Bioavailability of Amoxicillin Dissolved in Human Milk

January 15, 2020 updated by: Shinya Ito, The Hospital for Sick Children

Bioavailability of Amoxicillin Dissolved in Human Milk: An Adult Volunteer Study as a First Step Towards Defining Drug Doses for Infants

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5V1X8
        • The Hospital for Sick Children

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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)
  5. Participation in another clinical trial or receiving an investigational drug within 30 days of the study commencement or during the study
  6. Use of any prescription medication within 14 days prior to drug administration (except for hormonal contraceptives)
  7. 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)
  8. Any major surgery within 6 months prior to the start of the study
  9. History of allergy to amoxicillin, beta-lactams or amoxicillin excipients
  10. History of allergy to milk, or severe lactose intolerance
  11. Pregnancy or lactating
  12. Conditions associated with malabsorption
  13. Taking any form of antacids as they may increase the risk of orally transmitted viruses from human milk.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Area Under the Curve to Time Infinity (AUC to Time Infinity)
Time Frame: 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.
Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing
Area Under the Curve to 8h (AUC Last)
Time Frame: 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).
Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing
Cmax
Time Frame: 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
0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing
Tmax
Time Frame: 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
Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Elimination Half-life
Time Frame: 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.
Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.
Clearance/F
Time Frame: 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.
Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.
Volume of Distribution/F
Time Frame: 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.
Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Hospital for Sick Children

Collaborators

World Health Organization

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2011

Primary Completion (Actual)

September 1, 2013

Study Completion (Actual)

October 1, 2013

Study Registration Dates

First Submitted

September 15, 2011

First Submitted That Met QC Criteria

September 16, 2011

First Posted (Estimate)

September 19, 2011

Study Record Updates

Last Update Posted (Actual)

January 21, 2020

Last Update Submitted That Met QC Criteria

January 15, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1000021187

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Healthy

Clinical Trials on Water-dissolved amoxicillin

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Italy

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe