TMC278-TiDP6-C130: Pharmacokinetics, Safety and Tolerability of TMC278 in Subjects With Mildly or Moderately Impaired Hepatic Function.
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The purpose of this study is to investigate the pharmacokinetics (how the drug is absorbed into the bloodstream, distributed in the body and eliminated from the body) after a single dose and after repeated administration of TMC278 administered once daily for 11 days in subjects with mild or moderate hepatic impairment (impaired liver function), compared with healthy control subjects. Furthermore the short-term safety and tolerability (how well the body tolerates the drug) of TMC278 will be assessed.
Condition or disease
Human immunodeficiency virus (HIV)-infected patients are routinely being treated with combinations of 3 or 4 drugs (highly active antiretroviral therapy [HAART]), to reduce the risk of viral resistance development. Development of new potent antiretroviral (ARV) drugs is urgently needed to prolong suppression of viral replication in subjects infected with HIV. This is a Phase I, open-label, parallel, controlled, sequential study to investigate the single-dose and steady-state pharmacokinetics, and short-term safety and tolerability of TMC278 in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. The trial aims to provide guidance on administration and dose recommendations of TMC278 in subjects with mildly or moderately impaired hepatic function. The study population will consist of a total of 32 male and female subjects between 18 and 65 years. Panel A will consist of 8 subjects with mild hepatic impairment and 8 healthy subjects matched for sex, age (± 5 yrs), and BMI (± 15%). Panel B will consist of 8 subjects with moderate hepatic impairment and 8 healthy subjects matched for sex, age (± 5 yrs), and BMI (± 15%). Treatment in Panel A and Panel B will be conducted sequentially. Subjects in Panel A will receive a TMC278 25 mg tablet once daily for a total of 11 days. Recruitment for subjects for Panel B will start after evaluation of the safety, tolerability and pharmacokinetic data from subjects in Panel A. The anticipated dose of TMC278 to be administered to subjects in Panel B is the same dose as for Panel A (25 mg once daily for 11 days), but this dose might be adjusted depending on the results of Panel A.
The primary objective of this study is to assess the single-dose and steady-state pharmacokinetics of TMC278 in subjects with mild or moderate hepatic impairment compared to matched healthy control subjects.
Secondary Outcome Measures :
The secondary objective of this study is to assess the short-term safety and tolerability of TMC278 in subjects with mild or moderate hepatic impairment compared to matched healthy control subjects.
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Layout table for eligibility information
Ages Eligible for Study:
18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Non smoking or smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day for at least 3 months prior to selection
Body Mass Index (BMI, weight in kg divided by the square of height in meters) of 18.0 to 32.0 kg/m2, extremes included
Only for subjects with hepatic impairment: History of hepatic disease
Documented liver cirrhosis
Mild or moderate liver function impairment
Only for healthy control subjects: Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs and the results of blood biochemistry and hematology tests and a urinalysis
Matched to a subject with hepatic impairment with regards to sex, age (± 5 yrs), and BMI (± 15%).
No positive HIV test
No females, except if postmenopausal since more than 2 years, or posthysterectomy, or post tubal ligation
No barbiturate, amphetamine, recreational or narcotic drug use
No use of more than 1 unit of alcoholic beverages per day
No positive urine drug test
No active gastrointestinal disease (with the exception of liver cirrhosis in the hepatically impaired subjects), cardiovascular, neurologic, psychiatric, metabolic, renal, respiratory, inflammatory, or infectious disease
No currently significant diarrhea, gastric stasis, or constipation
No history of any significant skin disease
No previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e. TMC278)
Not previously participated in more than 1 trial with TMC125, TMC120 and/or TMC278 or having developed a rash, erythema or urticaria while participating in a trial with the aforementioned compounds
No participation in an investigational drug trial within 60 days prior to the first administration of trial medication
No donation of blood or plasma or significant blood loss within the 60 days preceding the first administration of trial medication
No vulnerable subjects
No subjects who are not able to read or write
Only for subjects with hepatic impairment: No acute or active hepatitis
No evidence of hepatic decompensation
No grade 3 or 4 encephalopathy
No hepatic carcinoma
No hepatorenal syndrome
No severe liver insufficiency
Not an active candidate for liver transplantation
No grade 3 laboratory abnormalities present with the exception of laboratory abnormalities related to hepatic impairment
Only for healthy control subjects: No hepatitis A, B or C infection