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This is a single center, open label, drug-drug interaction, Phase 1 study of TNP-2198 in approximately 32 healthy participants, includes 2 cohorts (16 participants per cohort): Midazolam cohort and Clarithromycin cohort. Midazolam cohort will evaluate the effect of multiple oral doses of TNP-2198 capsules on the pharmacokinetics (PK) parameters of a single oral dose of midazolam, a cytochrome P-450 (CYP) 3A sensitive substrate, in healthy participants; Clarithromycin cohort will evaluate the effect of multiple oral doses of clarithromycin tablets, a strong CYP3A and P-gp inhibitor, on the PK parameters of multiple oral doses of TNP-2198 in healthy participants.
Midazolam cohort: Midazolam oral solution will be administered orally at a dose of 2 mg once a day within 0.5 hours after breakfast on Day 1, and administered following TNP-2198 capsules within 0.5 hours after breakfast on Day 10. TNP 2198 capsules will be administered orally at a dose of 400 mg twice a day, within 0.5 hours after breakfast and dinner, from Day 3 to Day 11. PK blood sampling and safety tests were performed at specified time points.
Clarithromycin cohort: TNP-2198 capsules will be administered orally at a dose of 400 mg twice a day, within 0.5 hours after breakfast and dinner, from Day 1 to Day 7, and within 0.5 hours after breakfast on Day 8. Clarithromycin tablets will be administered at a dose of 0.5 g twice a day, within 0.5 hours after breakfast and dinner, from Day 16 to Day 25. TNP-2198 capsules will be administered within 0.5 hours after breakfast and dinner, followed by clarithromycin tablets, from Day 16 to Day 22. TNP-2198 capsules will be administrated within 0.5 hours after breakfast, followed by clarithromycin tablets on Day 23. PK blood sample collection and safety tests were performed at specified time points.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Midazolam cohort | Experimental | Midazolam Oral Solution will be given orally once daily within 0.5 hours after breakfast on Day 1 and Day 10. TNP-2198 Capsules will be given orally twice daily within 0.5 hours after breakfast and dinner from Day 3 to Day 11. |
|
| Clarithromycin cohort | Experimental | Clarithromycin tablets will be given orally within 0.5 hours after breakfast and dinner from Day 16 to Day 25. TNP-2198 Capsules will be given orally twice daily within 0.5 hours after breakfast and dinner from Day 1 to Day 7 and from Day16 to Day 22, and once daily within 0.5 hours after breakfast on Day 8 and Day 23. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midazolam | Drug | Midazolam Oral Solution 2 mg |
| |
| Clarithromycin |
| Measure | Description | Time Frame |
|---|---|---|
| Midazolam cohort: PK parameters of midazolam-Area under the plasma concentration versus time curve (AUC0-t) | Area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration (AUC0-t) | Within 1 hour prior to midazolam dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following midazolam dosing on Day 1 and Day 10, respectively. |
| Midazolam cohort: PK parameters of midazolam-Area under the plasma concentration versus time curve (AUC0-∞) | Area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC0-∞) | Within 1 hour prior to midazolam dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following midazolam dosing on Day 1 and Day 10, respectively. |
| Midazolam cohort: PK parameters of midazolam-Maximum observed plasma concentration (Cmax) | Maximum observed plasma concentration (Cmax) | Within 1 hour prior to midazolam dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following midazolam dosing on Day 1 and Day 10, respectively. |
| Clarithromycin cohort: PK parameters of TNP-2198-Area under the plasma concentration versus time curve(AUC0-t) | Area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration | Within 1 hour prior to TNP-2198 dosing and at 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours following TNP-2198 dosing on Day 8 and Day 23, respectively. |
| Clarithromycin cohort: PK parameters of TNP-2198-Area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC0-∞) | Area under the plasma concentration versus time curve from time 0 extrapolated to infinity |
| Measure | Description | Time Frame |
|---|---|---|
| Midazolam cohort: Percentage of Participants With Adverse Events (AEs) | An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Xiaojiao Li | The First Hospital of Jilin University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The First Hospital of Jinlin University | Changchun | Jilin | China |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| D017291 | Clarithromycin |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| Drug |
Clarithromycin tablets 0.5 g |
|
| TNP-2198 | Drug | TNP-2198 Capsules 400 mg |
|
| Within 1 hour prior to TNP-2198 dosing and at 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours following TNP-2198 dosing on Day 8 and Day 23, respectively. |
| Clarithromycin cohort: PK parameters of TNP-2198-Maximum observed plasma concentration (Cmax) | Cmax | Within 1 hour prior to TNP-2198 dosing and at 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours following TNP-2198 dosing on Day 8 and Day 23, respectively. |
| Day 1 to Day 12 |
| Clarithromycin cohort:Percentage of Participants With Adverse Events (AEs) | An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events | Day 1 to Day 26 |
| Midazolam cohort: PK parameters of midazolam Time to Maximum Plasma Concentration (Tmax) | Time to Maximum Plasma Concentration (Tmax) | Within 1 hour prior to midazolam dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following midazolam dosing on Day 1 and Day 10, respectively. |
| Midazolam cohort: PK parameters of midazolam Terminal Elimination Half-life (T1/2) | Terminal Elimination Half-life (T1/2) | Within 1 hour prior to midazolam dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following midazolam dosing on Day 1 and Day 10, respectively. |
| Clarithromycin cohort: PK parameters of TNP-2198 Time to Maximum Plasma Concentration (Tmax) | Time to Maximum Plasma Concentration (Tmax) | Within 1 hour prior to TNP-2198 dosing and at 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours following TNP-2198 dosing on Day 8 and Day 23, respectively. |
| Clarithromycin cohort: PK parameters of TNP-2198 Terminal Elimination Half-life (T1/2) | Terminal Elimination Half-life (T1/2) | Within 1 hour prior to TNP-2198 dosing and at 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours following TNP-2198 dosing on Day 8 and Day 23, respectively. |
| D006571 | Heterocyclic Compounds |
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |