HIV Infections
Conditions
Brief summary
The objective of this study is to evaluate the drug-drug interaction potential between BI 201335 and concomitantly administered tenofovir which is used in treatment regimens for HIV infection and/or Hepatitis B infection. Results of this study will serve as a basis for guidance of dose adjustments or other precautionary measures when BI201335 and tenofovir are coadministered.
Interventions
DRUGtenofovir/BI 201335
tenofovir medium dose once daily (qd) for first 15 days; BI 201335 medium dose twice daily (bid) on days 8 through 22 with last dose on morning of day 22
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males and female subjects and according to medical history, including the physical examination, vital signs (blood pressure, pulse rate), 12-lead electrocardiogram and clinical laboratory tests; all with acceptable findings. 2. Age =18 to =55 years 3. Weighing at least 50 kg, and body mass index \>=18.5 and BMI \<=29.9 kg/m2 (Body Mass Index). 4. Volunteers must not leave the research unit, during the entire length of the study and must be willing to comply with the protocol and complete all study-related activities.
Exclusion criteria
1. Any finding of the medical examination (including blood pressure, pulse rate and electrocardiogram) deviating from normal and of clinical relevance, as assessed by the investigator. 2. Active diseases of the gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, musculoskeletal, immunologic, rheumatologic, hormonal, neurological system, clinically relevant electrolyte disorders or bleeding disorders that require current medical treatment. 3. Diseases of the central nervous system or psychiatric disorders. 4. History of photosensitivity or recurrent rash. 5. History of orthostatic hypotension, fainting spells or blackouts. 6. Chronic or clinically relevant acute infections. 7. History of allergy/hypersensitivity (including drug allergy) which is deemed relevant. 8. Intake of drugs with a long half-life \>24:00 hours within at least one month or less than ten half lives of the respective drug before enrollment in the study (with the exception of hormonal contraceptives). 9. Use of any drugs which might influence the results of the trial up to 7 days prior to enrolment as nutraceuticals and herbal remedies that would interfere with either the absorption, distribution or metabolism of BI 201335 NA, or that prolong the QT/QTc interval. 10. Use of any investigational drug within 30 days prior to enrollment; or the planned use of any investigational drug during the course of the current study. 11. Smoking (\>10 cigarettes or \>3 cigars or \>3 pipes/day) 12. Inability to abstain from smoking more than 3 cigarettes/day during the period of dosing with study medication. 13. Drug and alcohol abuse (\>60g/day). 14. Blood donation (more than 100 mL within four weeks prior to administration or during the trial). 15. Excessive physical activities within one week prior to administration or during the trial. 16. Any laboratory value outside the reference range that is of clinical relevance at screening, according to the judgment of the investigator, and in consultation with the clinical monitor. 17. Known elevated liver enzymes in past with any compound (experimental or marketed). 18. Concomitant administration of any food product known to alter P450 enzyme activity such as grapefruit juice, Seville oranges, St. John's Wort. 19. Concomitant administration of oral contraceptives (subjects who stopped oral contraceptives at least 7 days prior to Day 1 may be included. 20. Inadequate venous access. 21. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTcF, or QTcB interval \>450 ms). 22. Infection with hepatitis B (HBV), or hepatitis C virus (HCV), 23. Positive test for HIV-1 or HIV-2. For women of child bearing potential (WOCBP) 24. Pregnancy or planning to become pregnant within 2 months of study completion 25. Positive pregnancy test at screening visit 26. No proof of sterilization, or not willing or unable to consistently use an acceptable method of double barrier contraception including IUD, or diaphragm with spermicidal cream/jelly and condoms for male partner, during and up to 3 months after completion/termination of the trial. 27. Lactation period with active breastfeeding from time of screening to 30 days after end of trial visit. For male subjects 28. No proof of sterilization, or not willing or unable to consistently use an acceptable method of double barrier contraception including a condom each time and female partner of child bearing potential consistently uses oral birth control pills, or an IUD, or a diaphragm with spermicidal cream/jelly). Male subjects must not father a child from administration of the first dose and up to 3 months after the last dose of study medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady-state Pharmacokinetics of C12hr of Faldaprevir on Day 15 and on Day 22 | 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 and 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00 hours on day 22 | Measured concentration of the analyte in plasma at 12 h (C12hr) after dosing, at steady state. |
| Steady-state Pharmacokinetics of AUC0-12 of Faldaprevir on Day 15 and on Day 22 | 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 and 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00 hours on day 22 | Area under the concentration-time curve (AUC) of the analyte in plasma over the time interval 0-12 hours, at steady state. |
| Steady-state Pharmacokinetics of Cmax of Faldaprevir on Day 15 and Day 22 | 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 and 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00 hours on day 22 | Maximum measured concentration of analyte in plasma (Cmax), at steady state. |
| Steady-state Pharmacokinetics of AUC0-24 of Tenofovir on Day 7 and on Day 15 | 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00, 168:00 hours on day 7 and 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 | Area under the concentration-time curve (AUC) of the analyte in plasma over the time interval 0-24 hours, at steady state. |
| Steady-state Pharmacokinetics of Cmax of Tenofovir on Day 7 and on Day 15 | 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00, 168:00 hours on day 7 and 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00. 192:00 hours on day 15 | Maximum measured concentration of analyte in plasma (Cmax), at steady state. |
| Steady-state Pharmacokinetics of C24hr of Tenofovir on Day 7 and on Day 15 | 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00, 168:00 hours on day 7 and 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 | Measured concentration of the analyte in plasma at 24 h (C24hr) after dosing, at steady state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Relevant Abnormalities for Physical Examination, Vital Signs, Safety Laboratory Tests and 12-lead ECG | From drug administration up to 32 days. | Clinical relevant abnormalities for physical examination, vital signs, safety laboratory tests and 12-lead ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Preferred term of relevant AE: Presyncope |
| Number of Patients With Drug Related Adverse Events During the Trial | From drug administration up to 32 days. | Outcome data are the numbers of subjects with investigator defined drug-related AEs |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants tenofovir medium dose (300mg) once daily (qd, oral) for first 15 days; Faldaprevir starting dose of 480mg and evening dose of 240mg on day 8; medium dose (300mg) twice daily (bid) on days 9 through day 22 (morning dose on day 22 only) | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treat. Period 3 (Faldaprevir) | Adverse Event | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 13 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 | 1 / 16 | 16 / 16 | 10 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Steady-state Pharmacokinetics of AUC0-12 of Faldaprevir on Day 15 and on Day 22
Area under the concentration-time curve (AUC) of the analyte in plasma over the time interval 0-12 hours, at steady state.
Time frame: 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 and 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00 hours on day 22
Population: All participants from the pharmacokinetic analysis set (PK set), including all subjects in the treated set who provided evaluable data for at least 1 observation for at least 1 primary PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir/Faldaprevir | Steady-state Pharmacokinetics of AUC0-12 of Faldaprevir on Day 15 and on Day 22 | 418000 ng*h/mL | Geometric Coefficient of Variation 69.3 |
| Faldaprevir | Steady-state Pharmacokinetics of AUC0-12 of Faldaprevir on Day 15 and on Day 22 | 523000 ng*h/mL | Geometric Coefficient of Variation 101 |
90% CI: [71.24, 85.15]ANOVA
Primary
Steady-state Pharmacokinetics of AUC0-24 of Tenofovir on Day 7 and on Day 15
Area under the concentration-time curve (AUC) of the analyte in plasma over the time interval 0-24 hours, at steady state.
Time frame: 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00, 168:00 hours on day 7 and 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15
Population: All participants from the pharmacokinetic analysis set (PK set), including all subjects who were documented to have taken at least one dose of trial medication (treated set) who provided evaluable data for at least 1 observation for at least 1 primary PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir | Steady-state Pharmacokinetics of AUC0-24 of Tenofovir on Day 7 and on Day 15 | 2700 ng*h/mL | Geometric Coefficient of Variation 26.5 |
| Tenofovir/Faldaprevir | Steady-state Pharmacokinetics of AUC0-24 of Tenofovir on Day 7 and on Day 15 | 3290 ng*h/mL | Geometric Coefficient of Variation 19.6 |
90% CI: [111.714, 132.999]ANOVA
Primary
Steady-state Pharmacokinetics of C12hr of Faldaprevir on Day 15 and on Day 22
Measured concentration of the analyte in plasma at 12 h (C12hr) after dosing, at steady state.
Time frame: 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 and 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00 hours on day 22
Population: All participants from the pharmacokinetic analysis set (PK set), including all subjects in the treated set who provided evaluable data for at least 1 observation for at least 1 primary PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir/Faldaprevir | Steady-state Pharmacokinetics of C12hr of Faldaprevir on Day 15 and on Day 22 | 31000 ng/mL | Geometric Coefficient of Variation 79.5 |
| Faldaprevir | Steady-state Pharmacokinetics of C12hr of Faldaprevir on Day 15 and on Day 22 | 40000 ng/mL | Geometric Coefficient of Variation 113 |
90% CI: [68.71, 82.45]ANOVA
Primary
Steady-state Pharmacokinetics of C24hr of Tenofovir on Day 7 and on Day 15
Measured concentration of the analyte in plasma at 24 h (C24hr) after dosing, at steady state.
Time frame: 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00, 168:00 hours on day 7 and 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15
Population: All participants from the pharmacokinetic analysis set (PK set), including all subjects in the treated set who provided evaluable data for at least 1 observation for at least 1 primary PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir | Steady-state Pharmacokinetics of C24hr of Tenofovir on Day 7 and on Day 15 | 54.0 ng/mL | Geometric Coefficient of Variation 26.7 |
| Tenofovir/Faldaprevir | Steady-state Pharmacokinetics of C24hr of Tenofovir on Day 7 and on Day 15 | 79.4 ng/mL | Geometric Coefficient of Variation 21.5 |
90% CI: [134.482, 160.943]ANOVA
Primary
Steady-state Pharmacokinetics of Cmax of Faldaprevir on Day 15 and Day 22
Maximum measured concentration of analyte in plasma (Cmax), at steady state.
Time frame: 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15 and 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00 hours on day 22
Population: All participants from the pharmacokinetic analysis set (PK set), including all subjects in the treated set who provided evaluable data for at least 1 observation for at least 1 primary PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir/Faldaprevir | Steady-state Pharmacokinetics of Cmax of Faldaprevir on Day 15 and Day 22 | 41700 ng/mL | Geometric Coefficient of Variation 51.4 |
| Faldaprevir | Steady-state Pharmacokinetics of Cmax of Faldaprevir on Day 15 and Day 22 | 50400 ng/mL | Geometric Coefficient of Variation 91.3 |
90% CI: [71.56, 93.34]ANOVA
Primary
Steady-state Pharmacokinetics of Cmax of Tenofovir on Day 7 and on Day 15
Maximum measured concentration of analyte in plasma (Cmax), at steady state.
Time frame: 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00, 168:00 hours on day 7 and 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00. 192:00 hours on day 15
Population: All participants from the pharmacokinetic analysis set (PK set), including all subjects in the treated set who provided evaluable data for at least 1 observation for at least 1 primary PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir | Steady-state Pharmacokinetics of Cmax of Tenofovir on Day 7 and on Day 15 | 300 ng/mL | Geometric Coefficient of Variation 27.3 |
| Tenofovir/Faldaprevir | Steady-state Pharmacokinetics of Cmax of Tenofovir on Day 7 and on Day 15 | 284 ng/mL | Geometric Coefficient of Variation 16.6 |
90% CI: [85.215, 105.29]ANOVA
Secondary
Clinical Relevant Abnormalities for Physical Examination, Vital Signs, Safety Laboratory Tests and 12-lead ECG
Clinical relevant abnormalities for physical examination, vital signs, safety laboratory tests and 12-lead ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Preferred term of relevant AE: Presyncope
Time frame: From drug administration up to 32 days.
Population: All subjects who were dispensed study medication and were documented to have taken at least one dose of study drug were included in the safety evaluation (treated set).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir | Clinical Relevant Abnormalities for Physical Examination, Vital Signs, Safety Laboratory Tests and 12-lead ECG | 1 participants |
| Tenofovir/Faldaprevir | Clinical Relevant Abnormalities for Physical Examination, Vital Signs, Safety Laboratory Tests and 12-lead ECG | 0 participants |
| Faldaprevir | Clinical Relevant Abnormalities for Physical Examination, Vital Signs, Safety Laboratory Tests and 12-lead ECG | 0 participants |
Secondary
Number of Patients With Drug Related Adverse Events During the Trial
Outcome data are the numbers of subjects with investigator defined drug-related AEs
Time frame: From drug administration up to 32 days.
Population: All subjects who were dispensed study medication and were documented to have taken at least one dose of study drug were included in the safety evaluation (treated set).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir | Number of Patients With Drug Related Adverse Events During the Trial | 0 participants |
| Tenofovir/Faldaprevir | Number of Patients With Drug Related Adverse Events During the Trial | 15 participants |
| Faldaprevir | Number of Patients With Drug Related Adverse Events During the Trial | 9 participants |