Phase 1
Completed N=26
A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function
Muscular Atrophy, Spinal
Source: ClinicalTrials.gov NCT03920865 ↗
Enrolled (actual)
26
Serious AEs
3.9%
Results posted
Feb 2021
Primary outcomePrimary: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) — 792; 987; 222; 263 h*ng/mL
Summary
This is a multi-center, open-label, non-randomized, parallel-group, 2-part study to evaluate the effect of hepatic impairment on the PK and safety and tolerability of a single oral dose of risdiplam compared to matched healthy participants with normal hepatic function.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) |
792; 987; 222; 263 | — |
| PRIMARY Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 |
773; 961; 197; 245 | — |
| PRIMARY Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 |
21.7; 22.8; 3.73; 3.92 | — |
| PRIMARY Part 2: AUCinf of Risdiplam and M1 |
1040; 971; 261; 275 | — |
| PRIMARY Part 2: AUClast of Risdiplam and M1 |
1020; 947; 243; 259 | — |
| PRIMARY Part 2: Cmax of Risdiplam and M1 |
29.9; 25.0; 4.10; 4.13 | — |
| SECONDARY Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 |
4.00; 4.00; 10.00; 10.00 | — |
| SECONDARY Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 |
41.3; 55.0; 32.9; 38.2 | — |
| SECONDARY Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 |
2.34; 2.53; 7.49; 6.28 | — |
| SECONDARY Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 |
0.0168; 0.0126; 0.0211; 0.0182 | — |
| SECONDARY Part 1: Apparent Total Clearance (CL/F) of Risdiplam |
6.31; 5.07 | — |
| SECONDARY Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 |
0.258; 0.255 | — |
| SECONDARY Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 |
0.165; 0.164 | — |
| SECONDARY Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 |
0.244; 0.245 | — |
| SECONDARY Part 2: Tmax of Risdiplam and M1 |
2.00; 4.00; 24.00; 11.00 | — |
| SECONDARY Part 2: t1/2 of Risdiplam and M1 |
45.6; 49.9; 34.5; 35.0 | — |
| SECONDARY Part 2: %AUCextrap of Risdiplam and M1 |
1.90; 2.41; 6.58; 5.68 | — |
| SECONDARY Part 2: λz of Risdiplam and M1 |
0.0152; 0.0139; 0.0201; 0.0198 | — |
| SECONDARY Part 2: CL/F of Risdiplam and M1 |
4.79; 5.15 | — |
| SECONDARY Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 |
0.239; 0.271 | — |
| SECONDARY Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 |
0.131; 0.158 | — |
| SECONDARY Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 |
0.227; 0.262 | — |
| SECONDARY Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |
62.5; 12.5; 0.0; 0.0; 12.5; 0.0 | — |
Eligibility Criteria
Inclusion Criteria
All Participants:
- BMI between 18.0 and 36.0 kilograms per square metre (kg/m2), inclusive, and body weight > / = 50 kg
- Females must not be pregnant or lactating and must be of non-childbearing potential
- Male participants (whether surgically sterilized or not) with female partners of childbearing potential must use methods of contraception from Screening until 4 months after their dose of the study drug as detailed in the protocol
- Male participants must not donate sperm from Check-in (Day -1) until 4 months after their dose of the study drug
Participants with Normal Hepatic Function Only:
- Matched to participants with mild or moderate hepatic function in sex, age, BMI, and smoking status
- In good health, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations
Participants with Hepatic Impairment Only:
- Documented chronic stable liver disease
- Currently on a stable medication regimen, defined as not starting new drug(s) or changing drug dose(s) within 3 months of administration of study drug
- Anemia secondary to hepatic disease will be acceptable, if hemoglobin >/= 9 gram per decilitre (g/dL). Participants must have a platelet count 150 millimetre of mercury (mmHg) or 159 mmHg or < 90 mmHg
- Values outside the normal range for liver function tests that are not consistent with their hepatic condition
- Use of a new medication, or a change in dose, for the treatment, or worsening of, hepatic encephalopathy
- Use of prescription drugs within 14 days of study drug administration
- Recent history of, or the treatment of, esophageal bleeding
- Presence of a portosystemic shunt
- Recent history of paracentesis
- Current functioning organ transplant or are waiting for an organ transplant
- Evidence of severe ascites
- History or current symptoms of hepatic encephalopathy Grade 2 or above
Data sourced from ClinicalTrials.gov (NCT03920865). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.