Drug Interaction, Pharmacokinetics, Safety Issues, Tolerability
Conditions
Brief summary
This is a phase I, open-label, fixed sequence design, drug-drug-interaction (DDI) study divided in 2 parts. Part I is designed to evaluate whether concomitant treatment with linaprazan glurate and clarithromycin, a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein P (PgP), leads to an effect on the systemic exposure to linaprazan glurate and linaprazan and whether there is an effect on the pharmacokinetics of clarithromycin after a single dose of linaprazan glurate. Part II is designed to evaluate the effect of repeated doses of linaprazan glurate on the pharmacokinetics (PK) of a sensitive substrate of CYP3A (midazolam).
Interventions
Investigational Medicinal Product: Linaprazan glurate (tablets). Part I: Linaprazan glurate in base form, 100 mg once daily Day 1 and Day 10. Part II: Linaprazan glurate hydrochloride (HCl), 75 mg twice daily for 13 days.
DRUGDrug drug interaction (DDI) - Clarithromycin (Part I)
Index inhibitor (perpetrator drug) Clarithromycin 500 mg twice daily for 9 days (tablets).
DRUGDrug drug interaction (DDI) - Midazolam (Part 2)
Substrate for CYP3A. Midazolam 2.5 mg once daily (2.5 mL oral solution).
Sponsors
Cinclus Pharma Holding AB
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Main Inclusion Criteria: 1. Willing and able to give written informed consent for participation in the study. 2. Healthy male and female subjects of non-childbearing potential aged 18 to 60 years, inclusive. 3. Body mass index ≥ 18.0 and ≤ 30.0 kg/m2. 4. Subjects as well as their partners, must agree to contraception requirements. Male subjects must refrain from donating sperm. Main
Exclusion criteria
1. Have known allergies to any components of the linaprazan glurate formulation, to clarithromycin/midazolam or to any drugs of a similar class including excipients associated with any of the drugs. 2. Use of CYP3A4 inhibitors, antacids, PPIs or any medication that changes gastric pH. 3. Use of any prescribed or non-prescribed CYP3A4-inducing medication or other metabolic enzyme inducers. 4. History of any clinically significant disease or disorder defined in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf | Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10). | Area under the plasma concentration curve from 0 to infinity (AUC0-inf). The AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz). |
| Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t | Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10). | AUC from time 0 to time t (AUC0-t). AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. |
| Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax | and 72 h after dosing (on dosing Days 1 and 10). | Maximum plasma concentration (Cmax). Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. |
| Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-inf | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). | Area under the plasma concentration curve from 0 to infinity - AUCinf. AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz). |
| Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-t | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). | AUC from time 0 to time t - AUC0-t. AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. |
| Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate - Cmax | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). | Maximum plasma concentration - Cmax. Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. |
Countries
Sweden
Participant flow
Recruitment details
Subjects were recruited from CTC's database of volunteers and from advertising in media (including social media).
Pre-assignment details
Screening details: The screening visits were performed within 28 days prior to dosing (Day 28 to Day -1) for both parts. Part I: 27 subjects were screened and 17 subjects were included in Part I of the study. Part II: 56 subjects were screened and 18 subjects were included in Part II of the study.
Participants by arm
| Arm | Count |
|---|---|
| Part I Linaprazan glurate in base form, tablets 100 mg administered under fasting conditions Day 1 and Day 10.
Drug drug interaction (DDI) - Clarithromycin (Part I): Index inhibitor (perpetrator drug) Clarithromycin 500 mg twice daily for 9 days (tablets). | 17 |
| Part II IMP Linaprazan glurate hydrochloride (HCl), tablets 75 mg twice daily for 13 days. Morning dose administered under fasting conditions on Day 2 and Day 14.
Drug drug interaction (DDI) - Midazolam: Substrate for CYP3A. Midazolam 2.5 mg once daily (2.5 mL oral solution) Day 1, Day 2 and Day 14. | 18 |
| Total | 35 |
Baseline characteristics
| Characteristic | Part I | Total | Part II |
|---|---|---|---|
| Age, Continuous | 37.5 years STANDARD_DEVIATION 13 | 36.2 years STANDARD_DEVIATION 12.7 | 35.0 years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 33 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 31 Participants | 15 Participants |
| Region of Enrollment Sweden | 17 participants | 35 participants | 18 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Male | 12 Participants | 28 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 11 / 17 | 8 / 18 |
| serious Total, serious adverse events | 0 / 17 | 0 / 18 |
Outcome results
Primary
Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-inf
Area under the plasma concentration curve from 0 to infinity - AUCinf. AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz).
Time frame: Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14).
Population: Data is presented for:~* Midazolam alone, Day 1~* Midazolam co-administered with linaprazan glurate, Day 2~* Midazolam co-administered with linaprazan glurate, Day 14
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-inf | Midazolam (alone) | 38.57 h*ng/mL | Standard Deviation 13.98 |
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-inf | Midazolam (co-admin) Day 2 | 40.78 h*ng/mL | Standard Deviation 16.04 |
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-inf | Midazolam (co-admin) Day 14 | 33.06 h*ng/mL | Standard Deviation 10.46 |
Primary
Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-t
AUC from time 0 to time t - AUC0-t. AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject.
Time frame: Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14).
Population: Data is presented for:~* Midazolam alone, Day 1~* Midazolam co-administered with linaprazan glurate, Day 2~* Midazolam co-administered with linaprazan glurate, Day 14
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-t | Midazolam (co-admin) Day 14 | 32.19 h*ng/mL | Standard Deviation 10.41 |
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-t | Midazolam (alone) | 37.12 h*ng/mL | Standard Deviation 13.86 |
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-t | Midazolam (co-admin) Day 2 | 39.66 h*ng/mL | Standard Deviation 16.01 |
Primary
Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate - Cmax
Maximum plasma concentration - Cmax. Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject.
Time frame: Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14).
Population: Data is presented for:~* Midazolam alone, Day 1~* Midazolam co-administered with linaprazan glurate, Day 2~* Midazolam co-administered with linaprazan glurate, Day 14
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate - Cmax | Midazolam (alone) | 12.24 ng/mL | Standard Deviation 4.091 |
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate - Cmax | Midazolam (co-admin) Day 2 | 13.69 ng/mL | Standard Deviation 5.892 |
| Part I | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate - Cmax | Midazolam (co-admin) Day 14 | 13.53 ng/mL | Standard Deviation 6.092 |
Primary
Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf
Area under the plasma concentration curve from 0 to infinity (AUC0-inf). The AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz).
Time frame: Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10).
Population: Data is presented for:~* Linaprazan (active metabolite) after 100 mg single dose administered alone~* Linaprazan (active metabolite) after 100 mg single dose co-administered with clarithromycin~* Linaprazan glurate (prodrug) after 100 mg single dose administered alone~* Linaprazan glurate (prodrug) after 100 mg single dose co-administered with clarithromycin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf | Linaprazan (alone) | 13950 h*nmol/L | Standard Deviation 5649 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf | Linaprazan (co-admin) | 42840 h*nmol/L | Standard Deviation 16260 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf | Linaprazan glurate (alone) | 137.3 h*nmol/L | Standard Deviation 52.02 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf | Linaprazan glurate (co-admin) | 165.9 h*nmol/L | Standard Deviation 79.56 |
Primary
Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t
AUC from time 0 to time t (AUC0-t). AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject.
Time frame: Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10).
Population: Data is presented for:~* Linaprazan (active metabolite) after 100 mg single dose administered alone~* Linaprazan (active metabolite) after 100 mg single dose co-administered with clarithromycin~* Linaprazan glurate (prodrug) after 100 mg single dose administered alone~* Linaprazan glurate (prodrug) after 100 mg single dose co-administered with clarithromycin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t | Linaprazan (alone) | 13870 h*nmol/L | Standard Deviation 5346 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t | Linaprazan (co-admin) | 39870 h*nmol/L | Standard Deviation 13840 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t | Linaprazan glurate (alone) | 133.6 h*nmol/L | Standard Deviation 51.87 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t | Linaprazan glurate (co-admin) | 160.6 h*nmol/L | Standard Deviation 81.64 |
Primary
Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax
Maximum plasma concentration (Cmax). Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject.
Time frame: and 72 h after dosing (on dosing Days 1 and 10).
Population: Data is presented for:~* Linaprazan (active metabolite) after 100 mg single dose administered alone~* Linaprazan (active metabolite) after 100 mg single dose co-administered with clarithromycin~* Linaprazan glurate (prodrug) after 100 mg single dose administered alone~* Linaprazan glurate (prodrug) after 100 mg single dose co-administered with clarithromycin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax | Linaprazan (alone) | 1844 nmol/L | Standard Deviation 712.4 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax | Linaprazan (co-admin) | 2742 nmol/L | Standard Deviation 1217 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax | Linaprazan glurate (alone) | 131.1 nmol/L | Standard Deviation 53.72 |
| Part I | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax | Linaprazan glurate (co-admin) | 176.8 nmol/L | Standard Deviation 114.3 |