Pharmacokinetics of single-dose dOLutegravir in HIV-serOnegative sub-jects with severe hepatic impairment compared to matched controls (POLO).

Phase 4

Withdrawn

Conditions: HIV
human immunodefìciency virus
10047438

Registration Number: NL-OMON47050

Lead Sponsor: Afdeling Apotheek

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Withdrawn

Sex: Not specified

Target Recruitment: 15

Inclusion Criteria

Hepatic impairment group:
1. Subject is at least 18 and not older than 90 years at screening.
2. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
3. Child-Pugh score 10 or greater (Appendix A). Expected to be in clinical stable condition for at least 4 weeks as assessed by the subject*s own hepatologist. This assessment takes into account the following aspects: MELD score, fibroscan results (if available), life expectancy, recent history of decompensation events and the rate of progression of hepatic insufficiency.;Matched controls:
1. Subject is at least 18 and not older than 90 years at screening.
2. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
3. Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix D). If laboratory results are not within the reference ranges, the subject is in-cluded on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
4. Subject has a normal blood pressure and pulse rate, according to the Investigator's judgement.

Exclusion Criteria

Hepactic impairment group:
1. Inability to understand the nature and extent of the study and the pro-cedures required.
2. Gilbert*s syndrome or other underlying disease (other than hepatic impairment) that causes alterations in the Child-Pugh class components (bilirubin, albumin, protombin, encephalopathy and ascites).
3. Therapy with strong inducers or inhibitors of UGT1A1 or drugs that are contra-indicated with concomitant use of dolutegravir (see appendix B). (NB. there are restrictions for intake of magnesium/aluminium-containing antacids, iron and calcium supplements, multivitamins and other cation-containing supplements.
4. Positive HIV test.
5. Participation in a drug study within 60 days prior to Day 1.
6. Febrile illness within 3 days before Day 1.;Matched controls:
1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
2. Positive HIV test.
3. Positive hepatitis B or C test.
4. Pregnant female (as confirmed by an hCG test performed less than 4 weeks before Day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception (see Appendix C).
5. Therapy with strong inducers or inhibitors of UGT1A1 or drugs that are contra-indicated with concomitant use of dolutegravir (see appendix B). (NB. there are restrictions for intake of magnesium/aluminium-containing antacids, iron- and calciumsupplements, multivitamins and other cation-containing supplements.
6. Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disor-ders, renal and hepatic disorders, hormonal disorders (especially dia-betes mellitus), coagulation disorders.
7. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
8. History of or current abuse of drugs, alcohol or solvents.
9. Inability to understand the nature and extent of the study and the pro-cedures required.
10. Participation in a drug study within 60 days prior to Day 1.
11. Donation of blood within 60 days prior to Day 1.
12. Febrile illness within 3 days before Day 1
13. UGT1A1 polymorphism (at least one *28, *37 or *6 allele)

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Geometric Mean and the 95% classical confidence interval of AUC0-24h, Cmax,<br /><br>C24h and median (range) of tmax for dolutegravir and dolutegravir glucuronide<br /><br>in hepatic impaired subjects.<br /><br><br /><br>Geometric Mean and the 95% classical confidence interval of CUnbound DTG, t=3h<br /><br>and CUnbound DTG, t=24h after administration. </p><br>

Secondary Outcome Measures