study was to investigate the pharmacokinetic profile of coadministration of the rosuvastatin 20-mg tablet and the olmesartan 40-mg tablet and the associated drug–drug interaction in healthy Korean male volunteers.

Methods

This was a randomized, open-label, 3-period, multiple-dose crossover study. Eligible subjects were aged 20 to 50 years and within 20% of their ideal body weight. After being randomly assigned to 6 groups of equal number, subjects received each of the following 3 formulations once a day for 7 consecutive days with an 8-day washout period between the formulations: rosuvastatin 20-mg tablet, olmesartan 40-mg tablet, and coadministration of the rosuvastatin 20-mg tablet and the olmesartan 40-mg tablet. 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. Adverse events were evaluated based on subject interviews and physical examinations.

Findings

Among the 36 enrolled subjects, 34 completed the study (mean [range] age, 28.6 [23–49] y; mean [range] weight, 66.4 [52.2–78.7] kg). The 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters for the coadministration of the 2 drugs to the mono-administration of each drug were 85.14% to 96.08% for AUC_τ and 81.41% to 97.48% for C_ss,max for rosuvastatin, and 77.55% to 89.48% for AUC_τ and 75.62% to 90.12% for C_ss,max for N-desmethyl rosuvastatin; those values were 95.61% to 102.57% for AUC_τ and 91.73% to 102.98% for C_ss,max for olmesartan. Dizziness was the most frequently noted adverse drug reaction, occurring in 1 subject receiving mono-administration of rosuvastatin, 1 subject receiving mono-administration of olmesartan, and 4 subjects receiving coadministration of rosuvastatin and olmesartan. All the adverse events were expected, and there was no significant difference in the incidence between the 2 formulations.

Implications

This study suggests that rosuvastatin and olmesartan did not significantly influence each other’s pharmacokinetics when coadministered. Although the pharmacokinetics of N-desmethyl rosuvastatin were influenced by olmesartan, such interactions were considered clinically insignificant. All 3 formulations were well tolerated, and no serious adverse events or drug reactions were noted.     

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.

Pharmacokinetic Interaction Between Rosuvastatin and Telmisartan in Healthy Korean Male Volunteers: A Randomized,Open-label,Two-period,Crossover, Multiple-dose Study

Purpose

Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and telmisartan, an angiotensin receptor blocker, are commonly prescribed in combination for the treatment of dyslipidemia accompanied by hypertension. However, the nature of the pharmacokinetic interaction between the 2 drugs is not clearly understood. The goal of the present study was to investigate the pharmacokinetic drug–drug interaction between rosuvastatin and telmisartan in a healthy Korean population.

Methods

This was a randomized, 2-part, open-label, 2-period, crossover, multiple-dose study, with each part composed of different subjects between the ages of 20 and 55 years. In part 1, each subject received rosuvastatin 20 mg with and without telmisartan 80 mg once daily for 6 consecutive days. In part 2, each subject received telmisartan 80 mg with and without rosuvastatin 20 mg once daily for 6 consecutive days. In both parts, there was a 16-day washout period between mono- and coadministration. Blood samples were collected up to 72 hours after the last dose. Adverse events (AEs) were evaluated through interviews and physical examinations.

Findings

In part 1, the 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters for coadministration of the 2 drugs to monoadministration of each drug were 1.0736–1.2932 for AUC_τ and 1.7442–2.3229 for C_max,ss for rosuvastatin and 0.9942–1.1594 for AUC_τ and 1.3593–1.7169 for C_max,ss for N-desmethyl rosuvastatin, whereas in part 2, the CIs were 1.0834–1.2672 for AUC_τ and 1.1534–1.5803 for C_max,ss for telmisartan. The most frequently noted AE was cough in part 1, which occurred in 2 subjects receiving the combination therapy, and oropharyngeal pain in part 2, which occurred in 3 subjects receiving the combination therapy. All reported AEs were mild or moderate, and there was no significant difference in incidence between the treatments.

Implications

These findings demonstrated that rosuvastatin and telmisartan mutually affected each other’s pharmacokinetics, suggesting a possibility of drug–drug interaction. However, based on dose–response characteristics of the 2 drugs and previous results from other interaction studies, the degree of drug interaction observed in this study was not regarded as clinically significant. All treatments were well tolerated, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01992601.     

Pharmacokinetic Interaction Between Rosuvastatin and Metformin in Healthy Korean Male Volunteers: A Randomized,Open-label, 3-period,Crossover, Multiple-dose Study

Purpose

Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers.

Methods

This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations.

Findings

Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin C_ss,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUC_tau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for C_ss,max and AUC_tau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments.

Implications

Although the C_ss,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.     

Effects of Food on the Pharmacokinetic Properties of Surufatinib: A Phase I,Single-dose,Randomized, Open-label Crossover Study in Healthy Subjects

PurposeSurufatinib is a potent and orally active small-molecule tyrosine kinase inhibitor targeting VEGFRs 1 to 3, FGFR-1, and CSF-1R, and thus may exert antitumor and antiangiogenic effects. The objective of this study was to determine the tolerability and effects of food intake on the pharmacokinetic properties of surufatinib in healthy Chinese subjects.MethodsA total of 24 healthy Chinese male subjects aged between 18 and 55 years were enrolled. Subjects were administered a single dose of surufatinib 250–mg capsules in the fasted and fed states in succession. Pharmacokinetic analysis was performed through the collection of blood samples at predose and at several time points after surufatinib administration. Tolerability assessments comprised physical examination including vital sign measurements, laboratory testing, and ECG to determine adverse events (AEs).FindingsThe 90% CIs of the geometric mean ratios of AUC_0–t and AUC_0–∞ in the fasted and fed states was within 0.80 to 1.25; and for C_max, within 0.70 to 1.43, indicating that food had no effect on the bioavailability of surufatinib in these healthy Chinese male subjects. Food intake delayed the time to peak absorption of surufatinib, as the median T_max in the fed state was longer than that in the fasted state (4.0 vs 2.0 h). Surufatinib was marginally excreted from urine (mean [SD] cumulative excretion fraction, 1.2% [0.4%]). AEs occurred in 7 of the 24 subjects (29.2%) and included upper respiratory tract infection, dizziness, merycism, intervertebral disc protrusion, influenza-like disease, hematuria, prostatitis, and elevated blood urea nitrogen. All AEs were grade 1 or 2.ImplicationsThe bioavailability of surufatinib was not affected by food intake prior to dosing. However, food intake led to delated T_max of surufatinib. The tolerability of a single oral dose of surufatinib 250 mg in the fasted and fed states was favorable in these healthy Chinese male subjects. These results indicate that surufatinib capsules could be administered before or after meals. ClinicalTrials.gov identifier: NCT02320409.     

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.     

Comparative Bioavailability Study of a New Orodispersible Formulation of Ibuprofen Versus Two Existing Oral Tablet Formulations in Healthy Male and Female Volunteers

PurposeThis study aimed to assess the comparative bioavailability between ibuprofen acid orodispersible tablets (Test product) and ibuprofen acid oral tablets (Reference product).MethodsThis was a randomized, single-dose, 3-way crossover, open-label, pharmacokinetic study in 36 healthy male and female volunteers. Blood samples were taken periodically over a 12-h period after dosing to derive total plasma ibuprofen and S(+)/R(−) ibuprofen enantiomer pharmacokinetic parameters; safety profile and tolerability were evaluated throughout the study.FindingsAfter a single-dose administration of ibuprofen acid oral tablets (2 × 200 mg), the total ibuprofen C_max and AUC_0–t (geometric least square [LS] mean) for the Test product was 29.4 μg/mL and 100.6 h/μg/mL, respectively, and for the Reference product it was 30.6 μg/mL and 98.7 h/μg/mL. The geometric LS mean Test/Reference ratio 90% CI for both total ibuprofen C_max (90.71–101.77) and AUC_0-t (98.72–105.23) was contained entirely within the predefined 80.00%–125.00% lower and upper limits; in addition, no statistically significant difference was found in T_max (P = 0.1819) after fasted administration of the Test and Reference products. There were 4 mild treatment emergent adverse events, considered unrelated to the study drug, reported by 2 volunteers during the study; no serious adverse events, no suspected unexpected serious adverse events. and no clinically significant changes in laboratory safety, vital signs, or 12-lead ECG measurements were reported. The enantiomer-specific analysis mirrored that of total ibuprofen, with the C_max and AUC_0–t LS mean Test/Reference ratio 90% CI for both ibuprofen S(+) and R(−) enantiomers contained entirely within the predetermined 80%–125.00% limits.ImplicationsThis study found that ibuprofen acid 200 mg orodispersible tablets and ibuprofen acid 200 mg tablets met the regulatory criteria for bioequivalence for AUC_0–t and C_max. Post hoc analysis of ibuprofen both S(+) and R(−) enantiomers mirrored the findings for total ibuprofen. All investigational products were found to be well tolerated. Clinicaltrials.gov identifier: NCT03180879.     

Pharmacokinetics and Safety of Subcutaneous Pasireotide and Intramuscular Pasireotide Long-acting Release in Chinese Male Healthy Volunteers: A Phase I,Single-center,Open-label,Randomized Study

Purpose

The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).

Methods

In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, C_max, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.

Findings

Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70–1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (C_max in single-dose SC administration) or significantly decreased (C_min,ss in multiple BID SC doses and first peak C_max in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.

Implications

The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.     

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.     

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.     

Safety,Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous Siponimod: A Randomized,Open-label Study in Healthy Subjects

PurposeThe goal of this study was to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of intravenous (IV) siponimod in healthy subjects.MethodsThis randomized, open-label study was conducted in 2 parts. In Part 1, a total of 16 eligible subjects received either a single oral dose of siponimod (0.25 mg) followed by a single IV infusion (0.25 mg/3 h) in Sequence 1, or vice versa in Sequence 2. In Part 2, a total of 17 eligible subjects received single IV infusions of siponimod (1 mg/24 h).FindingsNo clinically relevant effect on mean 5-minute or hourly average heart rate was observed following the siponimod IV dosing regimens and both remained above 50 beats/min. Observed atrioventricular blocks and sinus pauses were asymptomatic. The mean change in absolute lymphocyte count from baseline was comparable for the siponimod 0.25 mg oral regimen and the two IV siponimod regimens. Oral siponimod displayed a good absolute bioavailability of 84%. The mean peak exposure of oral siponimod was approximately 48% lower than that of IV siponimod. The M17 metabolite was found to be the most prominent systemic metabolite of siponimod in humans.ImplicationsSiponimod IV infusions were well tolerated, with safety and PD (absolute lymphocyte count) profiles similar to those of oral siponimod. The PD/PK findings supported the development of an innovative rapid IV titration regimen for patients with intracerebral hemorrhage.     

A Phase I,Randomized, Crossover,Open-label Study of the Pharmacokinetics of Solriamfetol (JZP-110) in Healthy Adult Subjects With and Without Food

Purpose

Solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, is currently being evaluated for the reduction of sleepiness and improvement of wakefulness in patients with narcolepsy and obstructive sleep apnea. The purpose of this study was to evaluate the effect of food on the pharmacokinetic (PK) parameters and bioavailability of solriamfetol at the highest intended therapeutic dose in healthy adults and to characterize its renal excretion under fasting conditions.