To determine the effect of chronic use of ginkgo biloba on the single-dose pharma-cokinetics (AUC0-inf, AUC0-12, Cmax, C12) of raltegravir 400mg in healthy volunteers.
ID
Source
Brief title
Condition
- Viral infectious disorders
- Cognitive and attention disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetic parameters of raltegravir (and metabolite).
Secondary outcome
Safety: adverse events and lab values.
Background summary
Ginkgo biloba was listed no. 4 on the top-20 selling herbal dietary supplements
in the US in 2004 and no. 1 on a similar top-20 list in Germany in 2003. As
mentioned above, it is claimed that the product has positive effects on
cognitive function and depressive symptoms, so will definitely be used among
the HIV-infected patient population.
Reductions in plasma exposures of 34% (on average) may be highly relevant for
antire-troviral agents as low plasma concentrations may select for resistance
and eventually result in virological failure. As a result, use of St John*s
wort is a contra-indication ac-cording to the Summary of Product
Characteristics of raltegravir, although the combination has not been studied
clinically. For other herbal agents who have the potential to negatively affect
the exposure to antiretroviral agents such as raltegravir, we are missing
evidence-based recommendations to either assure patients that these products
can be safely combined with antiretroviral therapy, or that they must be
advised not to take these products. In daily clinical practice, patients often
take these herbal products without informing their treating physician, and
patient information sheets do not contain specific warnings (other than for St
John*s wort). The recent case report on ginkgo biloba induced reductions in
efavirenz plasma concentrations with subsequent virological failure is a good
example of the clinical relevance of interactions between herbal agents and
antiretroviral therapy.
While there is some information on the potential effects of ginkgo biloba both
from in vitro and in vivo studies with CYP450 and PgP substrates and one in
vitro study investi-gating glucuronidation, there is currently no information
on its potential effects on glucuronidation in vivo. Many inducers of CYP450
and PgP are also UDG-glucuronyltransferase (UGT) inducers, hence at least
theoretically it can be expected that ginkgo biloba may reduce plasma
concentrations of the UGT substrate raltegravir.
Study objective
To determine the effect of chronic use of ginkgo biloba on the single-dose
pharma-cokinetics (AUC0-inf, AUC0-12, Cmax, C12) of raltegravir 400mg in
healthy volunteers.
Study design
Open-label, 2-period, randomized, cross-over, single-centre, phase-I trial.
Group A will receive 120mg ginkgo biloba BID (Tavonin®) for 15 days plus a
single dose of 400mg raltegravir on Day 15. After a washout period of 3 weeks
the subjects will receive a single dose of 400mg ral-tegravir on Day 36.
Group B will receive a single dose of 400mg raltegravir on Day 15. After a
washout period of 7 days they will receive 120mg ginkgo biloba BID (Tavonin®)
for 15 days plus a single dose of 400mg raltegravir on day 36.
Group will be assigned at random.
Intervention
Dosing with raltegravir (two times a doses of 400mg) and ginkgo biloba (14 days
twice daily 120mg; day 15 a single dose of 120mg).
Study burden and risks
Adverse events of the drugs raltegravir and ginkgo biloba.
Ginkgo biloba causes light gastro-intestinal complaints in rare cases, headache
or allergic skin reactions. In very rare cases bleeding was observed after long
term treatment with ginkgo biloba.
Adverse events of raltegravire include (in >10% of the users): sleeping
difficulties; abnormal dreams; dizziness; headache; bloated feeling in belly;
abdomial pain; diarrhea; flatulence; mailaise; vomiting; rash (more often
observed if combined with darunavir); fatigue, uncommon fatigue or weakness;
fever; abnormal (increased) results of livertests; abnormal white bloodcells;
increased concentration of lipids in the blood; increased concentrations of
saliva gland enzymes or pancreatic enzymes.
The possible adverse events of the combination of ginkgo biloba and raltegravir
are not yet known.
Needles used to draw blood may cause inconvenience or pain at the insertion
site.
Geert Grooteplein Zuid 10
6525 GA Nijmegen
NL
Geert Grooteplein Zuid 10
6525 GA Nijmegen
NL
Listed location countries
Age
Inclusion criteria
1. Subject is at least 18 and not older than 55 years at screening.
2. Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1
3. Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
4. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
5. Subject is in good age-appropriate health condition as estab-lished by medical history, physical examination, electrocardi-ography, results of biochemistry, haematology and urinalysis testing.
6. Subject has a normal blood pressure and pulse rate, according to the Investigator's judgement.
Exclusion criteria
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 the first dose) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the trial.
5. Therapy with any drug (for two weeks preceding dosing), ex-cept for paracetamol.
6. Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (espe-cially seizures and migraine), psychiatric disorders, glaucoma, gastro-intestinal disorders, renal and hepatic disorders, hor-monal disorders (especially diabetes mellitus), coagulation dis-orders.
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 trial and the procedures required.
10. Participation in a drug trial 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.
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 | EUCTR2010-018719-14-NL |
| CCMO | NL33543.091.10 |