Healthy
Conditions
Keywords
healthy adult volunteers, comparative bioavailability, amoxicillin, breast milk, Amoxicillin Bioavailability in breast milk
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.
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.
Interventions
DRUGHuman 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.
DRUGWater-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.
Sponsors
World Health Organization
The Hospital for Sick Children
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
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) 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Canada
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Entire Study Population | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 16 Participants | — |
| Age, Continuous | 36.3 years STANDARD_DEVIATION 9 | — |
| Height | 167.6 cm STANDARD_DEVIATION 12.3 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Canada | 16 participants | — |
| Sex: Female, Male Female | 8 Participants | — |
| Sex: Female, Male Male | 8 Participants | — |
| Weight | 67.1 kg STANDARD_DEVIATION 14.3 | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 0 / 16 | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
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).
Time frame: Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Water as a Vehicle of Amoxicillin | Area Under the Curve to 8h (AUC Last) | 1355.8 mcg*min/mL | Standard Deviation 254.2 |
| Human Milk as a Vehicle of Amoxicillin | Area Under the Curve to 8h (AUC Last) | 1435.0 mcg*min/mL | Standard Deviation 241.7 |
Comparison: 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.90% CI: [97.5, 115.7]
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.
Time frame: Baseline, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Water as a Vehicle of Amoxicillin | Area Under the Curve to Time Infinity (AUC to Time Infinity) | 1394.1 mcg*min/mL | Standard Deviation 256.1 |
| Human Milk as a Vehicle of Amoxicillin | Area Under the Curve to Time Infinity (AUC to Time Infinity) | 1477.2 mcg*min/mL | Standard Deviation 260.7 |
Comparison: 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.90% CI: [97.5, 115.4]
Primary
Cmax
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Water as a Vehicle of Amoxicillin | Cmax | 8653.8 ng/ml | Standard Deviation 2217.6 |
| Human Milk as a Vehicle of Amoxicillin | Cmax | 8690.6 ng/ml | Standard Deviation 1972.4 |
Comparison: 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.90% CI: [89.4, 114.9]
Primary
Tmax
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Water as a Vehicle of Amoxicillin | Tmax | 101.3 min | Standard Deviation 52.4 |
| Human Milk as a Vehicle of Amoxicillin | Tmax | 106.9 min | Standard Deviation 49 |
Comparison: 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.90% CI: [84.5, 137.8]
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.
Time frame: Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Water as a Vehicle of Amoxicillin | Clearance/F | 5.63 ml/kg/min | Standard Deviation 1.05 |
| Human Milk as a Vehicle of Amoxicillin | Clearance/F | 5.34 ml/kg/min | Standard Deviation 1.22 |
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.
Time frame: Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Water as a Vehicle of Amoxicillin | Elimination Half-life | 77.7 min | Standard Deviation 17 |
| Human Milk as a Vehicle of Amoxicillin | Elimination Half-life | 76.1 min | Standard Deviation 11.7 |
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.
Time frame: Data points were taken at 0, 0.25, 0.5, 1, 1.5, 3, 4 and 8 hours after dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Water as a Vehicle of Amoxicillin | Volume of Distribution/F | 0.63 l/kg | Standard Deviation 0.18 |
| Human Milk as a Vehicle of Amoxicillin | Volume of Distribution/F | 0.59 l/kg | Standard Deviation 0.16 |