Healthy Volunteer
Conditions
Brief summary
This open label, randomized, three-period crossover study will evaluate the effect of co-administration of Tamiflu (oseltamivir) and rimantadine on the pharmacokinetics of Tamiflu and rimantadine. Healthy volunteers will receive multiple oral doses of Tamiflu, rimantadine or Tamiflu plus rimantadine in random order, with a minimum wash-out period of 7 days between treatments. Anticipated time on study is up to 11 weeks.
Interventions
multiple oral doses
DRUGrimantadine
multiple oral doses
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Adults, aged 18 to 45 years * Healthy as judged by general physical examination, medical history, vital signs, 12-lead ECG and laboratory tests * Body Mass Index (BMI) 18-34 kg/m2 * Willing not to participate in any other trial including an investigational drug for 3 months following the last dose * Male subjects must agree to use a barrier contraception during the study and for 3 months after discontinuation of treatment * Female subjects of non-child bearing potential or under effective contraception who are either post-menopausal, surgically sterile, or who agree to use barrier contraception during the whole study in addition to an intrauterine device or hormonal contraception for at least 3 months prior to 1st dose, during the study and for 3 months after discontinuation of treatment
Exclusion criteria
* History of or current clinically significant disease or disorder * Positive Hepatitis B, Hepatitis C, HIV 1 or 2 test result * Positive pregnancy test or lactating women * Clinically relevant history of allergy or hypersensitivity * Clinically relevant history of abuse of alcohol or other drugs; tobacco smoking is allowed (\</= 10 cigarettes a day or equivalent of tobacco in cigars or pipe) * Any major illness within 30 days prior to screening examination * Administration of any medication during the 7 days prior to drug administration, except for paracetamol and aspirin (up to 48 hours before first dose) and oral contraceptives * Participation in a clinical study with an investigational drug within 3 months prior to study day 1 * Donation or loss of more than 500 mL of blood within the 3 months prior to study day 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | Oseltamivir carboxylate is active metabolite of oseltamivir. AUC0-12 of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine, using the linear trapezoidal rule. |
| Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Rimantadine | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | AUC0-12 of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir, using the linear trapezoidal rule. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Up to 11 weeks | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. |
| Number of Participants With Abnormal Vital Signs | Screening (Days -28 to -2); pre-dose and 2h post-dose on D1 and D5 of each treatment period; at Follow-up visit (10 -14 days after last dose) for blood pressure and HR; Screening; Day -1 of each treatment period; Follow-up visit for temperature | Vital signs included heart rate (HR), blood pressure (systolic blood pressure \[SBP\] and diastolic blood pressure \[DBP\]), and body temperature. Blood pressure and pulse rate were recorded when participants were rested in a supine position for at least 5 minutes and after standing for 2 minutes. Vital signs values that fall outside the investigator's normal ranges were recorded. |
| Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | Oseltamivir carboxylate is active metabolite of oseltamivir. Cmax of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine and was directly observed from the data. |
| Number of Participants With Clinically Significant or Treatment Related Changes in Electrocardiogram (ECG) | Screening; pre-dose on Day 1 and Day 5 of each treatment period; Follow-up visit | ECG was recorded when participants were rested in a supine position for at least 5 minutes. |
| Number of Participants With Marked Abnormality in Laboratory Parameters | Screening; Day -1 and Day 5 (pre-dose) of each treatment period; Follow-up visit | Laboratory analysis included hematology (hemoglobin, hematocrit, erythrocytes, platelets counts, leukocytes counts, neutrophils, eosinophils, lymphocytes, basophils, and monocytes);, biochemistry (aspartate aminotransferase , alanine aminotransferase, gamma glutamyl trans peptidase, total bilirubin, alkaline phosphatase, lactate dehydrogenase, albumin, creatinine, urea, creatine phosphokinase, total protein, sodium, chloride, calcium, phosphate, potassium, glucose (fasting), amylase, lipase, total cholesterol, and calculated creatinine clearance); and urinalysis. Marked laboratory test values (high and low) falling outside the marked reference range and which also represents a clinically relevant change from baseline of at least a designated amount were recoded. In this study, marked abnormality ranges for phosphate as 0.75 - 1.60 millimole (mmol)/L and proteinuria (0 to 4+, and 1). |
| Maximum Plasma Concentration (Cmax) of Rimantadine | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | Cmax of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir and was directly observed from the data. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at a single center in the United States from 04 August 2009 to 28 September 2009. A total of 40 participants were screened.
Pre-assignment details
Of 40 participants, 24 participants were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Oseltamivir; Rimantadine; Oseltamivir + Rimantadine Participants received treatments in 3 periods as: Oseltamivir 75 milligram \[mg\] (twice a day orally for 5 days), Rimantadine 100 mg (twice a day orally for 5 days), and Oseltamivir 75 mg + Rimantadine 100 mg (twice a day orally for 5 days) in a randomly determined sequence with a minimum 7-day wash out period between consecutive treatments periods. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Oseltamivir; Rimantadine; Oseltamivir + Rimantadine |
|---|---|
| Age, Continuous | 33.5 years STANDARD_DEVIATION 7.34 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 24 | 6 / 22 | 4 / 21 |
| serious Total, serious adverse events | 0 / 24 | 0 / 22 | 0 / 21 |
Outcome results
Primary
Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate
Oseltamivir carboxylate is active metabolite of oseltamivir. AUC0-12 of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine, using the linear trapezoidal rule.
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Population: Pharmacokinetics (PK) analysis population included all participants who were adhered to the protocol.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Oseltamivir | Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir | 5.092 hours (h)*nanogram (ng)/milliliter (mL) |
| Oseltamivir | Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate | 8.008 hours (h)*nanogram (ng)/milliliter (mL) |
| Oseltamivir + Rimantadine | Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate | 7.990 hours (h)*nanogram (ng)/milliliter (mL) |
| Oseltamivir + Rimantadine | Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir | 5.070 hours (h)*nanogram (ng)/milliliter (mL) |
Comparison: Mean exposure ratio of oseltamivir90% CI: [0.91, 1.05]
Comparison: Mean exposure ratio of oseltamivir carboxylate90% CI: [0.95, 1.02]
Primary
Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Rimantadine
AUC0-12 of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir, using the linear trapezoidal rule.
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Population: Pharmacokinetic analysis population included all participants who were adhered to the protocol.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Oseltamivir | Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Rimantadine | 8.371 h*ng/mL |
| Oseltamivir + Rimantadine | Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Rimantadine | 8.398 h*ng/mL |
Comparison: Mean exposure ratio of rimantadine90% CI: [1, 1.06]
Secondary
Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate
Oseltamivir carboxylate is active metabolite of oseltamivir. Cmax of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine and was directly observed from the data.
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Population: PK analysis population included all participants who were adhered to the protocol.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Oseltamivir | Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir | 4.395 ng/mL |
| Oseltamivir | Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate | 5.940 ng/mL |
| Oseltamivir + Rimantadine | Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir | 4.249 ng/mL |
| Oseltamivir + Rimantadine | Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate | 5.921 ng/mL |
Comparison: Mean exposure ratio of oseltamivir90% CI: [0.77, 0.96]
Comparison: Mean exposure ratio of oseltamivir carboxylate90% CI: [0.92, 1.05]
Secondary
Maximum Plasma Concentration (Cmax) of Rimantadine
Cmax of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir and was directly observed from the data.
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Population: PK analysis population included all participants who were adhered to the protocol.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Oseltamivir | Maximum Plasma Concentration (Cmax) of Rimantadine | 6.036 ng/mL |
| Oseltamivir + Rimantadine | Maximum Plasma Concentration (Cmax) of Rimantadine | 6.062 ng/mL |
Comparison: mean exposure ratio of rimantadine90% CI: [0.99, 1.06]
Secondary
Number of Participants With Abnormal Vital Signs
Vital signs included heart rate (HR), blood pressure (systolic blood pressure \[SBP\] and diastolic blood pressure \[DBP\]), and body temperature. Blood pressure and pulse rate were recorded when participants were rested in a supine position for at least 5 minutes and after standing for 2 minutes. Vital signs values that fall outside the investigator's normal ranges were recorded.
Time frame: Screening (Days -28 to -2); pre-dose and 2h post-dose on D1 and D5 of each treatment period; at Follow-up visit (10 -14 days after last dose) for blood pressure and HR; Screening; Day -1 of each treatment period; Follow-up visit for temperature
Population: Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oseltamivir | Number of Participants With Abnormal Vital Signs | High- DBP | 2 participants |
| Oseltamivir | Number of Participants With Abnormal Vital Signs | High- HR standing | 2 participants |
| Oseltamivir | Number of Participants With Abnormal Vital Signs | High- SBP standing | 7 participants |
| Oseltamivir | Number of Participants With Abnormal Vital Signs | High- HR | 2 participants |
| Oseltamivir | Number of Participants With Abnormal Vital Signs | High- SBP | 6 participants |
| Oseltamivir | Number of Participants With Abnormal Vital Signs | Low- Temperature | 7 participants |
| Oseltamivir | Number of Participants With Abnormal Vital Signs | High- DBP standing | 8 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- HR standing | 1 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- SBP | 1 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- DBP | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- DBP standing | 6 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- HR | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | Low- Temperature | 11 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- SBP standing | 4 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- DBP standing | 2 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- HR standing | 2 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- DBP | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- SBP | 2 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- SBP standing | 3 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | Low- Temperature | 8 participants |
| Oseltamivir + Rimantadine | Number of Participants With Abnormal Vital Signs | High- HR | 0 participants |
Secondary
Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect.
Time frame: Up to 11 weeks
Population: Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oseltamivir | Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | 8 participants |
| Oseltamivir + Rimantadine | Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | 6 participants |
| Oseltamivir + Rimantadine | Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | 4 participants |
Secondary
Number of Participants With Clinically Significant or Treatment Related Changes in Electrocardiogram (ECG)
ECG was recorded when participants were rested in a supine position for at least 5 minutes.
Time frame: Screening; pre-dose on Day 1 and Day 5 of each treatment period; Follow-up visit
Population: Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oseltamivir | Number of Participants With Clinically Significant or Treatment Related Changes in Electrocardiogram (ECG) | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Clinically Significant or Treatment Related Changes in Electrocardiogram (ECG) | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Clinically Significant or Treatment Related Changes in Electrocardiogram (ECG) | 0 participants |
Secondary
Number of Participants With Marked Abnormality in Laboratory Parameters
Laboratory analysis included hematology (hemoglobin, hematocrit, erythrocytes, platelets counts, leukocytes counts, neutrophils, eosinophils, lymphocytes, basophils, and monocytes);, biochemistry (aspartate aminotransferase , alanine aminotransferase, gamma glutamyl trans peptidase, total bilirubin, alkaline phosphatase, lactate dehydrogenase, albumin, creatinine, urea, creatine phosphokinase, total protein, sodium, chloride, calcium, phosphate, potassium, glucose (fasting), amylase, lipase, total cholesterol, and calculated creatinine clearance); and urinalysis. Marked laboratory test values (high and low) falling outside the marked reference range and which also represents a clinically relevant change from baseline of at least a designated amount were recoded. In this study, marked abnormality ranges for phosphate as 0.75 - 1.60 millimole (mmol)/L and proteinuria (0 to 4+, and 1).
Time frame: Screening; Day -1 and Day 5 (pre-dose) of each treatment period; Follow-up visit
Population: Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oseltamivir | Number of Participants With Marked Abnormality in Laboratory Parameters | Phosphate Low | 1 participants |
| Oseltamivir | Number of Participants With Marked Abnormality in Laboratory Parameters | Phosphate High | 1 participants |
| Oseltamivir | Number of Participants With Marked Abnormality in Laboratory Parameters | Proteinuria | 1 participants |
| Oseltamivir + Rimantadine | Number of Participants With Marked Abnormality in Laboratory Parameters | Phosphate Low | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Marked Abnormality in Laboratory Parameters | Phosphate High | 1 participants |
| Oseltamivir + Rimantadine | Number of Participants With Marked Abnormality in Laboratory Parameters | Proteinuria | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Marked Abnormality in Laboratory Parameters | Phosphate Low | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Marked Abnormality in Laboratory Parameters | Proteinuria | 0 participants |
| Oseltamivir + Rimantadine | Number of Participants With Marked Abnormality in Laboratory Parameters | Phosphate High | 1 participants |