The main purpose of this study is to evaluate the effect of varying degrees of impaired hepatic function (by Child Pugh classification) on the plasma PK of siremadlin after a single oral dose. In addition, safety and tolerability of siremadlin after a single oral dose will be evaluated. The results of this study will inform the decision whether a dose adjustment may be recommended when treating patients with various degrees of impaired hepatic function.
Participants will be recruited into one of 4 groups according to the Child-Pugh classification score. Participants with HI will be enrolled into either mild (Child-Pugh A; Group 2), moderate (Child Pugh B; Group 3) or severe (Child-Pugh C; Group 4) HI groups. Healthy control participants (Group 1) will be matched to 1 or more participants with HI with respect to age (± 10 years), body weight (± 20%) and sex. Each participant in the matched healthy control group (Group 1) can be matched to participant(s) in any HI group (Groups 2, 3, and 4). The study will enroll the four groups in parallel. Therefore, enrollment in Group 1 will remain open until enrollment in the mild, moderate and severe HI groups is complete and each HI participant has a matched healthy control (Group 1) participant. Participants from Group 1 will be enrolled after at least 3 participants from each of Groups 2 and 3 have completed all scheduled assessments. The study consists of a screening period of up to 28 days (Days -29 to -2), a baseline evaluation on Day -1, a single dose administration of siremadlin on Day 1 followed by PK sampling up to 144 hours post-dose (Day 7). All baseline safety evaluation results must be available and reviewed prior to the dosing. All eligible participants will be domiciled from Day -1 until Day 7. Safety assessments will include physical examinations, ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, urinalysis, coagulation), AE and serious adverse event (SAE) monitoring. All participants will have a post-study safety follow-up contact conducted approximately 30 days after administration of study treatment. The study will be considered complete once all the participants have finished the required assessments, dropped out, or been lost to follow-up before completing the required assessments. The total study duration for each participant is expected to be up to maximum of 59 days, including the Screening period and the 30-day post-study safety contact follow up period.
Study Type
INTERVENTIONAL
Allocation
HDM201 capsule
Clinical Pharmacology of Miami LLC
Miami, Florida, United States
Orlando Clinical Research Center
Orlando, Florida, United States
Texas Liver Institute
San Antonio, Texas, United States
Pharmacokinetics (PK): Cmax
Maximum Observed Blood Concentrations (Cmax) for siremadlin. Blood samples will be collected to measure Cmax at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): AUClast
Area Under Plasma Concentration-time Curve from time zero to the last measurable concentration sampling time (AUClast) for siremadlin. Blood samples will be collected to measure AUClast at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): AUC0-t
Area Under Plasma Concentration from time zero to time "t" (AUC0-t). The definition of "t" may be data driven post-hoc to mitigate bias in the exposure comparision due to between-group differences in Tlast for siremadlin. Blood samples will be collected to measure AUC0-t at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): AUC0-24h
Area Under Plasma Concentration from time zero to 24-hour post-dose sampling time (AUC0-24h) for siremadlin. Blood samples will be collected to measure AUC0-24h at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
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NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
38
Pharmacokinetics (PK): Tlast
Last measurable plasma concentration (Tlast) for siremadlin. Blood samples will be collected to measure Tlast at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): Tmax
Time to Reach Maximum Blood Concentrations (Tmax) for siremadlin. Blood samples will be collected to measure Tmax at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): CL/F
Apparent total body clearance of siremadlin from plasma (CL/F). Blood samples will be collected to measure CL/F at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): Vz/F
Apparent volume of distribution during terminal elimination phase (Vz/F) of siremadlin. Blood samples will be collected to estimate Vz/F at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): T1/2
Terminal Elimination Half-life (T1/2) for siremadlin. Blood samples will be collected to measure T1/2 at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours
Pharmacokinetics (PK): AUCinf
Area Under Plasma Concentration from time zero to infinity (AUCinf). Blood samples will be collected to measure AUCinf at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time frame: pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours