The aim of this multi-part Phase 1 study is to evaluate the drug-drug interaction (DDI) potential of ALG-097558 via co-administration with a P-gp substrate (dabigatran) and a CYP3A4 inhibitor/P-gp inhibitor (itraconazole). In addition, this study will evaluate the relative bioavailability and food effect of a new tablet formulation for ALG-097558. This study consists of 3 parts, all conducted in healthy volunteers (HV). Study Parts A and B are designed to assess the perpetrator or victim DDI risk of ALG-097558 mediated by CYP/P-gp interactions in healthy adult subjects. Part A will evaluate the potential impact of itraconazole, a CYP3A potent inhibitor, while Part B will investigate the potential impact of ALG-097558 (perpetrator) on dabigatran etexilate, a P-gp transporter substrate. Study Part C is designed to study the bioavailability of a new formulation of the ALG-097558 tablet and the food effect on this tablet. This study has one primary objective for each part of the study. For Part A: to evaluate the effect of a CYP3A4 inhibitor/Pg-p inhibitor, itraconazole, on the pharmacokinetics (PK) of ALG-097558 and the metabolite, ALG-097730. For Part B: to evaluate the effect of multiple doses of ALG-097558 on the pharmacokinetics of a P-gp substrate, dabigatran. For Part C: to evaluate the relative bioavailability of 2 different tablet formulations of ALG-097558 and effect of food on the pharmacokinetics of ALG-097558 and the metabolite, ALG-097730.
The aim of this multi-part Phase 1 study is to evaluate the drug-drug interaction (DDI) potential of ALG-097558 via co-administration with a P-gp substrate (dabigatran) and a CYP3A4 inhibitor/P-gp inhibitor (itraconazole). In addition, this study will evaluate the relative bioavailability and food effect of a new tablet formulation for ALG-097558. This study consists of 3 parts, all conducted in healthy volunteers (HV). As ALG-097558 is a substrate of CYP3A4 and P-gp transporters, any concomitant administration of an inhibitor or inducer drug may alter its exposures. Part A will evaluate the potential impact of itraconazole, a CYP3A potent inhibitor, on the ALG-097558 (victim) systemic exposure in a single group, partially-blinded study. Part B will investigate the potential impact of ALG-097558 (perpetrator) on dabigatran etexilate, a P-gp transporter substrate in a single group, open-label study. Study Part C is designed to study the bioavailability of a new formulation of the ALG-097558 tablet and the food effect on this tablet in an open-label, randomized, crossover study. This study has one primary objective for each part of the study. For Part A: to evaluate the effect of a CYP3A4 inhibitor/Pg-p inhibitor, itraconazole, on the pharmacokinetics (PK) of ALG-097558 and the metabolite, ALG-097730. For Part B: to evaluate the effect of multiple doses of ALG-097558 on the pharmacokinetics of a P-gp substrate, dabigatran. For Part C: to evaluate the relative bioavailability of 2 different tablet formulations of ALG-097558 and effect of food on the pharmacokinetics of ALG-097558 and the metabolite, ALG-097730.The study has secondary objectives for each part of the study as well. For Part A: to evaluate the safety and tolerability of single doses of ALG-097558 in HV participants when administered as monotherapy or in combination with itraconazole. For part B: to evaluate the safety and tolerability and PK of multiple doses of ALG-097558 in HV participants when administered alone or in combination with dabigatran. For part C: to evaluate the safety and tolerability of single doses of ALG-097558 in HV participants.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
51
A selective, reversible, and potent inhibitor of the SARS-CoV-2 3CLpro with pan-coronavirus activity
A direct thrombin inhibitor approved for the treatment and prevention of blood clots to reduce the risk of stroke
A substrate and strong dual inhibitor of CYP3A4/P-glycoprotein (P-gp)
Placebo
Dr. Vince Clinical Research
Overland Park, Kansas, United States
Area Under the Concentration-time Curve From Time Zero to Infinity [Extrapolated] (AUC0-inf): ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B
Drug-drug interaction in Parts A and B was evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A) and dabigatran (Part B) in the test treatment condition (combined-treatment condition) relative to the reference treatment condition (single-treatment condition) was estimated by ANOVA with the 90% CI calculated for AUC0-inf. The evaluation of the potential food effect on the PK of ALG-097558 and the relative bioavailability assessment of Formulation 2 versus Formulation 1 in Part C was performed in 2 separate 2-treatment ANOVAs.
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9
Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B
Drug-drug interaction in Parts A and B was evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A) and dabigatran (Part B) in the test treatment condition (combined-treatment condition) relative to the reference treatment condition (single-treatment condition) was estimated by ANOVA with the 90% CI calculated for AUClast. The evaluation of the potential food effect on the PK of ALG-097558 and the relative bioavailability assessment of Formulation 2 versus Formulation 1 in Part C was performed in 2 separate 2-treatment ANOVAs.
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9
Elimination Half-life (t1/2):ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B
Drug-drug interactions for t1/2 were evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A and Part C) and dabigatran (Part B)
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9
Maximum Observed Concentration (Cmax):ALG-097558 in Plasma in Part A and Part C, Dabigatran (Total) in Plasma in Part B
Drug-drug interaction in Parts A and B was evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A) and dabigatran (Part B) in the test treatment condition (combined-treatment condition) relative to the reference treatment condition (single-treatment condition) was estimated by ANOVA with the 90% CI calculated for Cmax. The evaluation of the potential food effect on the PK of ALG-097558 and the relative bioavailability assessment of Formulation 2 versus Formulation 1 in Part C was performed in 2 separate 2-treatment ANOVAs.
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9
Time of Observed Maximum Concentration (Tmax):ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B
Drug-drug interactions for Tmax were evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A and Part C) and dabigatran (Part B)
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9
Area Under the Concentration-time Curve From Time Zero to Infinity [Extrapolated] (AUC0-inf) for ALG-097730 Plasma in Part A and Part C
Drug-drug interactions for AUC0-inf were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9
Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for ALG-097730 in Plasma in Part A and Part C
Drug-drug interactions for AUClast were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9
Elimination Half-life (t1/2) for ALG-097730 in Plasma in Part A and Part C
Drug-drug interactions for t1/2 were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9
Maximum Observed Concentration (Cmax) for ALG-097730 in Plasma in Part A and Part C
Drug-drug interactions for Cmax were evaluated using the geometric mean ratio (log-transformed)in Part A and Part C
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9
Time of Observed Maximum Concentration (Tmax) for ALG-097730 in Part A and Part C
Drug-drug interactions for Tmax were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C
Time frame: Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9
Maximum Observed Concentration (Cmax) of ALG-097558 in Plasma After Co-administration With a Single Dose of Dabigatran in Part B
PK parameter of Cmax was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: 0 to 72 hours post dose on Days 1 to 8
Time of Observed Maximum Concentration (Tmax):ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B
PK parameter of Tmax was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B
PK parameter of AUClast was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Elimination Half-life (t1/2) of ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B
PK parameter of t1/2 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Time of Last Measurable Concentration (Tlast):ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B
PK parameter of Tlast was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Maximum Observed Concentration (Cmax) of ALG-097730 in Plasma After Co-administration of ALG-097558 With a Single Dose of Dabigatran in Part B
PK parameter of Cmax for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
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Time frame: 0 to 72 hours post dose on Days 1 to 8
Time of Observed Maximum Concentration (Tmax):ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B
PK parameter of Tmax for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for Metabolite ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B
PK parameter of AUClast for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Elimination Half-life (t1/2) for Metabolite ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B
PK parameter of t1/2 for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Time of Last Measurable Concentration (Tlast):ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B
PK parameter of Tlast for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8
Metabolite to Parent Area Under the Concentration-time Curve Ratio From Time Zero to the Last Measurable Concentration (MPAUClast) for ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B
PK parameter of MPAUClast for metabolite ALG-097730 was assessed following 600 mg ALG-097558 Q12H co-administered with a single 75 mg dabigatran dose
Time frame: Part B-0 to 72 hours post dose on Days 1 to 8