Drug Interaction
Conditions
Keywords
Drug-Drug-Interaction Study
Brief summary
The purpose of this study was to investigate how vamorolone affects the CYP3A4 enzyme in humans by measuring the pharmacokinetics of midazolam and its metabolite, 1'-hydroxymidazolam, in healthy subjects. The pharmacokinetics of midazolam were measured on Day 1 and then on Day 14 to investigate the potential interaction between the two compounds. The safety and the tolerability was also investigated.
Detailed description
This was a non-randomized, single-center, open-label, single-sequence, single-arm Phase I study. * Day 1: Participants received a single dose of 2.5 mg midazolam in fasted state in the morning. * Day 2: Wash-out period. * Days 3 to 13: Participants received daily doses of 6 mg/kg vamorolone in the morning within 30 minutes after start of a standard breakfast. * Day 14: Participants received single doses of 2.5 mg midazolam and 6 mg/kg vamorolone in fasted state in the morning. * Safety and tolerability parameters were collected during the entire study phase from screening to follow-up. * Blood samples for PK assessment of midazolam and 1'-hydroxymidazolam were collected from predose through 10 hours following the midazolam doses on Days 1 and 14. * Blood samples for PK assessment of vamorolone were collected throughout the vamorolone dosing period. * Blood and urine biomarkers samples for CYP3A4 induction assessment were collected throughout the treatment period. * On Day 28, a follow-up safety phone call was done
Interventions
DRUGVamorolone
Days 3 to 14: 6 mg/kg vamorolone once daily.
DRUGMidazolam
Day 1 and 14: Single oral doses of 2.5 mg midazolam
Sponsors
Santhera Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
A single-center, open-label, single-arm, fixed-sequence, design. Healthy male and female subjects (18 to 55 years, inclusive) are eligible.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age of 18 to 55 years inclusive, at the time of signing the informed consent. 2. Subject is overtly healthy as determined by medical evaluation including medical history, physical examination, vital signs, laboratory tests, and ECG. 3. Body weight ≥ 50 kg and a BMI ≥ 18 kg/m2 and ≤ 29.9 kg/m2 at screening. 4. Male and female. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male subjects: • If the subject is a sexually active man and not surgically sterilized, he must be willing to: * Abstain from sexual intercourse or * Use a condom plus another form of contraception, (e.g., spermicide, IUD, birth control pills taken by female partner) if engaging in sexual intercourse with a woman who could become pregnant. * Use a condom during sexual intercourse with pregnant or lactating women. * Must not father a child and must refrain from donating sperm from administration of the first dose and up to 3 months after the last dose of study treatment. Female subjects: All women (regardless of their status, i.e. WOCBP and WONCBP; for definitions see Section 10.4.1) must have a negative serum β-hCG pregnancy test prior to the initiation of the study treatments. FSH levels of suspected postmenopausal females must be > 30 mIU/mL. Vamorolone has the potential to induce CYP3A4, which may result in a reduction in the effectiveness of contraceptives that are metabolized by CYP3A4 such as hormonal contraceptives when co-administered with vamorolone. Therefore, hormonal contraceptives by any route of administration are contraindicated. Women participating in the study must be either: * WONCBP or * WOCBP using, during the length of the study and for at least 3 months after the stop of the study treatments, 1 of the following contraceptive methods plus a condom: * IUD during the study and up to 3 months after the last administration of the study treatments * Any IUD with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criteria) * Any other methods with published data showing that the lowest expected failure rate for birth control is less than 1% per year, or * Abstinent from intercourse for 2 weeks before exposure to the study treatments, throughout the clinical trial until 3 months following discontinuation of the study treatments, or * Have a male partner who is sterile prior to the woman's entry into the study and is the sole sexual partner for that woman during the study period. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 5. Subject is a non-smoker for at least 3 months prior exposure to the study treatments. Subject must also have abstained from use of other nicotine containing products (e.g., nicotine patch, chewing gum or e-cigarettes) for at least 3 months before exposure to the study treatments. 6. Capable of giving signed informed consent as described in Section 10.1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol prior to any clinical study specific procedure. 7. Supine systolic blood pressure ≥ 90 mmHg and ≤ 140 mmHg; diastolic blood pressure ≥ 50 mmHg and ≤ 90 mmHg and pulse rate ≥ 45 bpm and ≤ 90 bpm, and tympanic body temperature ≥ 35.0 °C and ≤ 37.5 °C at screening. 8. Subjects must be able to communicate well with the Investigator and comply with the protocol requirements, instructions, and protocol related restrictions (e.g. dietary, fluid and lifestyle restrictions from screening to study completion; Section 5.3). 9. Subjects must be able to swallow the study treatments as per protocol.
Exclusion criteria
10. A past medical history of clinically significant abnormalities or a history/family history of long QT interval syndrome, structural cardiac abnormalities (including but not limited to hypertrophic cardiomyopathy, valvulopathy, and congenital defects), or cardiogenic syncope. 11. An abnormal ECG, defined as: * PR > 215 msec and < 100 msec, QRS complex > 120 msec; QTcF > 450 msec by automated reading * Any clinically significant ST/T wave abnormalities * Any atrial or ventricular arrhythmias 12. A past medical history of myocardial infarction, angina pectoris, atherosclerosis or other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension). 13. A past medical history of peptic ulcers, diverticulitis, and non-specific ulcerative colitis. 14. History of complaints of frequent dizziness and /or vomiting spells or lightheadedness (frequent defined as incidence occurs more than once every week) or history of/or present sleep apnea. 15. Any history or evidence of any clinically relevant, gastrointestinal, respiratory, hepatic, renal, endocrinologic, hematologic, immunologic, metabolic, genitourinary, pulmonary, neurologic, dermatologic, musculoskeletal, and/or other major disease or malignancy as determined by medical evaluation (including physical examination) capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatments; or interfering with the interpretation of data. 16. Known Gilbert's syndrome. 17. Any clinically relevant history of allergic conditions requiring hospitalization or prolonged systemic treatment (including drug allergies, allergic asthma, eczema, allergies requiring therapy with corticosteroids or anaphylactic reactions); but excluding untreated, asymptomatic, seasonal allergies at time of dosing or allergic contact sensitizations (e.g., nickel allergy). 18. Known or suspected hypersensitivity or contraindications to vamorolone and/or midazolam or any components of the formulation used. 19. Relevant current acute or chronic/recurrent viral, bacterial, fungal, or parasitic infections (e.g., pulmonary/upper respiratory, gastrointestinal, urinary, skin, or ENT infections) at screening or within 28 days prior to administration of the study treatments. 20. Use of any concomitant medication or any drugs / medicines (including dietary supplements, natural and herbal remedies, and hormone replacement therapy) within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to the first administration of the study treatments. Occasional use of paracetamol up to 2 g/day or ibuprofen up to 1.2 g/day (medicinal products in their original packaging, approved and marketed in Germany) is permitted. Oral, injectable, and implantable contraceptives as outlined in Section 5.1 are permitted. 21. Previous exposure to vamorolone. 22. Any use of corticoids within 6 months prior to the first administration of the study treatments. 23. Administration of live, attenuated, replication-competent vaccines within 6 weeks prior to the first administration of the study treatments until 2 weeks after the follow-up visit. Administration of vector-based or mRNA COVID-19 vaccines within 2 weeks prior to the first administration of the study treatments until 2 weeks after the follow-up visit. 24. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to the first administration of the study treatments. 25. Use of any investigational drug or participation in any clinical study within 30 days or 5 half-lives (whichever is longer) prior to the expected date of first administration of study treatments or planning to take other investigational drugs during the study. 26. Positive results for HBsAg, anti-HCV, anti-HIV 1 and 2, and HIV 1-p24 antigen at screening. 27. Positive screen for alcohol, drugs of abuse and cotinine at screening. 28. Elevations in ALT > 1.1 x ULN, AST > 1.2 x ULN, serum bilirubin > 1.2 x ULN, creatinine > 1.1 x ULN and and HbA1c > ULN at screening. A case-by-case decision for any abnormality must be discussed with the Sponsor before inclusion. 29. TSH outside of normal ranges. 30. eGFR based on the CKD-EPI (details for calculation see Section 10.2) of < 90 mL/min at screening. 31. Potassium or magnesium blood concentration below the lower limit of normal at screening. 32. Subjects who are unwilling to adhere to contraceptive requirements. 33. Higher than low-risk alcohol consumption i.e., consumption of an average weekly alcohol intake of > 21 units/week for men and > 14 units/week for women. 1 unit (12 g) corresponds to 0.3 L of beer/day or 0.12 L of wine/day or 1 glass (at 2 cL) of spirits/day. 34. Excessive consumption of caffeine- or xanthine-containing food or beverages (> 5 cups of coffee a day or equivalent) or inability to stop consuming from 48 hours prior to first planned administration of study treatments. 35. Consumption of alcohol from 48 hours prior to admission. 36. Consumption of high dose resveratrol-containing products or products with enzyme-inducing or enzyme-inhibiting properties (for details refer to Section 5.3.1) 14 days prior to first administration of study treatment. 37. Regular consumption of poppy seed containing food prior to first administration of study treatment. 38. Any use of drugs-of-abuse or alcohol abuse within 1 month prior to dosing. 39. Subject with vegetarian, vegan, or restricted diet (e.g., gluten-free) or not willing or able to eat the complete standard meals. 40. Female subject who has been pregnant within 6 months prior to screening or breastfeeding or lactating within 3 months prior to screening or plans to become pregnant during the clinical study period and for 3 months after final study treatment administration. 41. Donation or loss of more than 400 mL of blood or received a transfusion of any blood or blood products within 30 days, or donated plasma within 30 days prior to first administration of study treatment. 42. Strenuous physical activity within 72 h to admission. 43. Employee of the Sponsor, the Nuvisan Group, or other Contract Research Organization involved in the clinical study. 44. Legal incapacity or limited legal capacity, or incarceration and vulnerable subjects. 45. Inability to understand or communicate reliably with the Investigator or considered by the Investigator to be unable to or unlikely to co-operate with the protocol requirements, instructions, and study-related restrictions. 46. History of non-compliance to medical regimens and subjects who are considered potentially unreliable (e.g., refuse to comply with study regulations). 47. Any other conditions or factors which in the opinion of the Investigator may interfere with study conduct. 48. Changes in medical conditions compared to screening, as judged by the Investigator. 49. Body weight < 50 kg. 50. Changes in prior/concomitant therapy compared to screening, as judged by the Investigator. 51. Positive screen for alcohol, drugs of abuse and cotinine test upon admission. 52. Changes in other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tlast of Midazolam | Day 1 and Day 14 | Area under the plasma concentration-time curve from 0 to the time of the last observed concentration (h\*pg/mL) on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose. |
| AUC0-inf of Midazolam | Day 1 and Day 14 | Area under the plasma concentration-time curve from zero to infinite time on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose and extrapolation to infinity. |
| Cmax of Midazolam | Day 1 and Day 14 | maximum measured concentration of midazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing on day 1 and day 14 |
| AUC0-tlast of 1'-Hydroxymidazolam | Day 1 and Day 14 | Area under the plasma concentration-time curve from 0 to the time of the last observed concentration (h\*pg/mL) on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose. |
| AUC-inf of 1'-Hydroxymidazolam | Day 1 and Day 14 | Area under the plasma concentration-time curve from 0 to the infinite time (h\*pg/mL) on day 1 and Day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose and extrapolation to infinity. |
| Cmax of 1'-Hydroxymidazolam | Day 1 and Day 14 | maximum measured concentration of 1'-Hydroxymidazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Predose Concentration (Ctrough) of Vamorolone | Day 3, Day 4, Day 7, Day 11, Day 13, Day 14 | Concentration measurements taken just before the first administration of vamorolone on day 3, and at the end of each vamorolone dosing interval before the next dose on days 4, 7, 11, 13, and 14. |
| Tmax of Midazolam | Day 1 and Day 14 | Time to reach observed maximal concentration of midazolam after administration of midazolam until the last collection time, i.e., 10 hours after administration on day 1 and day 14 |
| Plasma 4β-hydroxycholesterol Level | Day 1, Day 3, Day 4, Day 7, Day 11, Day 14, Day 15 | The plasma concentration of 4-β-hydroxycholesterol is used as an in vivo marker to assess CYP3A4 induction activity |
| Urinary 6β-hydroxycortisol to Cortisol Ratio | Day 1, Day 3, Day 4, Day 7, Day 11, Day 14, Day 15 | Urinary 6β-hydroxycortisol to cortisol ratio is used as in vivo biomarkers for CYP3A4 activity. The impact of vamorlone on adrenal suppression could result in alterations in urinary cortisol and 6-β-hydroxycortisol levels.. Thus, the 6-β-hydroxycortisol to cortisol ratio is an unreliable measure of vamorolone's CYP3A4 induction potential. |
| CL/F of Midazolam | Day 1 and Day 14 | The apparent clearance measures how quickly a drug leaves the body, considering how much reaches it after being taken orally. It was calculated using the formula: Dose/AUCinf on day 1 and day 14. The timepoints used were as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours on day 1 and day 14 |
| Vz/F of Midazolam | Day 1 and Day 14 | Vz/F is the ratio of the volume of distribution of a drug to its bioavailability. It describes how widely the drug is distributed in the body after oral administration. It was calculated based on the terminal phase (ℷz)using the formula: Dose /ℷz.AUCinf on day 1 and day 14. The timepoints were as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours. |
| t1/2 of Midazolam | Day 1 and Day 14 | Elimination half-life is the amount of time it takes for the concentration of the drug (midazolam) in the body to decrease by half after administration on day 1 and day 14. The collection times were predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours. |
| Tmax of 1'-Hydroxymidazolam | Day 1 and Day 14 | Time to reach observed maximal concentration of 1'-Hydroxymidazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing on day 1 and day 14 |
| t1/2 of 1'-Hydroxymidazolam | Day 1 and Day 14 | Elimination half-life is the amount of time it takes for the concentration of the drug (1'-Hydroxymidazolam) in the body to decrease by half on day 1 and day 14. The collection times were predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vamorolone/Midazolam both Test Drug (vamorolone) and Reference Drug (midazolam) are administered in this arm
Vamorolone: Days 3 to 14: 6 mg/kg vamorolone once daily.
Midazolam: Day 1 and 14: Single oral doses of 2.5 mg midazolam | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Vamorolone/Midazolam |
|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 9.55 |
| BMI | 23.81 kg/m2 STANDARD_DEVIATION 2.389 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 170.5 cm STANDARD_DEVIATION 10.55 |
| Premenopausal/Postmenopausal Status Postmenopausal Status | 2 Participants |
| Premenopausal/Postmenopausal Status Premenopausal Status | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment Germany | 18 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 8 Participants |
| Weight | 69.34 kg STANDARD_DEVIATION 10.876 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 2 / 18 | 8 / 18 | 2 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
AUC0-inf of Midazolam
Area under the plasma concentration-time curve from zero to infinite time on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose and extrapolation to infinity.
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | AUC0-inf of Midazolam | 38028.2 h*pg/mL | Standard Deviation 14556.59 |
| Midazolam Co-administered With Vamorolone on Day 14. | AUC0-inf of Midazolam | 30337.7 h*pg/mL | Standard Deviation 12238.52 |
Comparison: Linear model with treatment as fixed effect and subjects as random effect90% CI: [74.18, 95]
Primary
AUC0-tlast of 1'-Hydroxymidazolam
Area under the plasma concentration-time curve from 0 to the time of the last observed concentration (h\*pg/mL) on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose.
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | AUC0-tlast of 1'-Hydroxymidazolam | 11019.7 h*pg/ml | Standard Deviation 4377.21 |
| Midazolam Co-administered With Vamorolone on Day 14. | AUC0-tlast of 1'-Hydroxymidazolam | 12669.0 h*pg/ml | Standard Deviation 5085.13 |
Comparison: Linear model with treatment as fixed effect and subject as random effect90% CI: [101.59, 129.18]
Primary
AUC0-tlast of Midazolam
Area under the plasma concentration-time curve from 0 to the time of the last observed concentration (h\*pg/mL) on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose.
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | AUC0-tlast of Midazolam | 34331.8 h*pg/ml | Standard Deviation 11854.73 |
| Midazolam Co-administered With Vamorolone on Day 14. | AUC0-tlast of Midazolam | 28619.6 h*pg/ml | Standard Deviation 11447.17 |
Comparison: Linear model with treatment as fixed effect and subjects as random effect90% CI: [74.08, 93.59]
Primary
AUC-inf of 1'-Hydroxymidazolam
Area under the plasma concentration-time curve from 0 to the infinite time (h\*pg/mL) on day 1 and Day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose and extrapolation to infinity.
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | AUC-inf of 1'-Hydroxymidazolam | 11592.1 h*pg/ml | Standard Deviation 4592.86 |
| Midazolam Co-administered With Vamorolone on Day 14. | AUC-inf of 1'-Hydroxymidazolam | 13211.4 h*pg/ml | Standard Deviation 5225.69 |
Comparison: Linear model with treatment as fixed effect and subject as random effect90% CI: [101.29, 127.63]
Primary
Cmax of 1'-Hydroxymidazolam
maximum measured concentration of 1'-Hydroxymidazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | Cmax of 1'-Hydroxymidazolam | 5846 pg/ml | Standard Deviation 2748.8 |
| Midazolam Co-administered With Vamorolone on Day 14. | Cmax of 1'-Hydroxymidazolam | 7920 pg/ml | Standard Deviation 3988.6 |
Comparison: Linear model with treatment as fixed effect and subject as random effect90% CI: [105.36, 157.13]
Primary
Cmax of Midazolam
maximum measured concentration of midazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing on day 1 and day 14
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | Cmax of Midazolam | 15704 pg/ml | Standard Deviation 5495.3 |
| Midazolam Co-administered With Vamorolone on Day 14. | Cmax of Midazolam | 13875 pg/ml | Standard Deviation 4995.2 |
Comparison: Linear model with treatment as fixed effect and subject as random effect90% CI: [79.44, 98.79]
Secondary
CL/F of Midazolam
The apparent clearance measures how quickly a drug leaves the body, considering how much reaches it after being taken orally. It was calculated using the formula: Dose/AUCinf on day 1 and day 14. The timepoints used were as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours on day 1 and day 14
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | CL/F of Midazolam | 78.80 L/h | Standard Deviation 45.683 |
| Midazolam Co-administered With Vamorolone on Day 14. | CL/F of Midazolam | 93.27 L/h | Standard Deviation 31.471 |
Secondary
Plasma 4β-hydroxycholesterol Level
The plasma concentration of 4-β-hydroxycholesterol is used as an in vivo marker to assess CYP3A4 induction activity
Time frame: Day 1, Day 3, Day 4, Day 7, Day 11, Day 14, Day 15
Population: Safety Set: All subjects assigned to study treatment and who received at least 1 dose of study treatment. Subjects were analyzed according to the treatment they actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | Plasma 4β-hydroxycholesterol Level | 40.75 ng/ml | Standard Deviation 44.696 |
| Midazolam Co-administered With Vamorolone on Day 14. | Plasma 4β-hydroxycholesterol Level | 41.51 ng/ml | Standard Deviation 34.89 |
| Vamorolone on Day 11 | Plasma 4β-hydroxycholesterol Level | 40.36 ng/ml | Standard Deviation 33.582 |
| Vamorolone Alone on Day 13 | Plasma 4β-hydroxycholesterol Level | 45.53 ng/ml | Standard Deviation 34.426 |
| Vamorolone Coadministrated With Midazolam on Day 14 | Plasma 4β-hydroxycholesterol Level | 38.87 ng/ml | Standard Deviation 20.366 |
| Vamorolone Coadministrated With Midazolam on Day 14 | Plasma 4β-hydroxycholesterol Level | 36.73 ng/ml | Standard Deviation 19.713 |
| No Treatment on Day 15 | Plasma 4β-hydroxycholesterol Level | 38.93 ng/ml | Standard Deviation 19.328 |
Secondary
Predose Concentration (Ctrough) of Vamorolone
Concentration measurements taken just before the first administration of vamorolone on day 3, and at the end of each vamorolone dosing interval before the next dose on days 4, 7, 11, 13, and 14.
Time frame: Day 3, Day 4, Day 7, Day 11, Day 13, Day 14
Population: PK-Set Vamorolone: This analysis set is a subset of the safety set and includes all subjects who completed at least one scheduled vamorolone dose without vomiting within 4 hours immediately following that vamorolone administration and provided at least one valid PK concentration data for vamorolone.~This PK set was used for PK concentration summary and PK parameter summary for vamorolone
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | Predose Concentration (Ctrough) of Vamorolone | 9.397 ng/ml | Standard Deviation 20.182 |
| Midazolam Co-administered With Vamorolone on Day 14. | Predose Concentration (Ctrough) of Vamorolone | 3.486 ng/ml | Standard Deviation 5.0864 |
| Vamorolone on Day 11 | Predose Concentration (Ctrough) of Vamorolone | 3.816 ng/ml | Standard Deviation 5.1055 |
| Vamorolone Alone on Day 13 | Predose Concentration (Ctrough) of Vamorolone | 2.070 ng/ml | Standard Deviation 2.5436 |
| Vamorolone Coadministrated With Midazolam on Day 14 | Predose Concentration (Ctrough) of Vamorolone | 1.303 ng/ml | Standard Deviation 1.5972 |
Secondary
t1/2 of 1'-Hydroxymidazolam
Elimination half-life is the amount of time it takes for the concentration of the drug (1'-Hydroxymidazolam) in the body to decrease by half on day 1 and day 14. The collection times were predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours.
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | t1/2 of 1'-Hydroxymidazolam | 2.215 h | Standard Deviation 0.4131 |
| Midazolam Co-administered With Vamorolone on Day 14. | t1/2 of 1'-Hydroxymidazolam | 2.122 h | Standard Deviation 0.377 |
Secondary
t1/2 of Midazolam
Elimination half-life is the amount of time it takes for the concentration of the drug (midazolam) in the body to decrease by half after administration on day 1 and day 14. The collection times were predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours.
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | t1/2 of Midazolam | 2.980 h | Standard Deviation 0.7003 |
| Midazolam Co-administered With Vamorolone on Day 14. | t1/2 of Midazolam | 3.305 h | Standard Deviation 0.8752 |
Secondary
Tmax of 1'-Hydroxymidazolam
Time to reach observed maximal concentration of 1'-Hydroxymidazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing on day 1 and day 14
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midazolam Alone on Day 1 | Tmax of 1'-Hydroxymidazolam | 0.500 h |
| Midazolam Co-administered With Vamorolone on Day 14. | Tmax of 1'-Hydroxymidazolam | 0.500 h |
Secondary
Tmax of Midazolam
Time to reach observed maximal concentration of midazolam after administration of midazolam until the last collection time, i.e., 10 hours after administration on day 1 and day 14
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midazolam Alone on Day 1 | Tmax of Midazolam | 0.500 h |
| Midazolam Co-administered With Vamorolone on Day 14. | Tmax of Midazolam | 0.500 h |
Secondary
Urinary 6β-hydroxycortisol to Cortisol Ratio
Urinary 6β-hydroxycortisol to cortisol ratio is used as in vivo biomarkers for CYP3A4 activity. The impact of vamorlone on adrenal suppression could result in alterations in urinary cortisol and 6-β-hydroxycortisol levels.. Thus, the 6-β-hydroxycortisol to cortisol ratio is an unreliable measure of vamorolone's CYP3A4 induction potential.
Time frame: Day 1, Day 3, Day 4, Day 7, Day 11, Day 14, Day 15
Population: Safety Set: All subjects assigned to study treatment and who received at least 1 dose of study treatment. Subjects were analyzed according to the treatment they actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | Urinary 6β-hydroxycortisol to Cortisol Ratio | 3.496 ratio | Standard Deviation 1.4406 |
| Midazolam Co-administered With Vamorolone on Day 14. | Urinary 6β-hydroxycortisol to Cortisol Ratio | 2.856 ratio | Standard Deviation 1.1187 |
| Vamorolone on Day 11 | Urinary 6β-hydroxycortisol to Cortisol Ratio | 4.739 ratio | Standard Deviation 0.95864 |
| Vamorolone Alone on Day 13 | Urinary 6β-hydroxycortisol to Cortisol Ratio | 5.518 ratio | Standard Deviation 1.4118 |
| Vamorolone Coadministrated With Midazolam on Day 14 | Urinary 6β-hydroxycortisol to Cortisol Ratio | 5.234 ratio | Standard Deviation 1.4441 |
| Vamorolone Coadministrated With Midazolam on Day 14 | Urinary 6β-hydroxycortisol to Cortisol Ratio | 5.388 ratio | Standard Deviation 0.99344 |
| No Treatment on Day 15 | Urinary 6β-hydroxycortisol to Cortisol Ratio | 6.571 ratio | Standard Deviation 2.6256 |
Secondary
Vz/F of Midazolam
Vz/F is the ratio of the volume of distribution of a drug to its bioavailability. It describes how widely the drug is distributed in the body after oral administration. It was calculated based on the terminal phase (ℷz)using the formula: Dose /ℷz.AUCinf on day 1 and day 14. The timepoints were as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours.
Time frame: Day 1 and Day 14
Population: PK Set - Midazolam: a subset of the Safety Set and includes all subjects who completed the scheduled vamorolone and midazolam dosing and provided an evaluable midazolam PK profile on at least one of the following days Day 1 and Day 14. No vomiting should occur within 4 hours following midazolam and/or vamorolone administration.~This PK set was used for PK concentration summary and PK parameter summary for midazolam and 1'-hydroxymidazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone on Day 1 | Vz/F of Midazolam | 311.0 L | Standard Deviation 110.54 |
| Midazolam Co-administered With Vamorolone on Day 14. | Vz/F of Midazolam | 414.3 L | Standard Deviation 123.97 |