To determine the effect of antiretroviral agents (low-dose ritonavir + lopinavir, low-dose ritonavir + atazanavir, efavirenz) on the pharmacokinetics of single-dose atovaquone determined by intersubject comparison. Secondary objectives: - to…
ID
Source
Brief title
Condition
- Protozoal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The effect of lopinavir/ritonavir, atazanavir/ritonavir and efavirenz on
atovaquone pharmacokinetics (AUC, Cmax).
Secondary outcome
The effect of lopinavir/ritonavir, atazanavir/ritonavir and efavirenz on
proguanil pharmacokinetics (AUC, Cmax).
Adverse events of a single dose atovaquone/proguanil (250/100 mg), alone, or in
combination with lopinavir/ritonavir, atazanavir/ritonavir or efavirenz.
Background summary
Atovaquone is marketed in a 250mg QD dose with proguanil for use in the
treatment and prophylaxis of malaria (Malarone®). Due to its convenience, this
agent is frequently used as a prophylactic measure by HIV-infected patients who
travel from western countries to areas endemic with malaria such as Africa,
Asia and South America.
Unfortunately, there are indications for drug interactions of atovaquone with
some frequently prescribed antiretroviral drugs. Although no data are
available, the Summary of Product Characteristics of Kaletra®
(lopinavir/ritonavir) and Norvir® (ritonavir) warn for reduced atovaquone
plasma levels in combined use.
There is indirect evidence that increased glucuronidation of atovaquone is the
most likely mechanism of this potential interaction with antiretroviral agents.
Until recently, only high-dose ritonavir was known to induce glucuronosyl
transferase. Data are accumulating, though, that also low-dose ritonavir is
still able to induce glucuronidation enzymes.
The ability of low dose ritonavir to induce glucuronidation, makes that an
interaction between atovaquone and all boosted Protease Inhibitor regimes is
conceivable.
A similar interaction may occur between atovaquone and the NNRTIs nevirapine
and efavirenz. For instance, efavirenz reduces plasma concentrations of another
substrate for glucuronyltransferase, pravastatin, by 40%.
Summarizing, a substantial number of HIV patients that travel to areas endemic
with malaria use Malarone®. This makes it is very useful to know if any
relevant interaction occurs between atovaquone (and proguanil) and
antiretroviral agents. Therefore, we propose to do a clinical study on
potential interactions between antiretroviral agents and atovaquone/proguanil
when used as prophylaxis of malaria. Lopinavir/ritonavir and
atazanavir/ritonavir will be used as examples of boosted PIs and efavirenz as
an example of an NNRTI.
Study objective
To determine the effect of antiretroviral agents (low-dose ritonavir +
lopinavir, low-dose ritonavir + atazanavir, efavirenz) on the pharmacokinetics
of single-dose atovaquone determined by intersubject comparison.
Secondary objectives:
- to determine the effect of antiretroviral agents (low-dose ritonavir +
lopinavir,
low-dose ritonavir + atazanavir, efavirenz) on the pharmacokinetics of
single-
dose proguanil determined by intersubject comparison.
- To evaluate the safety of combined use of single-dose atovaquone/proguanil and
lopinavir/ritonavir, atazanavir/ritonavir and efavirenz.
Study design
Open-label, multi-centre, phase-IV, single-dose trial
Intervention
All subjects receive a single dose Malarone® (atovaquone / proguanil 250/100
mg).
Study burden and risks
Clinical studies concluded that Malarone® in the dosage used in the
prophylaxis of malaria, had no more side effects than placebo.
Likewise, clinical practice has proven that atovaquone/proguanil for malaria
prophylaxis is well tolerated.
The risk to which we expose all participants in this study with a single dose
of Ma-larone therefore seems very small.
The needles that are used for blood sampling may cause local irritation and
pain.
Postbus 9101 / Geert Grooteplein 10
6500 HB Nijmegen
Nederland
Postbus 9101 / Geert Grooteplein 10
6500 HB Nijmegen
Nederland
Listed location countries
Age
Inclusion criteria
Healthy volunteers:
1.Subject is at least 18 and not older than 65 years of age on the day of
dosing of atovaquone/proguanil.
2.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.
3.Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
4.Subject is in good age-appropriate health condition as established by medical
history, physical examination, results of biochemistry, haematology and
urinalysis testing within 4 weeks prior to the first dose.Results of biochemistry,
haematology and urinalysis testing should be within the laboratory's reference
ranges (see Appendix A). If not, the subject is included on condition that the
Investigator judges that the deviations are not clinically relevant. This should be
clearly recorded.
5.Subject has a normal blood pressure and pulse rate, according to the
Investigator's judgement.;HIV patients:
1.HIV-infected as documented by positive HIV antibody test and confirmed by Western Blot.
2.CD4+ > 200 * 106 /L.
3.Subject is at least 18 and not older than 65 years of age at the day of dosing of atovaquone/proguanil.
4.Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
5.Use of lopinavir/ritonavir, atazanavir/ritonavir or efavirenz for at least 1 month in a dose of 400/100mg bid, 300/100 mg QD, or 600 mg QD respectively.
Exclusion criteria
Healthy volunteers:
1.History of sensitivity/idiosyncrasy to atovaquone/proguanil or chemically related
compounds or excipients.
2.Positive HIV test.
3.Positive HbsAg test (hepatitis B) or positive hepatitis C test.
4.Therapy with any drug (for two weeks preceding dosing), except for paracetamol.
5.Creatinine clearance < 60 mL/min (calculated from serum creatinine).
6.Current diarrhoea.
7.History of or current abuse of drugs, alcohol or solvents.
8.Participation in a drug trial within 60 days prior to the first dose.
9.Donation of blood within 60 days prior to the first dose.
10.Pregnant female (as confirmed by an HCG test performed less than 3 weeks fore the first dose) or breast-feeding female.
11.Abnormal serum transminases, determined as levels being > 3 times up-per limit of normal (see Appendix A for normal ranges of clinical laboratory values).
12.Febrile illness within 3 days before the first dose;HIV patients:
1.History of sensitivity/idiosyncrasy to atovaquone/proguanil or chemically related compounds or excipients.
2.Suspicion of non-adherence to the HIV medication.
3.Current diarrhoea.
4.Pregnant female (as confirmed by an HCG test performed less than 3 weeks before the first dose) or breast-feeding female.
5.Abnormal serum transminases determined as levels being > 3 times upper limit of normal (see Appendix A for normal ranges of clinical laboratory values).
6.Creatinine clearance < 60 mL/min (calculated from serum creatinine).
7.Any change in antiretroviral medication within 1 month immediately preceding the dose of atovaquone/proguanil.
8.Concomitant use of medications that interfere with atovaquone or proguanil pharmacokinetics: anti-coagulants, aurothioglucose, chloroquine, cimetidine, fluoxetine, fluvoxamine, metoclopramide, omeprazole, magnesiumtrisilicate, rifabutin, rifampin, tetracycline, thyphoid vaccine, topiramate.
9.Use of a HAART regime containing both lopinavir/ritonavir and an other protease inhibitor or an NNRTI.
10.Use of a HAART regime containing both atazanavir/ritonavir and an other protease inhibitor or an NNRTI.
11.Use of a HAART regime containing both efavirenz and one or more protease inhibitors or nevirapine.
12.Active hepatobiliary or hepatic disease
13.Alcohol abuse
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 | EUCTR2006-002864-24-NL |
| CCMO | NL12993.091.06 |