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.     

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.     

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.     

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.     

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

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

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.     

Evaluation of the Pharmacokinetic Interaction Between Ticagrelor and Venlafaxine,a Cytochrome P-450 2D6 Substrate,in Healthy Subjects

Purpose

Ticagrelor is a reversibly binding P2Y₁₂ receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor has been shown in vitro to be a weak inhibitor of cytochrome P-450 (CYP) 2D6, a clinically important enzyme for the metabolism of many drugs. This study assessed the effects of coadministration of ticagrelor on the pharmacokinetics of the CYP2D6 substrate venlafaxine. The impact of venlafaxine on ticagrelor pharmacokinetic parameters was also investigated.

Methods

Healthy subjects (N = 22) received a single 180-mg oral dose of ticagrelor on days 1 and 9 and oral doses of venlafaxine on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). Plasma concentrations of ticagrelor, venlafaxine, and their metabolites (AR-C124910XX and O-desmethylvenlafaxine [ODV], respectively) were quantified for pharmacokinetic analyses. Safety and tolerability were assessed throughout the study.

Findings

Overall, 19 of 25 subjects were male; 14 were white, 10 were black, and 1 was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m². Ticagrelor had no effect on overall exposure to venlafaxine, as assessed by the AUC_0–τ (geometric least squares mean ratio, 110.32 ng · h/mL [90% CI, 106.27–114.52]). Venlafaxine C_max was increased by 22% in the presence of ticagrelor (121.83 ng/mL [90% CI, 111.80–132.75]). ODV AUC_0–τ and C_max were unaffected by coadministration with ticagrelor (98.71 ng · h/mL [90% CI, 96.61–100.85] and 101.44 ng/mL [90% CI, 98.34–104.65], respectively). Venlafaxine had no effect on the C_max or AUC_0–∞ of ticagrelor (96.54 ng/mL [90% CI, 85.03–109.61] and 89.67 ng · h/mL [90% CI, 82.78–97.14]) or AR-C124910XX (106.39 ng/mL [90% CI, 96.10–117.78] and 106.32 ng · h/mL [90% CI, 97.28–116.21], respectively). Ticagrelor and venlafaxine were well tolerated whether given alone or in combination.

Implications

Ticagrelor had no clinically relevant effect on the plasma levels of venlafaxine and its CYP2D6-generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the pharmacokinetics of ticagrelor.     

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.     

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.     

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.     

Comparison of Scaled-average,Population, and Individual Bioequivalence on 2 Tablets of Pitavastatin Calcium: A 3-Period,Reference-replicated,Crossover Study in Healthy Chinese Volunteers

Background

Pitavastatin, a fully synthetic β-hydroxy-β-methylglutaryl–coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject variability and interchangeability of this newly developed generic product and the branded innovator product have rarely been investigated in the Chinese population.

Purpose

The aim of this study is to develop and compare the scaled-average, population, and individual bioequivalence (BE) of pitavastatin calcium tablets in healthy Chinese volunteers. This study will be used to allow for the interchangeability (switchability and prescribability) of the 2 products in clinical medication in China.

Methods

A single-dose, reference-replicated, 3-period crossover BE study was conducted in 36 healthy male volunteers. Plasma samples were collected before and after oral administration of 2-mg test or reference tablets. A LC-MS/MS method was used to determine the concentration of pitavastatin calcium. A noncompartmental method was used to investigate the pharmacokinetic parameters. The ANOVA and 90% CIs of ln(AUC_0–t) and ln(C_max) were used for statistical analysis of scaled-average BE. A nonparametric test (Wilcoxon signed rank test) was performed to T_max. The analyses of population BE and individual BE were used to assess the switchability and prescribability of the 2 products.

Findings

Thirty-six volunteers were enrolled in this clinical research; 33 volunteers completed the 3 treatment periods. The mean (SD) relative bioavailability calculated from the ratios (T/R) of AUC_0–t was 101.3% (19.7%). The mean ln(AUC_0–t) and ln(C_max) were 98.64 (90% CI, 93.44–104.13) and 98.68 (90% CI, 91.88–105.99) within previously stipulated ranges recommended by the US Food and Drug Administration and the China Food and Drug Administration (CFDA). The intrasubject %CVs of AUC_0–t and C_max were 12.0% and 18.0% for the reference tablet and 13.0% and 17.0% for the test tablet. No significant differences were found among T_max (0.742 ± 0.276, 0.674 ± 0.202, and 0.689 ± 0.226, respectively) for reference tablet 1, reference Supplemental Table II in the online version at 10.1016/j.clinthera.2014.06.21, and test tablet by a Wilcoxon test (P > 0.05). For ln(AUC_0–t) and ln(C_max), the statistical test-reference ratios were 99.13% and 98.95%, respectively. After inspecting the results for reference and mixed scaling, all the upper confidence limits were <0; therefore, population and individual BE were given.

Implications

In the healthy Chinese males, the generic and branded name tablets of pitavastatin calcium are bioequivalent at the rate and extent of absorption after a comparison of scaled-average, population, and individual BE and thus may be used interchangeably. Both the formulations are generally well tolerated. Chinese Clinical Trial identifier: ChiCTR-TTRCC-13003973.     

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,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.     

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.     

Comparison of the Pharmacokinetics,Safety, and Tolerability of Vitamin D3 in DP-R206 (150-mg Ibandronate/24,000-IU Vitamin D3 Tablet) and as Monotherapy (24,000 IU) in Healthy Male Korean Adults

Background

Combined treatment with a bisphosphonate and vitamin D has been proposed for postmenopausal osteoporosis. A new, fixed-dose combination tablet of ibandronate plus vitamin D₃ has been developed for monthly administration to treat postmenopausal osteoporosis.

Objectives

The main objective of the present study was to compare the pharmacokinetics of vitamin D₃ administered in 2 forms: a newly developed ibandronate 150-mg/vitamin D₃ 24,000-IU tablet (DP-R206, test drug) and a stand-alone vitamin D₃ 24,000-IU tablet (reference drug). A secondary objective was to evaluate the safety and tolerability of DP-R206 in healthy adult male Korean volunteers.

Methods

This study was a single-dose, open-label, randomized-sequence, 2-treatment, 2-way crossover trial. Blood samples were collected from 24 hours’ predose to 120 hours’ postdose. The plasma concentrations of vitamin D₃ were analyzed by using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated, and the 90% CIs of the ratios of the geometric means of the parameters were determined from the logarithmically transformed data by using ANOVA.

Results

Thirty-sex healthy adult male Korean volunteers with a mean (SD) age of 25.8 (2.7) years, a mean height of 174.0 (5.9) cm, and a mean weight of 69.1 (6.2) kg were enrolled; 29 participants completed the study. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-corrected C_max, AUC_0–last, and AUC_0–∞ values were 0.93 to 1.24, 0.89 to 1.19, and 0.87 to 1.18, respectively. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-uncorrected C_max, AUC_0–last, and AUC_0–∞ values were 0.93 to 1.24, 0.88 to 1.19, and 0.87 to 1.18, respectively. Eighty-four adverse events (AEs) were reported in 24 of 32 subjects receiving DP-R206, and 14 AEs were reported in 8 of 29 subjects receiving the vitamin D₃ 24,000-IU tablet. All of the subjects who experienced AEs recovered without sequelae, and no serious AEs were observed.

Conclusions

The vitamin D₃ pharmacokinetics were similar for DP-R206 and the 24,000-IU vitamin D₃ tablet. DP-R206 was well tolerated. ClinicalTrials.gov identifier: NCT01577849.     

Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin,a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Background

Dapagliflozin, a selective, orally active, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action.

Objectives

These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dynamic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China.

Methods

In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose administration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharmacokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glucose excretion), and tolerability were assessed.

Results

Fourteen subjects completed the dapagliflozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/m² in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (T_max, ≤1.5 h), accumulation (defined as the geometric mean ratio of AUC_τ at day 10 to AUC_τ at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median T_max (≤2 h) but a similar plasma concentration–time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7% of the dapagliflozin dose) was excreted in urine, while ≤1.9% of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well tolerated; one dapagliflozin 10 mg–treated subject discontinued the study because of a serious adverse event (bronchitis) considered by the investigator as unrelated to dapagliflozin dosing.

Conclusions

Pharmacokinetic and pharmacodynamic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapagliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited.     

Multiple-dose Safety,Tolerability, Pharmacokinetics,and Pharmacodynamics of Oral LCB01-0371 in Healthy Male Volunteers

Purpose

LCB01-0371 is a novel oxazolidinone broad-spectrum antibacterial that is more potent than linezolid against systemic infections in animals. The goal of this investigation was to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple-dose LCB01-0371 as well as the pharmacokinetic characteristics of a new 400-mg tablet formulation.

Effects of Hydrochlorothiazide on the Pharmacokinetics,Pharmacodynamics, and Tolerability of Canagliflozin,a Sodium Glucose Co-transporter 2 Inhibitor,in Healthy Participants

Background

Many patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated.

Objective

This study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants.

Methods

This Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated.

Results

Thirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUC_τ,ss) and C_max at steady state (C_max,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08–1.17) and 1.15 (1.06–1.25), respectively. AUC_τ,ss and C_max,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was −0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments.

Conclusions

Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.     

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     

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.