The Effect of Food on the Pharmacokinetics of Metformin Given Either as Metformin Hydrochloride SR 1000mg Tablet or as a Fixed Dose Combination of Metformin Hydrochloride SR 1000mg/Glimepiride 2mg Tablet in Healthy Indian Volunteers.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 30
- 主要终点
- Maximum Observed Concentration (Cmax)
研究概览
简要总结
Metformin hydrochloride in its immediate release (IR) form has been successfully used for decades in the treatment of type 2 diabetes; however the IR formulation may be associated with gastrointestinal side effects (especially nausea, diarrhea) in 20-30% patients, which can limit the tolerated dose, reduce adherence and result in discontinuation of therapy. Metformin hydrochloride extended release formulations have been developed to overcome these problems. In India, extended release formulations of metformin hydrochloride include metformin SR 1000mg tablet and combination of metformin hydrochloride SR 1000mg/glimepiride 2mg tablet. In the combination tablet, only metformin hydrochloride is in the extended release form. In view of the fact that extended release metformin hydrochloride is usually recommended with a meal, that food is known to affect the pharmacokinetic (PK) parameters of metformin and that there is a potential for dose dumping with extended release formulations that may lead to side effects similar to IR formulations, a study to estimate the magnitude of the food effect for these formulations in fed state compared to the fasting state is warranted. This study will be a randomized, single-center, open-label, single-dose, three-period, 6 sequence crossover study in 30 healthy adult volunteers to estimate the bioavailability of metformin from metformin hydrochloride 1000mg SR tablet given in fasting condition relative to metformin hydrochloride 1000mg SR tablet and a fixed dose combination of metformin hydrochloride 1000mg SR /glimepiride 2mg tablet, each given in fed condition. The safety and tolerability profile of metformin SR 1000mg tablet and metformin hydrochloride SR 1000mg/glimepiride 2mg tablet will also be evaluated in this study. The primary PK endpoints will be Cmax and AUC (0-∞). The secondary PK endpoints will include AUC (0-t), Tmax , T lag, Kel and t1/2. Safety endpoints will include vital signs, ECG, physical examination, clinical laboratory tests and adverse event reporting.
详细描述
Background:
Metformin hydrochloride, a biguanide, is an effective treatment for type 2 diabetes, lowering both basal and postprandial hyperglycemia either as monotherapy or in combination with other antihyperglycemic drugs. Metformin hydrochloride in its immediate release form (IR) has been used for decades in the treatment of type 2 diabetes. An IR formulation releases the entire drug within 1-2 h after dosing, resulting in high drug concentrations in the GI (gastrointestinal) tract which may be associated with GI side effects (especially nausea, diarrhea) in 20-30% patients. This can limit the tolerated dose, reduce adherence and result in discontinuation of therapy. In addition, the frequent need to administer metformin two or three times daily may also not support good adherence to therapy.
Metformin hydrochloride extended release (ER) formulations have been developed to overcome these problems. Because metformin gets absorbed in the first part of the small intestine, extended release metformin hydrochloride formulations employ various novel gastric-retentive techniques. The polymeric matrix (hydroxyl propyl methyl cellulose) of the extended release metformin tablet is designed to swell in the gastric fluid. As the matrix swells, it becomes resistant to peristalsis and is more easily retained in the stomach. Gastric fluid penetrates the matrix, dissolving the drug which then diffuses out of the matrix in the liquefied form. Metformin hydrochloride is thus slowly released from the matrix of the tablet and is absorbed when this gastric fluid passes through the small intestine. The slow release of the drug in the GI tract permits once daily dosing and also reduces the incidence of nausea (6.5%) and diarrhea (9.6%). These factors are particularly relevant for increasing treatment adherence to long term therapies like anti-diabetic medication.
Glimepiride, a new generation sulphonylurea, in doses of 1-8mg/day, is an effective treatment option for non-insulin dependent diabetes mellitus (NIDDM) patients. Oral bioavailability is approximately 100% and the absence of a food interaction guarantees highly reproducible pharmacokinetics with this drug. A combination tablet formulation of sustained release metformin hydrochloride and glimepiride is beneficial in terms of convenience of administration and patient compliance.
Metformin hydrochloride extended-release formulation should generally be given once daily with the evening meal. Administration with food increases the bioavailability of metformin hydrochloride. Food increases the extent of absorption (AUC) of metformin hydrochloride (AUC 13306 ng h/ml with high fat breakfast, AUC 10200 ng h/ml with a low fat breakfast, AUC 7506 ng h/ml in fasting condition). Food can either cause no change or an increase in Cmax of the drug. One study has reported no effect of food on the Cmax of metformin [high fat meal (1018 ng/ml), low fat meal (992 ng/ml) and fasting condition (1022 ng/ml)]. In contrast, in a healthy volunteer study with Glucophage SR 1000mg, food increased the extent of absorption (AUC) by 77%, peak plasma concentration (Cmax) by 26% and prolonged time to peak plasma concentration (Tmax) by about 1 hour as compared to the fasting state.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, 12 lead ECG and chest-x-ray. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Medical Investigator agrees that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- •Males between 18 and 50 years of age (both inclusive), who are willing to participate in the study and provide a written signed and dated informed consent.
- •Body weight more than or equal to 60 kg and BMI within the range 18.5-24.9 kg/m2 (inclusive).
- •Availability of a study volunteer for the entire study period and willingness to adhere to protocol requirements as evidenced by written informed consent.
排除标准
- •A positive pre-study urine drug screen.
- •A positive test for HIV antibody.
- •Subject has clinically significant abnormal values of laboratory parameters.
- •Regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits (CTRI, 2010).
- •The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
- •Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.
- •History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator contraindicates their participation.
- •Where participation in another study would result in donation of blood or blood products in excess of 350 ml within a 90 day period prior to this study.
- •Unwillingness or inability to follow the procedures outlined in the protocol.
- •Subject is mentally or legally incapacitated or the subject is incapable of understanding the informed consent.
- •Subject has any evidence of impaired renal, hepatic, cardiac, lung or gastrointestinal function. Study volunteers with a history of tuberculosis, epilepsy, asthma (during past 5 years), diabetes, psychosis or glaucoma will not be eligible for the study.
- •History of sensitivity to heparin or heparin-induced thrombocytopenia.
- •Regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
- •Subject is intolerant to venipuncture.
- •Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice [and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices] from 7 days prior to the first dose of study medication.
研究组 & 干预措施
Metformin hydrochloride prolonged release
1000mg in fasting state
干预措施: metformin hydrochloride prolonged release (Drug)
metformin hydrochloride prolonged release
1000mg In fed state
干预措施: metformin hydrochloride prolonged release (Drug)
Metformin hydrochloride sustained release/Glimepiride
1000/2mg In fed state
干预措施: Metformin hydrochloride sustained release/Glimepiride (Drug)
结局指标
主要结局
Maximum Observed Concentration (Cmax)
时间窗: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing
Pharmacokinetic (PK) blood samples for estimation of Cmax were collected at 0.0 (pre-dose) and 0.5,1,2,2.5,3,3.5,4,4.5,5,6,7,8,10, 12, 16,24 and 30 hours after dosing. Point estimates and corresponding 90% confidence interval was constructed for the ratio of the geometric mean of the test treatment (fed condition) to the geometric mean of the reference treatment (fasting condition).
Area Under Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC (0-infinity)]
时间窗: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing
PK blood samples for estimation of AUC (0-infinity) were collected at 0.0 (pre-dose) and 0.5,1,2,2.5,3,3.5,4,4.5,5,6,7,8,10, 12, 16,24 and 30 hours after dosing. Point estimates and corresponding 90% confidence interval was constructed for the ratio of the geometric mean of the test treatment (fed condition) to the geometric mean of the reference treatment (fasting condition).
次要结局
- PK Lag Time (Tlag)(0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing)
- Time of Occurrence of Cmax (Tmax)(0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing)
- Elimination Constant (Kel)(0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing)
- AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments [AUC (0-t)](0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing)
- Terminal Phase Half Life (t1/2)(0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing)
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to approximately 24 days (during treatment and washout) after initiation of study)