Bioavailability of Amoxicillin Dissolved in Human Milk

• Sponsor: The Hospital for Sick Children (Other)
• Overall Status: Completed
• CT.gov ID: NCT01435824
• Collaborator: World Health Organization (Other)
• Enrollment: 16
• Location: 1
• Arms: 2
• Duration (Months): 28
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Human milk-dissolved amoxicillin; Drug: Water-dissolved amoxicillin	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: 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.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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bioavailability of Amoxicillin Dissolved in Human Milk: An Adult Volunteer Study as a First Step Towards Defining Drug Doses for Infants
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Water as a vehicle of amoxicillin Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state.	Drug: Water-dissolved amoxicillin; 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.; Other Names: Novamoxin 250 from Novopharm, Toronto, Canada: Lot#35422063A
Experimental: Human milk as a vehicle of amoxicillin Amoxicillin 500 mg was dissolved in 10 ml human milk and orally administered in a fasting state.	Drug: 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.; Other Names: Novamoxin 250 from Novopharm, Toronto, Canada: Lot#35422063A Frozen human milk was obtained from the Mother's Milk Bank of Ohio (USA)

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve to Time Infinity (AUC to Time Infinity) [Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing]

   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.

2. Area Under the Curve to 8h (AUC Last) [Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing]

   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).

3. Cmax [0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing]

   A maximum plasma concentration of amoxicillin within the time frame of a dosing

4. Tmax [Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.]

   Time to reach Cmax after administration

Secondary Outcome Measures

1. Elimination Half-life [Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.]

   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.

2. Clearance/F [Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.]

   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.

3. Volume of Distribution/F [Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy adult volunteers (>18 and <60 years old)

2. An approximate 50% of the volunteers will be female

3. Body mass index (BMI) within 18.5 to 29.9 kg/m2

4. Healthy according to medical history, vital signs and a brief physical examination as determined by the principal investigator/Sub-investigators.

5. 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.

6. Capable of giving written informed consent prior to receiving study medication

7. Smoking is not an exclusion criterion but we will identify smokers.

8. Female participants will be required to fulfill at least one of the following:

• Agree to avoid pregnancy and use medically acceptable method of contraception from at least 30 days prior to the study, during the study, and until 30 days after to the study has ended (last study procedure). Medically acceptable methods of contraception include hormonal patch, implant or injection intrauterine device, or double barrier method (condom with foam or vaginal spermicidal suppository, diaphragm with spermicidal). Complete abstinence alone can be used as a method of contraception. Oral contraceptives prior to the study are acceptable as a method of contraception, but an alternative method of contraception will be required during the study and after the study has ended.

• Be surgically sterile for a minimum of 6 months

• Post menopausal for a minimum of 1 year.

Exclusion Criteria:

1. 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

2. History of any clinically significant illness within 30 days prior to dosing

3. History of any significant physical or organ abnormality

4. Known history of:

• Alcohol abuse or dependence within one year prior to drug administration

• Drug abuse or dependence

• Food allergies and/or presence of any dietary restrictions

• Severe allergic reactions (e.g. anaphylactic reactions, angioedema)

1. Participation in another clinical trial or receiving an investigational drug within 30 days of the study commencement or during the study

2. Use of any prescription medication within 14 days prior to drug administration (except for hormonal contraceptives)

3. 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)

4. Any major surgery within 6 months prior to the start of the study

5. History of allergy to amoxicillin, beta-lactams or amoxicillin excipients

6. History of allergy to milk, or severe lactose intolerance

7. Pregnancy or lactating

8. Conditions associated with malabsorption

9. Taking any form of antacids as they may increase the risk of orally transmitted viruses from human milk.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Hospital for Sick Children	Toronto	Ontario	Canada	M5V1X8

Sponsors and Collaborators

• The Hospital for Sick Children
• World Health Organization

Investigators

• Principal Investigator: Shinya Ito, MD, The Hospital for Sick Children

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to published study results

Publications

None provided.

• Responsible Party: Shinya Ito, Division Head, Clinical Pharmacology and Toxicology, The Hospital for Sick Children
• ClinicalTrials.gov Identifier: NCT01435824
• Other Study ID Numbers: 1000021187
• First Posted: Sep 19, 2011
• Last Update Posted: Jan 21, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by Shinya Ito, Division Head, Clinical Pharmacology and Toxicology, The Hospital for Sick Children: healthy adult volunteers; comparative bioavailability; amoxicillin; breast milk; Amoxicillin Bioavailability in breast milk
• Additional relevant MeSH terms: Amoxicillin

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Water-based First, Then Milk-based Administration	Milk-based First, and Then Water-based Drug Administration
Arm/Group Description	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.	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. .
Period Title: First Intervention
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	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.
Overall Participants	16
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.3 (9.0)
Sex: Female, Male (Count of Participants)
Female	8 50%
Male	8 50%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
Canada	16 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	167.6 (12.3)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	67.1 (14.3)

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve to Time Infinity (AUC to Time Infinity)
Description	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.
Time Frame	Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Water as a Vehicle of Amoxicillin	Human Milk as a Vehicle of Amoxicillin
Arm/Group Description	Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. Water-dissolved amoxicillin: 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.	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.
Measure Participants	16	16
Mean (Standard Deviation) [mcg*min/mL]	1394.1 (256.1)	1477.2 (260.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Water as a Vehicle of Amoxicillin, Human Milk as a Vehicle of Amoxicillin
	Comments	A 2x2 crossover design was chosen to examine bioequivalence of milk-based amoxicillin preparation, based on the FDA-recommended design for bioavailability studies. The recommendation suggests that 12 subjects is the minimum number of subjects acceptable for this type of design. We have decided to enrol 16 subjects to account for problems or attrition.
	Type of Statistical Test	Equivalence
	Comments	Bioequivalence is assessed by means of ratios of AUC, Cmax and Tmax between the comparison group and the reference group. According to a common regulatory definition, the comparison preparation (human milk-dissolved amoxicillin in this project) is considered bioequivalent to a standard preparation (water dissolved) if 90% CIs of these ratios between the two preparations for Cmax, Tmax, AUClast and AUC∞ are within a range between 0.80 and 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	mean %ratio and 90% confidence interval
	Estimated Value	106.1
	Confidence Interval	(2-Sided) 90%; 97.5 to 115.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Area Under the Curve to 8h (AUC Last)
Description	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).
Time Frame	Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Water as a Vehicle of Amoxicillin	Human Milk as a Vehicle of Amoxicillin
Arm/Group Description	Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. Water-dissolved amoxicillin: 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.	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.
Measure Participants	16	16
Mean (Standard Deviation) [mcg*min/mL]	1355.8 (254.2)	1435.0 (241.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Water as a Vehicle of Amoxicillin, Human Milk as a Vehicle of Amoxicillin
	Comments	A 2x2 crossover design was chosen to examine bioequivalence of milk-based amoxicillin preparation, based on the FDA-recommended design for bioavailability studies. The recommendation suggests that 12 subjects is the minimum number of subjects acceptable for this type of design. We have decided to enrol 16 subjects to account for problems or attrition.
	Type of Statistical Test	Equivalence
	Comments	Bioequivalence is assessed by means of ratios of AUC, Cmax and Tmax between the comparison group and the reference group. According to a common regulatory definition, the comparison preparation (human milk-dissolved amoxicillin in this project) is considered bioequivalent to a standard preparation (water dissolved) if 90% CIs of these ratios between the two preparations for Cmax, Tmax, AUClast and AUC∞ are within a range between 0.80 and 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	mean %ratio and 90% confidence interval
	Estimated Value	106.2
	Confidence Interval	(2-Sided) 90%; 97.5 to 115.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Cmax
Description	A maximum plasma concentration of amoxicillin within the time frame of a dosing
Time Frame	0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Water as a Vehicle of Amoxicillin	Human Milk as a Vehicle of Amoxicillin
Arm/Group Description	Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. Water-dissolved amoxicillin: 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.	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.
Measure Participants	16	16
Mean (Standard Deviation) [ng/ml]	8653.8 (2217.6)	8690.6 (1972.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Water as a Vehicle of Amoxicillin, Human Milk as a Vehicle of Amoxicillin
	Comments	A 2x2 crossover design was chosen to examine bioequivalence of milk-based amoxicillin preparation, based on the FDA-recommended design for bioavailability studies. The recommendation suggests that 12 subjects is the minimum number of subjects acceptable for this type of design. We have decided to enrol 16 subjects to account for problems or attrition.
	Type of Statistical Test	Equivalence
	Comments	Bioequivalence is assessed by means of ratios of AUC, Cmax and Tmax between the comparison group and the reference group. According to a common regulatory definition, the comparison preparation (human milk-dissolved amoxicillin in this project) is considered bioequivalent to a standard preparation (water dissolved) if 90% CIs of these ratios between the two preparations for Cmax, Tmax, AUClast and AUC∞ are within a range between 0.80 and 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	mean %ratio and 90% confidence interval
	Estimated Value	101.3
	Confidence Interval	(2-Sided) 90%; 89.4 to 114.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Tmax
Description	Time to reach Cmax after administration
Time Frame	Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Water as a Vehicle of Amoxicillin	Human Milk as a Vehicle of Amoxicillin
Arm/Group Description	Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. Water-dissolved amoxicillin: 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.	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.
Measure Participants	16	16
Mean (Standard Deviation) [min]	101.3 (52.4)	106.9 (49.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Water as a Vehicle of Amoxicillin, Human Milk as a Vehicle of Amoxicillin
	Comments	A 2x2 crossover design was chosen to examine bioequivalence of milk-based amoxicillin preparation, based on the FDA-recommended design for bioavailability studies. The recommendation suggests that 12 subjects is the minimum number of subjects acceptable for this type of design. We have decided to enrol 16 subjects to account for problems or attrition.
	Type of Statistical Test	Equivalence
	Comments	Bioequivalence is assessed by means of ratios of AUC, Cmax and Tmax between the comparison group and the reference group. According to a common regulatory definition, the comparison preparation (human milk-dissolved amoxicillin in this project) is considered bioequivalent to a standard preparation (water dissolved) if 90% CIs of these ratios between the two preparations for Cmax, Tmax, AUClast and AUC∞ are within a range between 0.80 and 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	mean %ratio and 90% confidence interval
	Estimated Value	107.9
	Confidence Interval	(2-Sided) 90%; 84.5 to 137.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Elimination Half-life
Description	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.
Time Frame	Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Water as a Vehicle of Amoxicillin	Human Milk as a Vehicle of Amoxicillin
Arm/Group Description	Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. Water-dissolved amoxicillin: 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.	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.
Measure Participants	16	16
Mean (Standard Deviation) [min]	77.7 (17)	76.1 (11.7)

6. Secondary Outcome

Title	Clearance/F
Description	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.
Time Frame	Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Water as a Vehicle of Amoxicillin	Human Milk as a Vehicle of Amoxicillin
Arm/Group Description	Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. Water-dissolved amoxicillin: 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.	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.
Measure Participants	16	16
Mean (Standard Deviation) [ml/kg/min]	5.63 (1.05)	5.34 (1.22)

7. Secondary Outcome

Title	Volume of Distribution/F
Description	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.
Time Frame	Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Water as a Vehicle of Amoxicillin	Human Milk as a Vehicle of Amoxicillin
Arm/Group Description	Amoxicillin 500 mg was dissolved in 10 ml water and orally administered in a fasting state. Water-dissolved amoxicillin: 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.	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.
Measure Participants	16	16
Mean (Standard Deviation) [l/kg]	0.63 (0.18)	0.59 (0.16)

Adverse Events

Time Frame	1 week
Arm/Group Title	Water-based Amoxicillin Administration		Human Milk-based Amoxicillin Administration
Arm/Group Description	Amoxicillin was dissolved in water and administered for PK sampling.		Amoxicillin was dissolved in human milk and administered for PK sampling.
All Cause Mortality
	Water-based Amoxicillin Administration		Human Milk-based Amoxicillin Administration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)
Serious Adverse Events
	Water-based Amoxicillin Administration		Human Milk-based Amoxicillin Administration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Water-based Amoxicillin Administration		Human Milk-based Amoxicillin Administration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)

Limitations/Caveats

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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.