Primary objective:To assess the effect of multiple dose atorvastatin on the steady state pharmacokinetics of raltegravir and vice versa by intrasubject comparison in healthy subjects.• The comparison of steady state raltegravir (400 mg BID for 7…
ID
Source
Brief title
Condition
- Viral infectious disorders
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic
parameters (AUC0-t, Cmax, Ct) of raltegravir for raltegravir with atorvastatine
vs. raltegravir alone and of atorvastatine for atorvastatine with raltegravir
vs. atorvastatine alone.
Secondary outcome
The safety profile of the combined use of raltegravir and atorvastatin.
The comparison of change in LDL cholesterol of short-term atorvastatine use
with or without raltegravir.
Background summary
Dyslipidemia is highly prevalent among patients with HIV infection and
contributes to the increased cardiovascular disease risk in this patient
population. Atorvastatin lowers plasma low-density lipoprotein (LDL)
cholesterol levels and is used for prevention of artherosclerotic disease.
Raltegravir, an HIV integrase inhibitor, could be one of the preferred
antiretroviral agents in HIV patients with dyslipidemia because it has a
beneficial lipid profile.
Theoretically, no clinically relevant drug interaction is expected between
atorvastatin and raltegravir. However, atorvastatin and raltegravir share
similar metabolic pathways which could be relevant in the occurrence of
pharmacokinetic interactions. In order to be able to recommend raltegravir and
atorvastatin concomitant use, a pharmacokinetic study in healthy volunteers is
proposed.
Study objective
Primary objective:
To assess the effect of multiple dose atorvastatin on the steady state
pharmacokinetics of raltegravir and vice versa by intrasubject comparison in
healthy subjects.
• The comparison of steady state raltegravir (400 mg BID for 7 days)
pharmacokinetics (AUC0-12h, Cmax, C12h) with atorvastatin (20 mg QD for 7 days)
vs. raltegravir alone by intrasubject compari-son.
• The comparison of steady state atorvastatin (20 mg QD for 7 days)
pharmacokinetics (AUC0-24h, Cmax, C24h) with raltegravir (400 mg BID for 7
days) vs. atorvastatin alone by intrasubject compari-son.
Secondary objective:
• To evaluate the safety and tolerability of co administration of raltegravir
and atorvastatin in healthy subjects.
• To investigate the non-steady state changes in serum LDL cholesterol
secondary to short-term atorvastatin use in the presence or absence of
raltegravir.
Study design
The 24 subjects will be divided into 6 groups of 4 subjects.
Each group will take the following treatments, but in a different order.
Washout periods of 14 days will be scheduled between treatments.
Treatments:
A. Raltegravir 400 mg BID for 7 days
B. Atorvastatin 20 mg QD for 7 days
C. Raltegravir 400 mg BID + Atorvastatin 20 mg QD for 7 days
Treatment sequence per group:
• Group 1: ABC
• Group 2: ACB
• Group 3: BCA
• Group 4: BAC
• Group 5: CAB
• Group 6: CBA
On day 7 of each treatment periode blood samples will be collected for a
pharmacokinetic plasmaconcentration-time curve of raltegravir and/or
atorvastatin.
Intervention
Administration of raltegravir 400 mg BID for two times 7 days. Administration
of atorvastatin 20 mg once daily for two tomes 7 days.
Study burden and risks
The study participants are healthy volunteers and will not benefit from the
participation in this clinical trial.
Atorvastatin is widely used in clinical practice and generally well tolerated;
adverse effects are mostly mild and not frequently observed. Common adverse
effects are: nausea, abdominal discomfort, increased liver function (ASAT,
ALAT) and headaches. To minimize the risk of concentration related adverse
events, such as myopathy, a relatively low dose of atorvastatin (20 mg QD) will
be used in this drug interaction trial.
Raltegravir has been tested in both treatment-naïve and -experienced pa-tients
and has an excellent risk/benefit ratio. The most common adverse events (> 5%
incidence) associated with raltegravir were gastro-intestinal-related effects,
headeache and dizziness, which were generally transient, self-limiting and
mild-to moderate in severity. The possible adverse events of the combination of
raltegravir and atorvastatin are not yet known. Because both raltegravir and
atorvastatin have been associated with cases of myopathy, this could be an
additional risk factor when used in combination. Lab safety is performed
regularly throughout the study and participants are asked about possible
adverse events on each visit. Subjects are asked to notify the trial
physician/investigator immediately when unexplained muscle ache occurs.
Participants will visit the clinical research centre for a screening visit, 12
short visits (1 hour) and 3 full days (13 hours). The duration of the entire
trial (excluding screening period) is 50 days. Duration of treatment with study
medication is 3 weeks.
For pharmacokinetic purposes 62 blood samples will be taken in total. For
safety assessment (haematology and clinical chemistry), hCG bloodtest, blood
glucose and pharmacogenetic testing a total of 34 blood samples will be
collected. The total bloodvolume taken will be 485 mL maximum. During the days
that blood samples will be collected for a pharmacokinetic curve an intravenous
cannula will be inserted to facilitate blood sampling and limit the amount of
venous punctions.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
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 the first dosing
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 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, haematology and urinalysis testing should be within the laboratory's reference ranges. 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.
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 day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterec-tomy, 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 study.
5. Therapy with any drug (for two weeks preceding dosing), except for acetaminophen.
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, musculoskeletal and con-nective tissue disorders.
7. Relevant history or current condition that might interfere with drug ab-sorption, 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 the first dose.
11. Donation of blood within 60 days prior to the first dose.
12. 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 | EUCTR2012-005147-24-NL |
| CCMO | NL43180.091.13 |