洛美沙星片剂和胶囊剂的相对生物利用度研究

对９名男性健康自愿受试者单剂随机三交叉口服试验洛美沙星片和胶囊及参比胶囊４０ｍｇ后的药代动力学参数和相对生物利用度进行了比较。血、尿药浓度用ＨＰＬＣ柱切换样本直接进样法进行检测，按统计矩进行药代动力学分析。     

Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers

Purpose

Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices–compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development.

Single‐ and multiple‐dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects

Chemoattractant receptor‐homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G‐protein‐coupled receptor for prostaglandin D₂ (PGD₂), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single‐ and multiple‐dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double‐blind, placebo‐controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one‐dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single‐ and multiple‐dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single‐ and multiple‐dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half‐life between 10 and 18 h. Steady‐state conditions were reached after 2–3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry‐into‐human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders.     

Relative Oral Bioavailability of an Abuse-deterrent,Extended-release Formulation of Morphine Versus Extended-release Morphine: A 2-period,Single-dose,Randomized Crossover Study in Healthy Subjects

Purpose

Morphine ARER is a novel oral, abuse-deterrent, extended-release (ER) formulation of morphine sulfate with physical and chemical properties that deter misuse and abuse by nonoral routes of administration. Here we evaluate the relative bioavailability of morphine ARER and extended-release morphine.

Safety,Pharmacokinetics, and Pharmacodynamics Study in Healthy Subjects of Oral NEO6860, a Modality Selective Transient Receptor Potential Vanilloid Subtype 1 Antagonist

Most previous transient receptor potential vanilloid subtype 1 (TRPV1) antagonist programs have been put on hold, mainly because of on-target adverse events: hyperthermia and impaired noxious heat sensation. NEO6860 is a TRPV1 antagonist, blocking capsaicin activation of the target, with little or no effect against pH or heat activation. The hypothesis is that this pharmacological profile will translate into analgesia without undesired effects on the body temperature or heat-pain threshold. This phase I, double blind, placebo controlled, ascending dose study, included 64 subjects. Pharmacodynamics (intradermal capsaicin test) was explored. The study was comprised of 6 dose levels (50, 100, 200, 400, 800, and 1,200 mg) and 2 doses of 500 mg, 12 hours apart. NEO6860 was rapidly absorbed and systemic exposure increases were less than dose proportional. Median time of maximum observed plasma concentration values ranged from 2 to 3 hours. The mean apparent plasma terminal elimination half-life was between 4 and 8 hours. No significant food-effect or gender-effect was observed. The most frequently reported events were feeling hot, headache, paresthesia, nausea, and dizziness. Single oral doses of up to 800 mg and two 500-mg doses administered 12 hours apart of NEO6860 were well tolerated in this study. Unlike other TRPV1 antagonists, no clinically significant increase in temperature or heat pain threshold/tolerance was noted despite thorough and specific monitoring of these parameters. At all doses, most subjects reported a sensation of “feeling hot,” with a rapid onset and transient. NEO6860 showed an improvement in the pharmacodynamics parameters (evoked pain and secondary hyperalgesia) at 3 and 8 hours post NEO6860 dosing.

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

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

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

Background

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

Objective

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

Methods

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

Results

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

Conclusions

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

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

Background

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

Objective

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

Methods

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

Results

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

Conclusion

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

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.     

Pharmacokinetic Interaction Among Telmisartan,Amlodipine, and Hydrochlorothiazide After a Single Oral Administration in Healthy Male Subjects

PurposeHypertension is a major risk factor for cardiovascular diseases, necessitating hypertension control. Antihypertensive drugs are more potent when administered in combinations of 2 or 3 different classes of drugs. One such therapy includes a combination of an angiotensin receptor blocker, a calcium channel blocker, and a diuretic. The objective of this study was to evaluate the pharmacokinetic interaction among telmisartan, amlodipine, and hydrochlorothiazide.Methods: A randomized, open-label, 3-period, 6-sequence, 3-treatment, single-dose crossover study was conducted in healthy male subjects. Subjects were randomly assigned to 1 of 6 sequences and one of the following treatments was administered in each period: treatment A, co-administration of one tablet of telmisartan 80 mg and one tablet of amlodipine 10 mg; treatment B, one tablet of hydrochlorothiazide 25 mg alone; and treatment C, co-administration of all 3 investigational products. Serial blood samples were collected up to 144 hours postdose. Plasma drug concentrations were measured by using LC/MS–MS. Pharmacokinetic parameters, including C_max and AUC_0–last, were determined by using noncompartmental analysis. The geometric least squares mean ratios and associated 90% CIs of log-transformed C_max and AUC_0–last for separate administration or co-administration were calculated to evaluate pharmacokinetic interactions.FindingsTwenty-seven subjects completed the study. The geometric least squares mean ratios and 90% CIs of C_max and AUC_0–last were 1.02 (0.85–1.21) and 1.04 (0.97–1.13) for telmisartan; 1.00 (0.95–1.04) and 0.95 (0.91–0.99) for amlodipine; and 0.88 (0.82–0.96) and 0.86 (0.82–0.90) for hydrochlorothiazide, respectively. No serious adverse events were recorded, and all reported adverse events were of mild intensity.ImplicationsThe pharmacokinetic parameters of telmisartan, amlodipine, and hydrochlorothiazide when administered separately or co-administered were compared, and all the parameters met the criteria for pharmacokinetic equivalence. Combination therapy of these 3 drugs had no significant impact on the pharmacokinetic parameters of each drug. (ClinicalTrials.gov Identifier: NCT03889145)     

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

Background

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

Objective

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

Methods

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

Results

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

Conclusion

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

Pharmacokinetic 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.     

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

Background

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

Objective

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

Methods

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

Results

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

Conclusion

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

布洛芬混悬液在正常人体内的相对生物利用度和药代动力学

【目的】比较研究布洛芬混悬液和市售布洛芬片的生物利用度和药代动力学。【方法】选择８ 名健康男性志愿者,随机分为两组,进行单次混悬液或片剂交叉给药６００ ｍ ｇ 后,利用 Ｈ Ｐ Ｌ Ｃ 法测定血浆中布洛芬浓度。【结果】两组血浆的布洛芬浓度分别在（０ ．９２ ±０ ．３３） 和（１ ．６８ ±０ ．５１） ｈ 达到峰值（１３ ．８８ ±１ ．９２） 和（１１ ．０７ ±２ ．５１） μｇ／ｍｌ。血药浓度曲线下面积（ Ａ Ｕ Ｃ） 分别达（４７ ．７７ ±３ ．４６） 和（４５ ．２３ ±５ ．２１） μｇ／（ ｍｉｎ·ｍｌ） ,混悬液的相对生物利用度（ Ｆ） 为（１０５ ．６ ±１１ ．３） ％ 。【结论】布洛芬混悬液和市售布洛芬片两种制剂具有生物等效性。     

A Phase I Study to Show the Relative Bioavailability and Bioequivalence of Fixed-Dose Combinations of Ambrisentan and Tadalafil in Healthy Subjects

PurposePulmonary arterial hypertension (PAH) is a life-threatening disease that typically causes shortness of breath and exercise intolerance. Combination therapy with ambrisentan and tadalafil has proven to be more effective at preventing clinical failure events in patients with PAH than either drug alone. The aim of this study was to evaluate the bioequivalence of an ambrisentan/tadalafil fixed-dose combination (FDC) compared with co-administration of the 2 monotherapies.MethodsThis 3-part, randomized, single-dose, open-label crossover study was conducted in healthy volunteers. The first part of the study consisted of a 5-way crossover that compared the relative bioavailability of 4 FDC formulations (10-mg ambrisentan + 40-mg tadalafil) with co-administered reference monotherapies. One formulation was selected and its relative bioavailability was assessed when produced in 3 different granulation sizes during the second part of the study. In the third part of the study, the bioequivalence of the candidate FDC with the reference monotherapies was evaluated for the 10-mg/40-mg dose strength, in addition to 2 other dose strengths (5 mg/20 mg and 5 mg/40 mg). For all parts of the study, blood samples were taken at regular intervals after each dose, ambrisentan and tadalafil concentrations determined, and pharmacokinetic (PK) parameters (C_max, AUC_0–∞, and AUC_0–t) obtained. Test/reference ratios of the geometric means of PK parameters were used to evaluate bioequivalence. Safety and tolerability were assessed by recording adverse events and monitoring vital signs, ECGs, and clinical laboratory data.FindingsOf the 174 subjects screened for eligibility, 112 were allocated to a randomized treatment sequence across all study parts, and 100 completed their full assigned treatments. All 4 FDC formulations tested during part 1 of the study yielded PK parameters similar those of the reference treatments. In part 2, granulation size was found to not affect the relative bioavailability of the selected formulation. In part 3, the selected FDC was found to be bioequivalent to co-administration of the monotherapies in both the fasted and fed states. The FDC was also found to be bioequivalent to the reference treatments at the 2 additional dose strengths. All but one of the adverse events was mild to moderate in intensity, and no serious adverse events were reported.ImplicationsAn ambrisentan/tadalafil FDC was bioequivalent to concurrently administered monotherapies and therefore represents a viable alternative treatment to co-administration. Use of an FDC is likely to be associated with reduced costs and improved patient compliance. ClinicalTrials.gov identifier: NCT02688387.     

Tolerability,Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin,a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration

BackgroundHenagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus.PurposeTo evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers.MethodsTwo clinical studies were conducted. One was a single ascending dose (SAD) study (2.5–200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25–100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies.FindingsNo serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a T_max of 1.5–3 h, and then eliminated from plasma with a half-life of 11–15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5–200 mg (SAD) and 1.25–100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%–5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration.ImplicationsHenagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.     

Comparative Pharmacokinetics of a Controlled-release Pregabalin Tablet (GLA5PR GLARS-NF1) and an Immediate-release Pregabalin Capsule in Healthy Male Volunteers

Purpose

Pregabalin is a widely used drug for the management of neuropathic pain. This study compared the pharmacokinetics of the GLA5PR GLARS-NF1 tablet, a 150-mg controlled-release formulation of pregabalin taken once daily, with those of a 75-mg immediate-release (IR) capsule formulation of pregabalin taken twice daily with a 12-h interval between doses.

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

Purpose

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

乳酸左氧氟沙星片剂的健康人体药代动力学和相对生物利用度研究

目的:研究乳酸左旋氧氟沙星片剂的健康人体药代动力学和相对生物利用度。方法:18名健康受试者单次,交叉口服乳酸左旋氧氟沙星片200 mg后,用HPLC-荧光法测定血浆中左氧氟沙星浓度,用BAPP2.0软件进行数据处理,计算药代动力学参数。结果:供试与参比制剂的药时曲线可用二室模型拟合,两者主要药代动力学参数Cmax分别为(2.92±0.60)μg/mL(、3.22±0.53)μg/mL;Tmax分别为(0.9±0.3)h(、0.9±0.3)h;t1/2分别为(7.27±1.02)h、(6.83±0.80)h;AUC0~24分别为(17.18±2.46)μg/(mL.h)(、17.19±2.55)μg/(mL.h),乳酸左氧氟沙星片供试制剂的相对生物利用度为(100.3±9.4)%。结论:供试与参比制剂具有生物等效性。     

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.