Hepatic Impairment
Conditions
Keywords
Pharmacokinetics, Hepatic impaired patients, Healthy volunteers, Varying degrees of hepatic impairment
Brief summary
The purpose of this international study was to assess the effect of varying degrees of impaired hepatic function compared to a normal hepatic function (Child-Pugh classification) on the pharmacokinetics and safety of midostaurin.
Detailed description
Midostaurin was developed for the treatment of patients with hematological and nonhematological malignancies. However, disease complications and various co-medications made it difficult to perform a hepatic impairment study in the targeted patient population. Metabolism and elimination of midostaurin predominantly occurs in the liver. Patients with impaired hepatic function may have a higher risk to have a decreased elimination or metabolism of midostaurin which may lead to increased systemic exposure or toxicity, hence understanding the impact of an impaired hepatic function on midostaurin PK is important. Cumulative safety data from over 900 subjects exposed to midostaurin showed that the drug was well tolerated in patients and in healthy subjects, thus, it was appropriate and justifiable to study midostaurin in subjects with varying degrees of hepatic impairment. Due to the difficulty in enrolling subjects with severe hepatic impairment, an interim analysis was performed when all mild and moderate hepatic impaired subjects, and the respective control subjects, had completed the trial, in order to obtain interim results on the PK and safety of midostaurin in patients with mild and moderate hepatic impairment. The protocol was amended in April 2018 to make the inclusion / exclusion criteria more fitting with enrolling the severe hepatic impairment group. The final study analysis was performed when all severe hepatic impaired subjects, and the matching controls, had completed the study.
Interventions
DRUGMidostaurin
Midostaurin 25 mg soft gelatin capsules (2 capsules). The midostaurin capsules will be administered orally with 240 mL of non-carbonated water in the morning (between 8-10 AM), and in the evening (after a 12 hour break) from Day 1 to Day 6. On Day 7, midostaurin will be administered in the morning only (between 8-10 AM).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Adult male or female subjects age 18-70 years * Negative serum beta-hCG pregnancy test for all women prior to starting treatment * Normal vital signs, body weight, BMI and laboratory test results * Willing to comply with dietary, fluid and lifestyle restrictions * Able to communicate well with the Investigator and comply with the requirements of the study. Additional Inclusion Criteria for hepatic impaired subjects * Physical signs consistent with hepatic impairment * CPC score consistent with degree of hepatic impairment * Serum creatinine \<=2xULN * ANC \>1000cells/mm3, hemaglobin \>9g/dL, platelet count \> 50,000/mm3 (group 2-3 only) Key
Exclusion criteria
* Significant neurologic or psychiatric disorder which could compromise participation in the study. * History of: seizures requiring anti-convulsant therapy; unstable COPD; GI or rectal bleeding 3 weeks prior to study start; Myocardial Infarction within 12 months; unstable or poorly controlled angina or other clinically significant heart disease; clinically significant urinary obstruction or difficulty voiding; clinically significant ECG abnormalities or long QT-interval syndrome; pancreatic injury or pancreatitis * Concurrent severe / uncontrolled medical conditions * Significant illness within 2 weeks prior to dosing or hospitalisation within 4 weeks prior to dosing * Any surgical or medical condition that may significantly affect absorption, distribution, metabolism or excretion of drugs * Clinically significant ECG abnormalities at screening * Cotinine levels greater than 500ng/mL (group 1-3) or smokers not willing to limit tobacco or nicotine products equivalent to 10 cigarettes per day (group 4 and 5) for 1 week prior to dosing and throughout hospital confinement * Consumption of alcohol within 3 days (group 1-3) or within 2 days (groups 4 and 5) prior to dosing or during the study. * Administration of CYP3A4/5 or P-gp inducing or inhibiting drugs within 14 days prior to dosing or during the study * Sexually active males unless they use condom during intercourse while taking midostaurin and for at least 3 months after the last exposure to drug. * Use of any prescription drug within 2 weeks or over the counter medication within 72 hours prior to dosing * Consumption of grapefruit, grapefruit juice, Seville oranges, start fruit / juice within 72 hours prior to dosing Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentrations (Cmax) for midostaurin and its metabolites, CGP52421 and CGP62221 | at different timepoints from Day 1 to Day 7 | In subjects with Child Pugh A, Child Pugh B (and matching healthy volunteers) Cmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and matching healthy volunteers) Cmax will be measured at Day 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CYP3A4 induction by midostaurin in the hepatic impaired population | At different timepoints from Day 3 to Day 11 | CYP3A4 induction will be measured by assessing endogenous biomarkers (6beta-hydroxycortisol to cortisol ratio) applicable to multiple dosing Child Pugh A and Child Pugh B subjects and matching healthy volunteers) |
| Protein binding (free fraction) of midostaurin and it's metabolites | Day 1 and Day 7 | Free fraction of midostaurin and it's metabolites, CGP62221 and CGP52421, will be assessed by measuring their unbound concentration in plasma samples 3 hours post last dose on Day 1 (group 4 and 5) and Day 7 (group 1-3). |
| Apparent volume of distribution (Vz/F) of midostaurin | Day 1 and Day 7 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), volume of distribution will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), volume of distribution will be measured at Day 1. |
| Incidence of treatment emergent adverse events (AEs) | During the study and until 28 days follow-up period | Safety and tolerability of midostaurin measured by the number of treatment emergent adverse events in subjects with hepatic impairment (and matching healthy volunteers) |
| Elimination half life (t½) of midostaurin and its metabolites, CGP52421 and CGP62221 | Day 1 and Day 7 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), elimination half life will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), elimination half life will be measured at Day 1. |
| Time to maximum plasma concentration (tmax) for midostaurin and its metabolites, CGP52421 and CGP62221 | Day 1 and Day 7 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), tmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and healthy volunteers), tmax will be measured at Day 1. |
| Area under the plasma concentration versus time curves (AUCs) for midostaurin and its metabolites, CGP52421 and CGP62221 | Day 1 and Day 7 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), AUC will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and healthy volunteers), AUC will be measured at Day 1. |
| Total body apparent clearance of drug (CL/F) of midostaurin | Day 1 and Day 7 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), total body clearance will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), total body clearance will be measured at Day 1. |
Countries
Belgium, Bulgaria, Germany, Lithuania, Romania, United States
Outcome results
None listed