Primary Objectives:• To assess the effects of VOR 200 mg BID on the steady-state PK of ATV administered as ATV/RTV300/100 mg QD in healthy subjects• To assess the effects of ATV/RTV 300/100 mg QD on the steady-state PK of VOR 200 mg BID inhealthy…
ID
Source
Brief title
Condition
- Other condition
- Fungal infectious disorders
Synonym
Health condition
HIV infectie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Pharmacokinetic Measures: Multiple-dose pharmacokinetic parameters (Cmax,
Tmax,
AUC(TAU), and Ctrough) will be derived from plasma concentration versus time
for ATV, RTV
and VOR and the combined use of these drugs.
Secondary outcome
• Safety Outcome Measures: Safety assessments will be based on medical review
of adverse event
reports and the results of vital sign measurements, ECGs, physical
examinations, and clinical
laboratory tests. The incidence of observed adverse events will be tabulated
and reviewed for
potential significance and clinical importance.
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. As a result of highly active
antiretroviral therapy (HAART), the incidence and prevalence of most
opportunistic infections has decreased. OPC remains however the most frequent
HIV-associated oral disease in resource limited settings or in non-compliant
patients.
The occurrence of OPC and CE is associated with low CD4 T-lymphocyte counts,
high viral loads and disease progression, 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.
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. Voriconazole is a second generation
triazole with antifungal activity against a broad range of yeast and moulds
that has been proven to be a valid alternative for fluconazole.
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. 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.
Atazanavir is a substrate as well as a potent inhibitor of CYP3A4. Ritonavir
potently inhibits CYP3A4 and is used at low dose (100 mg QD) with ATV as a
pharmacoenhancer. Ritonavir also induces multiple phase I and II enzymes
including
CYP1A2, CYP2C9, CYP2C19, as well as glucuonosyl transferase.4 Voriconazole is
extensively metabolized in the liver, primarily by CYP2C19 and to a lesser
extent by CYP2C9 as well as CYP3A4. Voriconazole is also an inhibitor of the 3
enzymes. Given the metabolic properties of these compounds, drug - drug
interactions via enzyme inhibition /induction are expected upon
co-administration.
Collectively, based on the metabolic properties of ATV, RTV and VOR, the net
effect of ATV/RTV on VOR exposures should not deviate significantly from the
reported range after VOR and RTV 100 mg BID; VOR is unlikely to affect ATV
concentrations when dosed with ATV/RTV.
The current study is designed to test this hypothesis. When there is an
indication for antifungal therapy in an HIV-infected patient, combined use of
voriconazole and atazanavir / ritonavir would be an attractive option for
treatment of HIV and fungal infection.
Study objective
Primary Objectives:
• To assess the effects of VOR 200 mg BID on the steady-state PK of ATV
administered as ATV/RTV
300/100 mg QD in healthy subjects
• To assess the effects of ATV/RTV 300/100 mg QD on the steady-state PK of VOR
200 mg BID in
healthy subjects.
Secondary Objective(s):
• To assess the effects of VOR 200 mg BID on the steady-state PK of RTV
administered as ATV/RTV
300/100 mg QD in healthy subjects
• To assess the safety and tolerability of coadministration of ATV/RTV 300/100
mg QD and VOR 200
mg BID in healthy subjects.
Study design
This is an open-label, 3-period, single-sequence, multiple dose study in
healthy subjects.
Intervention
During this study, which lasts 31 days in total, subjects have to take study
medication during three treatment-periods which last from 3, 10 and 10 days
each.
There will be 24 participants
There is a wash-out periods of 7 days between the first and second treatment
period.
Study burden and risks
Both voriconazole and atazanavir / ritonavir are well tolerated.
Participants are monitered frequently for adverse events.
Intake of medication is for a limited time period only. 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.
Vijzelmolenlaan 9
3447 GX Woerden
NL
Vijzelmolenlaan 9
3447 GX Woerden
NL
Listed location countries
Age
Inclusion criteria
1) Signed Written Informed Consent
a) The signed informed consent form.
2) Target Population
a) Healthy subjects as determined by no clinically significant deviation from normal
in medical history, physical examination, ECGs, and clinical laboratory
determinations.
b) Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive. BMI = weight (kg)/
[height (m)]2.
3) Age and Sex
a) Women who are not of childbearing potential (ie, who are postmenopausal or
surgically sterile) and men, ages 18 to 45 inclusive.
Women are considered surgically sterile only if they have undergone a
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy. Post menopause
is defined as:
• Amenorrhea >= 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
> 35 mIU/mL
Exclusion criteria
1) Sex and Reproductive Status
a) WOCBP
• WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or is not postmenopausal. Women who
are using oral contraceptives, other hormonal contraceptives (vaginal
products, skin patches, or implanted or injectable products), or mechanical
products such as an intrauterine device or barrier methods (diaphragm,
condoms, spermicides) to prevent pregnancy, or are practicing abstinence or
where their partner is sterile (eg, vasectomy) should be considered to be of
childbearing potential.
b) Women who are pregnant or breastfeeding
c) Women with a positive pregnancy test on enrollment or prior to administration of
investigational product.
d) Sexually active fertile men not using effective birth control if their partners are
WOCBP.
2) Medical History and Concurrent Diseases
a) Proven or suspected acute hepatitis (within 12 months prior to the 1st dose)
b) Any significant acute or chronic medical illness.
c) Current or recent (within 3 months) gastrointestinal disease.
d) Any major surgery within 4 weeks prior to study drug administration.
e) Any gastrointestinal surgery that could impact upon the absorption of study drug.
f) Donation of blood or plasma to a blood bank or in a clinical study (except a
screening visit) within 4 weeks prior to study drug administration.
g) Blood transfusion within 4 weeks prior to study drug administration.
h) Inability to tolerate oral medication.
i) Inability to be venipunctured and/or tolerate venous access.
j) Smoking more than 5 cigarettes per day.
k) Recent (within 6 months) drug or alcohol abuse as defined in DSM IV, Diagnostic
Criteria for Drug and Alcohol Abuse (Appendix 2).
l) Any other sound medical, psychiatric and/or social reason as determined by the
investigator.
m) Consumption of alcohol within 3 days prior to the first dose of study drug.
n) Intractable diarrhea (>= 6 loose stools/day for at least 7 consecutive days) within
30 days prior to the first dose of study drug.
o) History of any hemolytic disorders (including drug-induced hemolysis).
p) History of acute or chronic pancreatitis.
q) History of hypochlorhydria or achlorhydria.
3) Physical and Laboratory Test Findings
a) Men and Women < 40 Kg
b) Homozygous CYP2C19 poor metabolizers
c) Evidence of organ dysfunction or any clinically significant deviation from normal
in physical examination, vital signs, ECG or clinical laboratory determinations
beyond what is consistent with the target population.
d) Positive urine screen for drugs of abuse.
e) Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or HIV
viral RNA or HIV-1, -2 antibody.
f) Liver enzymes (alkaline phosphatase, AST, ALT) above the upper limit of normal
at screening or prior to dosing.
g) QT interval >= 500 msec, QTcF interval >= 450 msec either at screening or prior to
dosing (confirmed by repeat ECG).
h) PR interval >= 210 msec, QRS interval >= 120 msec either at screening or prior to
dosing (confirmed by repeat ECG).
i) First, second- or third-degree A-V block or clinically relevant ECG abnormalities
either at screening or prior to dosing.
4) Allergies and Adverse Drug Reactions
a) History of allergy to ATV, RTV, VOR and related compounds.
b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
c) Patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption.
5) Prohibited Treatments and/or Therapies
a) Exposure to any investigational drug or placebo within 4 weeks prior to study
drug administration.
b) Use of any prescription drugs or over-the-counter acid controllers within 4 weeks
prior to study drug administration.
c) Use of any other drugs, including over-the-counter medications and herbal
preparations, within 1 week prior to study drug administration.
d) Use of an oral, injectable or implantable hormonal contraceptive agent within
3 months prior to study drug administration.
e) Use of St. John*s Wort (Hypericum) within 4 weeks prior to the first dose of study
drug and throughout the study.
f) Consumption of grapefruit, seville orange and grapefruit juice, seville orange -
containing products within 7 days prior to the first dose of study drug and
throughout the study.
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
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 | EUCTR2009-009095-13-NL |
| CCMO | NL27011.091.09 |