Effect of Clarithromycin on PK of Linaprazan, Linaprazan on PK of Clarithromycin and Linaprazan on PK of Midazolam

Phase 1

Completed

• Conditions: Tolerability; Safety Issues; Pharmacokinetics; Drug Interaction
• Interventions: Drug: Linaprazan glurate; Drug: Drug drug interaction (DDI) - Clarithromycin (Part I); Drug: Drug drug interaction (DDI) - Midazolam (Part 2)

• Registration Number: NCT05633147
• Lead Sponsor: Cinclus Pharma Holding AB

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-11-21
• Study First Submitted QC: 2022-11-21
• Study Start: 2022-11-27
• Study First Posted: 2022-12-01
• Primary Completion: 2023-05-30
• Study Completion: 2023-05-30
• Results First Submitted: 2024-02-08
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-14
• Last Update Submitted: 2024-11-14
• Results First Posted: 2025-01-03
• Last Update Posted: 2025-01-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 35

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
linaprazan glurate	Drug drug interaction (DDI) - Midazolam (Part 2)	Part I: Linaprazan glurate in base form, 100 mg once daily will be administered under fasting conditions at day 1 and day 10. Part II: Linaprazan glurate hydrochloride (HCl), 75 mg twice a day for 13 days. The morning dose will be administered under fasting conditions on Day 2 and Day 14.
linaprazan glurate	Drug drug interaction (DDI) - Clarithromycin (Part I)	Part I: Linaprazan glurate in base form, 100 mg once daily will be administered under fasting conditions at day 1 and day 10. Part II: Linaprazan glurate hydrochloride (HCl), 75 mg twice a day for 13 days. The morning dose will be administered under fasting conditions on Day 2 and Day 14.
linaprazan glurate	Linaprazan glurate	Part I: Linaprazan glurate in base form, 100 mg once daily will be administered under fasting conditions at day 1 and day 10. Part II: Linaprazan glurate hydrochloride (HCl), 75 mg twice a day for 13 days. The morning dose will be administered under fasting conditions on Day 2 and Day 14.

Primary Outcome Measures

Name	Time	Method
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 - 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 - 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.

Trial Locations

Locations (1)

CTC Clinical Trials Consultants AB; 🇸🇪 Uppsala, Sweden