Primary: To determine the influence of posaconazole on unboosted fosamprenavir pharmacokinetics, and vice versa, in healthy volunteersSecondary: To determine the safety of combined use of fosamprenavir with posaconazole in healthy vol-unteers
ID
Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-To determine the effect of posaconazole on fosamprenavir pharmacokinetics
(AUC, Cmax, Cmin)
-To determine the effect of fosamprenavir on posaconazole pharmacokinetics
(AUC, Cmax, Cmin)
Secondary outcome
-Adverse effects which are either due to posaconazole, fosamprenavir/ ritonavir
or combined use of posaconazole and
fosamprenavir.
Background summary
Infections with fungi and yeast frequently occur in patients infected with the
human immu-nodeciency virus type 1 (HIV-1). Oropharyngeal candidiasis (OPC) and
candida esophagitis (CE) have been reported to occur in up to 90% of the
subjects infected with HIV and these are therefore the most common encountered
opportunistic infections in these patients (1-3). As a result of highly active
antiretroviral therapy (HAART), the incidence and prevalence of most
opportunistic infections has decreased (4;5). OPC remains however the most
frequent HIV-associated oral disease in resource limited settings or in
non-compliant patients (6).
The occurrence of OPC and CE is associated with low CD4 T-lymphocyte counts,
high viral loads and disease progression (2;4), but at the same time OPC tends
to be one of the earliest opportunistic infections seen in patients with CD4
T-lymphocyte counts > 200 cells/mm3. As HIV infection progresses with declining
CD4+ cells and increasing HIV viral loads, the se-verity of OPC increases with
more frequent relapses, for which systemic therapy may be nec-essary (7).
Azole antifungal drugs are first line therapy in the treatment of oropharyngeal
candidiasis and invasive fungal infections. Fluconazole is first line therapy
to treat fungal infections in HIV positive patients with oral candidiasis.
However, with the emergence of resistant strains, fluconazole might not provide
adequate protection in all patients (8-10). Posaconazole is a second generation
triazole with antifungal activity against a broad range of yeast and moulds
that has been proven to be a valid alterna-tive for fluconazole (11;12).
The combination of antiretroviral drugs (either non-nucleoside reverse
transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs)) with azole
antifungal drugs is not without risk. NNRTIs may reduce the efficacy of many
azole antifungals due to induction of hepatic me-tabolism (13). PIs themselves
are influenced to a large extent when combined with potent inhibitors of
enzymatic pathways (such as the azoles) leading to increased exposure to the PI
with possible increased toxicity (13).
Fosamprenavir is a PI that is used to treat HIV-infection in combination with
ritonavir. Once hydrolyzed to amprenavir, this substance is a substrate for
CYP3A4. Ritonavir is an ex-tremely potent inhibitor of CYP3A4 and serves as a
booster of the pharmacokinetics of am-prenavir (14). Posaconazole is a very
potent CYP3A4 inhibitor and therefore might enhance amprenavir pharmacokinetics
in a similar way as ritonavir.
The current study is designed to test this hypothesis. When there is an
indication for antifun-gal therapy in an HIV-infected patient, temporal
replacement of ritonavir by posaconazole would be an attractive option for
combined treatment of HIV and fungal infection.
Study objective
Primary:
To determine the influence of posaconazole on unboosted fosamprenavir
pharmacokinetics, and vice versa, in healthy volunteers
Secondary:
To determine the safety of combined use of fosamprenavir with posaconazole in
healthy vol-unteers
Study design
This is an open-label, sequential, 3-period, cross-over, single-centre,
phase-I, multiple-dose trial in 24 healthy volunteers.
Intervention
During this study, which lasts 67 days in total, subjects have to take study
medication during three treatment-periods which last 10 days each.
The 24 participants will be divided into 6 groups that receive the three
treatments in a different order.
There are two wash-out periods of 17 days between these three treatment
periods.
Study burden and risks
Both posaconazole and fosamprenavir/ ritonavir are well tolerated.
Participants are monitered frequently for adverse events.
Intake of medication is for a limited time period only (10 days). Also combined
intake is for a limited period (10 days).
On the day of dosing an indwelling Venflon I.V. cannula will be inserted in a
peripheral vein of each subject by a physician or an authorised nurse to
facilitate repeated blood sampling. The use of these needles might cause some
degree of dyscomfort. The risk for the patient is very limited.
For specific, drug related, side effects, we refer to the study protocol.
Postbus 9101
6500 HB Nijmegen
Nederland
Postbus 9101
6500 HB Nijmegen
Nederland
Listed location countries
Age
Inclusion criteria
-Subject is at least 18 and not older than 55 years of age on the day of the first dosing.
- Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to the first dosing.
- Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes in-cluded.
- Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
- 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 the first dose. Results of biochemistry, hae-matology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A) If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
- Subject has a normal blood pressure and pulse rate, according to the Investigator's judgement.
Exclusion criteria
- Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
- Positive HIV test.
- Positive hepatitis B or C test.
- Pregnant female (as confirmed by an HCG test performed less than 4 weeks before the first dose) or breast-feeding female.
-Therapy with any drug (for two weeks preceding dosing), except for paracetamol.
- Subjects with an ECG with QTc interval greater than 450 msec for men, and greater than 470 msec for women at screening.
-Relevant history or presence of pulmonary disorders (especially COPD), cardiovascu-lar disorders, neurological disorders (especially seizures and migraine), gastro-intestinal disorders, renal and hepatic disorders, hormonal disorders (especially diabe-tes mellitus), coagulation disorders.
-Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
- History of or current abuse of drugs, alcohol or solvents.
- Inability to understand the nature and extent of the trial and the procedures required.
11. Participation in a drug trial within 60 days prior to the first dose.
12. Donation of blood within 60 days prior to the first dose.
13. Febrile illness within 3 days before the first dose
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-006243-39-NL |
| CCMO | NL25510.091.08 |