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.     

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.     

Efficacy and Tolerability Exposure–Response Relationship of Retigabine (Ezogabine) Immediate-Release Tablets in Patients With Partial-Onset Seizures

Background

Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (K_v7) potassium channel activity.

Objectives

The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials.

Methods

Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC_0–τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated.

Results

AUC_0–τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC_0–τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure–response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC_0–τ.

Conclusions

Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600–1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%–50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC_0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.     

Pharmacokinetic interaction of telmisartan with s-amlodipine: an open-label, two-period crossover study in healthy Korean male volunteers

BackgroundTelmisartan belongs to a class of orally active angiotensin II receptor blockers (ARBs), and S-amlodipine is an enantiomer of amlodipine. Amlodipine is a racemic mixture and the calcium channel blocking (CCB) effect is confined to S-amlodipine, whereas R-amlodipine has a 1000-fold lower activity and no racemization occurs in vivo in human plasma. Combination therapy of ARBs with CCBs provides advantages for blood pressure control and vascular protection over monotherapy.ObjectiveTo investigate the effects of coadministration of telmisartan and S-amlodipine on the steady-state pharmacokinetic properties of each drug as a drug–drug interaction study required before developing the fixed-dose combination agent.MethodsThis study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-sequence, 2-period, crossover study in healthy male Korean volunteers. In part A, volunteers were administered 80 mg of telmisartan, either alone or with 5 mg of S-amlodipine. In part B, volunteers were administered 5 mg of S-amlodipine, either alone or with 80 mg of telmisartan. Blood samples were taken on days 9 and 37, following the final dose of each treatment, and at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration in part A, and were taken at 0 (predose), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, and 24 hours after administration in part B. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic properties of each drug after coadministration of telmisartan and S-amlodipine were compared with those of each drug administered alone. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews.ResultsFifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B). The geometric mean ratios (GMRs) (90% CI) for the C_max,ss and AUC_τ,ss of telmisartan (with or without S-amlodipine) were 1.039 (0.881–1.226) and 1.003 (0.926–1.087), respectively. The GMRs (90% CI) for C_max,ss and AUC_τ,ss of S-amlodipine (with or without telmisartan) were 0.973 (0.880–1.076) and 0.987 (0.897–1.085). Total 11 adverse events (AEs) were reported in 7 volunteers (21.9%) in part A. A total of 9 AEs were reported in 6 volunteers (25.0%) in part B. Statistical analysis confirmed that the 90% CIs for these pharmacokinetic parameters were within the commonly accepted bioequivalence range of 0.8 to 1.25, indicating that the extent of bioavailability of S-amlodipine was not affected by telmisartan. The intensity of all AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations.ConclusionsFollowing multiple-dose coadministration of high doses of telmisartan and S-amlodipine, the steady-state pharmacokinetic properties of telmisartan were not significantly affected, and telmisartan had no significant effect on the pharmacokinetic properties of S-amlodipine at steady state in these selected groups of healthy volunteers. Both formulations were generally well-tolerated. ClinicalTrials.gov identifiers: NCT01356017 and NCT01356043.     

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.     

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.     

Pharmacokinetic and Pharmacodynamic Responses of Insulin Degludec in African American,White, and Hispanic/Latino Patients With Type 2 Diabetes Mellitus

Background

Pharmacokinetic and pharmacodynamic profiles of exogenous insulin may be affected by intrinsic factors, such as age, ethnicity/race, and hepatic and renal function. Insulin degludec (IDeg) is a basal insulin with an ultralong duration of action and a flat and stable glucose-lowering effect profile.

Objective

The purpose of this study was to investigate whether the pharmacokinetic and pharmacodynamic responses to IDeg at steady state vary according to patient race/ethnicity.

Methods

This randomized, single-center, double-blind, 2-period crossover trial investigated responses to IDeg in 59 patients with type 2 diabetes mellitus from 3 groups: African American, Hispanic/Latino, and white. Patients were allocated randomly to a sequence of 2 treatment periods, separated by a 7- to 21-day washout period, with once-daily IDeg or insulin detemir dosing for 6 days at a predefined fixed dose level (0.6 U/kg). Differences in pharmacokinetic and pharmacodynamic variables among groups were analyzed using an ANOVA with treatment period, an interaction between race/ethnicity, and treatment as fixed factors, subject as a random effect, and residual variance, depending on treatment.

Results

Total exposure to IDeg during one dosing interval at steady state (AUC_IDeg,τ,SS) was similar among the racial/ethnic groups (ratio [95% CI]: African American vs white, 1.10 [0.91–1.31]; African American vs Hispanic/Latino, 1.13 [0.95–1.34]; and Hispanic/Latino vs white, 0.97 [0.82–1.16]). The total glucose-lowering effect of IDeg (AUC_GIR,τ,SS) was also similar among the groups, with no statistically significant difference in pairwise comparisons (1940, 1735, and 2286 mg/kg in African American, white, and Hispanic/Latino patients, respectively). Steady state was reached in all groups after 2 to 3 days of dosing. In all groups, both exposure and glucose-lowering effect for IDeg were evenly distributed between the first and second 12 hours of the 24-hour dosing interval at steady state (mean AUC_{IDeg,0–12h,SS}/AUC_IDeg,τ,SS = 53%–54%; AUC_{GIR,0-–12h,SS}/AUC_GIR,τ,SS = 47%–52%).

Conclusion

The similar pharmacokinetic and pharmacodynamic responses to IDeg in 3 racial/ethnic groups of patients with type 2 diabetes mellitus suggest that the flat, stable, and ultralong pharmacokinetic and pharmacodynamic profiles of IDeg are preserved irrespective of race/ethnicity. Although insulin doses must be adjusted on an individual basis, similar pharmacokinetic and pharmacodynamic responses to IDeg are observed in patients with differing race/ethnicity.     

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.     

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

Background

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

Objective

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

Methods

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

Results

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

Conclusions

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

Pharmacokinetic 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.     

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 Interactions Between Gemigliptin and Metformin,and Potential Differences in the Pharmacokinetic Profile of Gemigliptin Between the Mexican and Korean Populations: A Randomized,Open-label Study in Healthy Mexican Volunteers

Purpose

The aim of this study was to assess the pharmacokinetic interactions between a newly developed dipeptidyl peptidase (DPP)-4 inhibitor, gemigliptin, and metformin in healthy Mexican male volunteers, and the differences in the pharmacokinetic profile of gemigliptin between Korean and Mexican healthy volunteers.

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.     

Pharmacokinetics of Empagliflozin, a Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitor, Coadministered with Sitagliptin in Healthy Volunteers

Introduction

This randomized, open-label, crossover study investigated potential drug-drug interactions between the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin and the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin. Empagliflozin is a potent and selective SGLT-2 inhibitor that lowers blood glucose levels by inhibiting renal glucose reabsorption, leading to an increase in urinary glucose excretion. Sitagliptin lowers blood glucose through an insulin-dependent mechanism of action.

Methods

Sixteen healthy male volunteers received three treatments (A, B, C) in one of two treatment sequences (AB then C, or C then AB). In treatment AB, 50 mg empagliflozin was administered once daily (q.d.) for 5 days (treatment A), immediately followed by coadministration of 50 mg empagliflozin q.d. and 100 mg sitagliptin q.d. over 5 days (treatment B). In treatment C, 100 mg sitagliptin was administered q.d. for 5 days. A washout period of ≥7 days separated treatments AB and C.

Results

Coadministration of sitagliptin with empagliflozin did not have a clinically relevant effect on the area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ (AUC_τ,ss) (geometric mean ratio [GMR] 110.4; 90% confidence interval [CI] 103.9, 117.3) or maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ (C _max,ss) (GMR 107.6; 90% CI 97.0, 119.4) of empagliflozin. Coadministration of empagliflozin with sitagliptin did not have a clinically meaningful effect on the AUC_τ,ss (GMR 103.1; 90% CI 98.9, 107.3) or C _max,ss (GMR 108.5; 90% CI 100.7, 116.9) of sitagliptin. Empagliflozin and sitagliptin were well tolerated when given alone or in combination. Five subjects (31.3%) reported at least one adverse event (AE): three (18.8%) experienced an AE while receiving empagliflozin monotherapy and three (18.8%) while receiving sitagliptin monotherapy. No adverse events were reported during the coadministration period. No AEs were regarded as drug-related by the investigator.

Conclusion

These results indicate that empagliflozin and sitagliptin can be coadministered without dose adjustments.     

Effect of Food on the Pharmacokinetic Properties of the Oral Sarpogrelate Hydrochloride Controlled-Release Tablet in Healthy Male Korean Subjects

Background

A new controlled-release formulation of sarpogrelate, a 5-hydroxytryptamine receptor subtype 2 antagonist that blocks serotonin-induced platelet aggregation, has been developed for once-daily administration.

Objective

This study evaluated the effect of food on the pharmacokinetic properties of controlled-release sarpogrelate (sarpogrelate CR) in healthy volunteers.

Methods

A randomized, open-label, two-period, two-treatment crossover study was performed in healthy male Korean subjects. Following an overnight fast, a single dose of sarpogrelate CR 300 mg was administered either in the fasted condition or immediately after a high-fat breakfast. Pharmacokinetic parameters were calculated using a noncompartmental analysis. Tolerability was determined using clinical laboratory testing and physical examination, including vital sign measurements, electrocardiography, and interviews with the volunteers regarding adverse events (AEs).

Results

A total of 24 healthy subjects were enrolled, 23 of whom completed the study (mean [range] age, 26 years [21–45]; weight, 68.1 kg [56.0–79.9]; body mass index, 22.1 kg/m² [18.8–25.0]). Sarpogrelate C_max and AUC_last were decreased In the fed condition compared with those in the fasted condition, with geometric mean ratios (90% CI) of 0.4868 (0.4041–0.5864) and 0.7394 (0.6809–0.8028), respectively. T_max was delayed from 0.75 to 4.0 hours after a high-fat meal, but the fed condition exhibited a similar elimination profile to that of the fasted condition. The most commonly reported AE was headache (n = 2), and other AEs were reported in 1 subject each. All of the AEs were considered mild in intensity, and the participants recovered without treatment.

Conclusions

Compared with the administration of sarpogrelate CR 300 mg in the fasted condition, administration with food was associated with a decreased rate and extent of absorption, as assessed by C_max and AUC_last, respectively. The drug was well-tolerated by the healthy subjects in this study.     

Efficacy and Safety of Triple Therapy With Telmisartan,Amlodipine, and Rosuvastatin in Patients With Dyslipidemia and Hypertension: The Jeil Telmisartan,Amlodipine, and Rosuvastatin Randomized Clinical Trial

Purpose

Fixed-dose combination therapy with telmisartan, amlodipine, and rosuvastatin is needed in patients with hypertension and dyslipidemia for better adherence and cost-effectiveness than free–equivalent combination therapies. This study aimed to compare the efficacy and safety of combination therapy with telmisartan, amlodipine, and rosuvastatin versus telmisartan plus amlodipine or telmisartan plus rosuvastatin in patients with hypertension and dyslipidemia.

Tolerability of Fluticasone Furoate/Vilanterol Combination Therapy in Children Aged 5 to 11 Years With Persistent Asthma

Background

Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β₂-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β₂-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β₂-agonist.

Objective

We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β₂-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma.

Methods

In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC_0–4, C_max) and PD (serum potassium [0–4 hours], serum cortisol [0–12 hours], and glucose [0–4 hours]) parameters on day 14.

Results

Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC_0–4 (1.02 [0.86–1.22]) and FF C_max (0.98 [0.65–1.48]) were similar. For serum glucose (0–4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19–0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study.

Conclusions

Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.     

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.     

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.     

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.