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Study to Determine the Pharmacokinetics on TPV/r in Subjects With Mild and Moderate Hepatic Insufficiency

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ClinicalTrials.gov Identifier: NCT02249442
Recruitment Status : Completed
First Posted : September 25, 2014
Last Update Posted : September 26, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
To determine the pharmacokinetics of single-dose and steady-state Tipranavir/Ritonavir (TPV/r) 500/200 mg in subjects with mild to moderate hepatic insufficiency

Condition or disease Intervention/treatment Phase
Hepatic Insufficiency Drug: Tipranavir (TPV) Drug: Ritonavir (r) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Study to Determine the Pharmacokinetics of Single-dose and/or Steady-state TPV/r 500/200 mg in Subjects With Mild and Moderate Hepatic Insufficiency
Study Start Date : October 2003
Actual Primary Completion Date : June 2004

Resource links provided by the National Library of Medicine

Drug Information available for: Tipranavir

Arm Intervention/treatment
Experimental: Scheme A, mild hepatic subjects
multi-dose
Drug: Tipranavir (TPV)
Drug: Ritonavir (r)
Experimental: Scheme B, moderate hepatic subjects
single dose
Drug: Tipranavir (TPV)
Drug: Ritonavir (r)



Primary Outcome Measures :
  1. AUC0-∞ (area under the concentration time curve of drug in plasma over the time interval from 0 extrapolated to infinity) [ Time Frame: Up to day 12 after first drug administration ]
  2. AUC0-12h (area under the concentration time curve of drug in plasma over the time interval from 0 to 12h) [ Time Frame: Up to 12 hours after drug administration ]
  3. Cmax (maximum concentration of drug in plasma) [ Time Frame: Up to day 12 after first drug administration ]
  4. Cp12h (drug concentration in plasma at 12 hours after administration) for the mild hepatic subjects [ Time Frame: Up to 12 hours (h) after drug administration ]

Secondary Outcome Measures :
  1. time from dosing to the maximum concentration (tmax) [ Time Frame: Up to day 12 after first drug administration ]
  2. elimination half-life (t1/2) [ Time Frame: Up to day 12 after first drug administration ]
  3. oral clearance (CL/F) [ Time Frame: Up to day 12 after first drug administration ]
  4. volume of distribution (Vz/F) [ Time Frame: Up to day 12 after first drug administration ]
  5. Relationship between pharmacokinetic parameters and baseline covariates [ Time Frame: Up to day 12 after first drug administration ]
    Covariates = age, weight, race, cigarette smoking and hepatic impairment

  6. Relationship between pharmacokinetic parameters and baseline covariates [ Time Frame: Up to day 12 after first drug administration ]
    Covariates = age, weight, race, cigarette smoking and the child-Pugh score as linear and quadratic terms

  7. Number of patients with abnormal changes in clinical laboratory parameters [ Time Frame: Up to day 12 after first drug administration ]
  8. Number of patients with adverse events [ Time Frame: Up to day 12 after first drug administration ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent prior to trial participation.
  2. Male and female subjects with:

    • Diagnostically established hepatic disease with mild hepatic insufficiency (defined as maximum ever Child-Pugh score ≤6) or
    • Diagnostically established hepatic disease with moderate hepatic insufficiency (defined as maximum ever Child-Pugh score ≤9) for less than 5 years. Current Child-Pugh score must be less than 9 or
    • Subjects matched by gender, race, age (±3 years), and weight (±3 kg) and cigarette smoking (matched where possible by +/- .25 pack years) to subjects with mild or moderate hepatic impairment already enrolled in the study.
  3. Body Mass Index (BMI) between 18 and 29 kg/m2
  4. Subjects ≥18 and ≤75 years old.
  5. Ability to swallow multiple large capsules without difficulty.
  6. Laboratory values that indicate adequate baseline organ function are required at the time of screening. All subjects (including healthy controls) should have all laboratory values less than or equal to Grade 1, based on the AIDS Clinical Trial Group (ACTG) Grading Scale.The following exceptions will be made only for subjects with mild or moderate hepatic insufficiency:

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <5 x upper limit normal (ULN) (≤ Grade 2)
    • Alkaline Phosphatase <2 x ULN
    • Hemoglobin >10.0 g / dL
    • Platelets >75,000 / μl
  7. Willingness to abstain from alcohol starting 2 days prior to administration of study drug up to the end of the study.
  8. Willingness to abstain from the following 72 hours prior to pharmacokinetic (PK) sampling: Garlic supplements, methylxanthine containing drinks (coffee, tea, cola, energy drinks, chocolate, etc.).
  9. Willingness to abstain from over the counter herbal medications for the duration of the study.
  10. Acceptable medical history, physical examination and chest X-ray (at investigator's discretion) are required prior to entering the treatment phase of the study.
  11. Willingness to abstain from the following starting 14 days prior to administration of study drug up until the end of the study: Grapefruit or grapefruit juice; Red wine; Seville oranges (marmalade); St. John's Wort or Milk Thistle.
  12. Willingness to abstain from vigorous physical exercise during intense PK study days (Days 1 and 7).
  13. Reasonable probability for completion of the study, including dosing requirements of TPV/r and risk for hepatic decompensation among subjects with mild and moderate hepatic insufficiency.

Exclusion Criteria:

  1. Female subjects who are of reproductive potential who:

    • Have positive serum β-hCG (Human chorionic gonadotropin test for pregnancy) at Visit 1 or on Day 0.
    • Have not been using a barrier contraceptive method for at least 3 months prior to Day 0 (Visit 2).
    • Are not willing to use a reliable method of at least barrier contraception, during the trial and 60 days after completion/termination.
    • Are breast-feeding.
  2. Participation in another trial with an investigational medicine within 60 days prior to Day 0 (Visit 2).
  3. Use of any medication listed in the protocol within 30 days prior to Day 0 (Visit 2).
  4. Use of any pharmacological contraceptive (including oral or patch) for one month prior to study initiation and for the duration of the study. Use of implantable or injectable contraceptive agents is excluded for at least six months prior to study start.
  5. Use of hormone replacement therapy with estrogen-based preparations for at least 1 month prior to study initiation and for the duration of the study.
  6. Administration of antimicrobial agents within 10 days prior to Day 0 (Visit 2) or during the trial.
  7. Subjects with a history of spontaneous bacterial peritonitis, advanced hepatic cirrhosis (including Child's-Pugh score >8), active esophageal variceal disease, or asterixis.
  8. Subjects with active or untreated hepatocellular carcinoma or who test positive for serum alpha fetoprotein (>10mg/dL).
  9. Subjects with active coagulopathy.
  10. Have serological evidence of exposure to, or infection with, HIV.
  11. Recent history of alcohol or substance abuse (within 6 months of study period).
  12. Blood or plasma donations within 30 days prior to Day 0 (Visit 2).
  13. Subjects with a seated systolic blood pressure either <100 mm Hg or >150 mm Hg; resting heart rate either <50 beats/min or >90 beats/min. For subjects with a resting heart rate below 50, or above 90, the investigator could discuss exclusion with the medical monitor on a case-by-case basis.
  14. Subjects with a history of any illness or allergy that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering TPV and ritonavir (RTV).
  15. Subjects who have had an acute illness within 2 weeks prior to Day 0 (Visit 2).
  16. Current use of any medications to control symptoms of hepatic disease within 30 days prior to Day 0, (Visit 2) or for the duration of the trial.
  17. Known hypersensitivity to TPV, Ritonavir or the sulphonamide class of drugs.
  18. Inability to adhere to the requirements of the protocol.
Additional Information:
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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02249442    
Other Study ID Numbers: 1182.32
First Posted: September 25, 2014    Key Record Dates
Last Update Posted: September 26, 2014
Last Verified: September 2014
Additional relevant MeSH terms:
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Hepatic Insufficiency
Liver Failure
Liver Diseases
Digestive System Diseases
Ritonavir
Tipranavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors