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| Name | Class |
|---|---|
| World Health Organization | OTHER |
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The investigators propose to study amoxicillin absorption in a 2-stage program that will progressively produce, for the first time, information leading to pediatric pharmacology recommendations for the administration to children of amoxicillin dissolved in human milk. The investigators study will enroll adult volunteers as number of blood extractions, volume of blood required and subject availability, among other issues, generate a number of ethical and logistical constraints that make it almost impossible to carry such an intensive sampling study in infants.
As recommended by the Expert Committee on Selection and Use of Essential Medicines, WHO (http://www.who.int/selection\_medicines/committees/en/index.html), oral solid formulations are the preferred forms of medicines for children, especially in developing countries, because of relatively inexpensive and less complicated manufacturing, transporting and storage processes. Whereas solid dosage forms are advantageous in these pharmaceutical logistics, administering solid formulations to infants and children is a challenging issue. Dissolving medicines in water may be acceptable, but safety of drinking water for infants in developing countries and water solubility of the drug itself are major concerns. These challenges are exemplified in the treatment of infectious diseases and diarrhea in infants. Commonly used drugs for infants in low income settings include antibiotics such as amoxicillin. Expert sources have suggested that drug administration in breast milk may be effective. However, little data is currently available to support the recommendation to administer medications dissolved in breast milk to infants.
The second stage of the project will use the information obtained from the first stage, combined with pre-existing data, to define a rational dosing schedule of the target drug dissolved in human milk for young children, using population PK modeling and simulation. This is a study in silico.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Water as a vehicle of amoxicillin | Active Comparator | Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. |
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| Human milk as a vehicle of amoxicillin | Experimental | Amoxicillin 500 mg was dissolved in 10 ml human milk and orally administered in a fasting state. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Human milk-dissolved amoxicillin | Drug | An amoxicillin suspension bottle containing 5 grams of amoxicillin (powder) will be resuspended in 60 ml of breast milk to have 100mL of a 50mg/mL suspension. |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Curve to Time Infinity (AUC to Time Infinity) | Amoxicillin plasma concentrations were determined by HPLC-MS/MS and AUC∞ (to time infinity) was estimated using a model-independent approach. Specifically, the log-trapezoidal method was used to calculate AUC last (AUC from time 0 to 8 h), and AUC∞ was further estimated with the elimination rate constant (Kel) of the terminal log-linear phase (β phase) of the concentration time profile extrapolating to time infinity as follows: AUC∞ = AUC last + [C]8h/Kel; where [C]8h is the plasma concentration at time 8 h postdose. | Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing |
| Area Under the Curve to 8h (AUC Last) | Amoxicillin plasma concentrations were determined by HPLC-MS/MS and PK parameters were estimated using a model-independent approach. Specifically, the log-trapezoidal method was used to calculate AUC last (AUC from time 0 to 8 h). | Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing |
| Cmax | A maximum plasma concentration of amoxicillin within the time frame of a dosing | 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing |
| Tmax | Time to reach Cmax after administration | Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
| Measure | Description | Time Frame |
|---|---|---|
| Elimination Half-life | Elimination rate constant (Kel) was estimated from the terminal log-linear phase of the concentration-time profiles. Then, elimination half-life was calculated as follows: ln2/Kel. | Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
| Clearance/F |
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Inclusion Criteria:
Healthy adult volunteers (>18 and <60 years old)
An approximate 50% of the volunteers will be female
Body mass index (BMI) within 18.5 to 29.9 kg/m2
Healthy according to medical history, vital signs and a brief physical examination as determined by the principal investigator/Sub-investigators.
Systolic blood pressure between 100-140 mmHg, inclusive and diastolic blood pressure between 60-90 mmHg, inclusive, and heart rate between 50-100 bpm, unless deemed not clinically significant by the principal investigator/Sub- investigators.
Capable of giving written informed consent prior to receiving study medication
Smoking is not an exclusion criterion but we will identify smokers.
Female participants will be required to fulfill at least one of the following:
Exclusion Criteria:
Known history of any clinically significant hepatic (e.g. hepatic necrosis, jaundice, hepatobiliary disease), renal, gastrointestinal (e.g. peptic ulcer), cardiovascular (e.g. angina, myocardial infarction), cerebrovascular, pulmonary, endocrine (e.g. diabetes, hypophosphatemia), immunological, musculoskeletal (e.g. rhabdomyolysis, myopathy), neurological, psychiatric, dermatological, or haematological disease or condition
History of any clinically significant illness within 30 days prior to dosing
History of any significant physical or organ abnormality
Known history of:
Participation in another clinical trial or receiving an investigational drug within 30 days of the study commencement or during the study
Use of any prescription medication within 14 days prior to drug administration (except for hormonal contraceptives)
Use of any over the counter medications )including herbal and/or dietary supplements and/or teas) within 24 hrs prior to drug administration (except for spermicidal/barrier contraceptive products)
Any major surgery within 6 months prior to the start of the study
History of allergy to amoxicillin, beta-lactams or amoxicillin excipients
History of allergy to milk, or severe lactose intolerance
Pregnancy or lactating
Conditions associated with malabsorption
Taking any form of antacids as they may increase the risk of orally transmitted viruses from human milk.
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| Name | Affiliation | Role |
|---|---|---|
| Shinya Ito, MD | The Hospital for Sick Children | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Hospital for Sick Children | Toronto | Ontario | M5V1X8 | Canada |
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| Label | URL |
|---|---|
| Link to published study results | View source |
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Participants were interviewed and underwent basic vital sign checking, and filled health status questionnaire to declare lack of any significant medical conditions. Urine pregnancy tests, with consents, were performed before dosing for female participants.Wash-out period between water and human milk phases was 1-2 weeks.
Healthy young adults were enrolled. 16 individuals were assessed and randomly assigned to either "water-based first, then milk-based amoxicillin administration" or "milk-based first and then water-based administration" arms. The washout period was 1-2 weeks. The study was conducted at Hospital for Sick Children in Toronto, Canada.
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| ID | Title | Description |
|---|---|---|
| FG000 | Water-based First, Then Milk-based Administration | First, participants were orally given 10 mL of water-dissolved amoxicillin (50mg/mL) in a fasting state. A PK sampling was performed. The washout period was for 1-2 weeks and then participants underwent the milk-based administration of amoxicillin, followed by PK sampling. |
| FG001 | Milk-based First, and Then Water-based Drug Administration | First, participants were orally given 10 mL of human milk-dissolved amoxicillin (50mg/mL) in fasting state, followed by PK sampling. The washout period was for 1-2 weeks and then participants underwent a water-based administration if amoxicillin followed by PK sampling. . |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
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| Washout of 1-2 Weeks |
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| Second Intervention |
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | This study was designed as a randomized 2x2 crossover single-dose study where participants either given water-dissolved amoxicillin first or human milk-dissolved amoxicillin first switched over during period 2. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Curve to Time Infinity (AUC to Time Infinity) | Amoxicillin plasma concentrations were determined by HPLC-MS/MS and AUC∞ (to time infinity) was estimated using a model-independent approach. Specifically, the log-trapezoidal method was used to calculate AUC last (AUC from time 0 to 8 h), and AUC∞ was further estimated with the elimination rate constant (Kel) of the terminal log-linear phase (β phase) of the concentration time profile extrapolating to time infinity as follows: AUC∞ = AUC last + [C]8h/Kel; where [C]8h is the plasma concentration at time 8 h postdose. | Posted | Mean | Standard Deviation | mcg*min/mL | Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing |
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1 week
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Water-based Amoxicillin Administration | Amoxicillin was dissolved in water and administered for PK sampling. |
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Participants ingested amoxicillin dissolved in 10 mL of milk or water. We cannot rule out that larger volumes of milk can change absorption profile of the drug.
PK parameters in adults may be different from those reported in neonates and infants.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Shinya Ito | The Hospital for Sick Children | 416-813-5776 | 205776 | shinya.ito@sickkids.ca |
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Participants underwent 2 arms in a cross-over design: 1 ) amoxicillin disolved in water; and 2) amoxicillin dissolved in human milk. The order of the 2 arms were randomized.
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| Water-dissolved amoxicillin | Drug | An amoxicillin suspension bottle containing 5 grams of amoxicillin (powder) will be resuspended in 60 ml of water to have 100mL of a 50mg/mL suspension. |
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The log-trapezoidal method was used to calculate AUC last (AUC from time 0 to 8 h), and AUC∞ was estimated using an elimination rate constant (Kel) of the terminal log-linear phase (β phase) of the concentration time profile extrapolating to time infinity. Then, CL/F was derived from Dose/AUC∞. F is bioavailability, which cannot be determined in this study, and therefore, we estimate CL/F, but not CL itself. |
| Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
| Volume of Distribution/F | It was estimated from (Clearance/F)/Kel. Elimination rate constant (Kel) was estimated from the terminal log-linear phase of the concentration-time profiles. Then, elimination half-life was calculated as follows: ln2/Kel. | Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
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| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Height | Mean | Standard Deviation | cm |
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| Weight | Mean | Standard Deviation | kg |
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| OG001 | Human Milk as a Vehicle of Amoxicillin | Amoxicillin 500 mg was dissolved in 10 ml human milk and orally administered in a fasting state. Human milk-dissolved amoxicillin: An amoxicillin suspension bottle containing 5 grams of amoxicillin (powder) will be resuspended in 60 ml of breast milk to have 100mL of a 50mg/mL suspension. |
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| Primary | Area Under the Curve to 8h (AUC Last) | Amoxicillin plasma concentrations were determined by HPLC-MS/MS and PK parameters were estimated using a model-independent approach. Specifically, the log-trapezoidal method was used to calculate AUC last (AUC from time 0 to 8 h). | Posted | Mean | Standard Deviation | mcg*min/mL | Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing |
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| Primary | Cmax | A maximum plasma concentration of amoxicillin within the time frame of a dosing | Posted | Mean | Standard Deviation | ng/ml | 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing |
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| Primary | Tmax | Time to reach Cmax after administration | Posted | Mean | Standard Deviation | min | Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
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| Secondary | Elimination Half-life | Elimination rate constant (Kel) was estimated from the terminal log-linear phase of the concentration-time profiles. Then, elimination half-life was calculated as follows: ln2/Kel. | Posted | Mean | Standard Deviation | min | Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
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| Secondary | Clearance/F | The log-trapezoidal method was used to calculate AUC last (AUC from time 0 to 8 h), and AUC∞ was estimated using an elimination rate constant (Kel) of the terminal log-linear phase (β phase) of the concentration time profile extrapolating to time infinity. Then, CL/F was derived from Dose/AUC∞. F is bioavailability, which cannot be determined in this study, and therefore, we estimate CL/F, but not CL itself. | Posted | Mean | Standard Deviation | ml/kg/min | Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
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| Secondary | Volume of Distribution/F | It was estimated from (Clearance/F)/Kel. Elimination rate constant (Kel) was estimated from the terminal log-linear phase of the concentration-time profiles. Then, elimination half-life was calculated as follows: ln2/Kel. | Posted | Mean | Standard Deviation | l/kg | Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing. |
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| 0 |
| 16 |
| 0 |
| 16 |
| 0 |
| 16 |
| EG001 | Human Milk-based Amoxicillin Administration | Amoxicillin was dissolved in human milk and administered for PK sampling. | 0 | 16 | 0 | 16 | 0 | 16 |
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