HIV InfectionsNCT03515772
Drug-drug Interactions Between Antiretroviral Drugs and Cardiovascular Drugs in Elderly Patients
An observational study of HIV Infections and Drug Interactions, run by Centre Hospitalier Universitaire Vaudois at 2 sites in Switzerland.
Trial summary
Ageing is characterized by physiological changes, which can impact drug pharmacokinetics and thereby cause drug-drug interactions. This study aims to assess the pharmacokinetics of amlodipine, atorvastatin and rosuvastatin in the presence of darunavir/ritonavir (inhibitor of drug metabolizing enzymes and drug… Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- HIV Infections, Drug Interactions, Cardiovascular Diseases
- What is being tested?
- Co-administration of darunavir with a cardiovascular drug
- How many people
- 21 participants
- Where
- 2 sitesSwitzerland
- Study dates
- 23 Apr 2018to 29 Aug 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Child, Adult, Older adult
Study population: HIV patients treated with the anti-HIV agents dolutegravir or darunavir, while simultaneously receiving cardiovascular agents, namely amlodipine, atorvastatin or rosuvastatin
Who may be able to join
- documented HIV-infection
- informed consent as documented by signature (Appendix Informed Consent Form)
- included in the SHCS and followed-up in the HIV Clinic in Lausanne or in Basel
- treatment with a HIV therapy including either once-daily ritonavir-boosted darunavir or dolutegravir (or others ARV drugs for the exploratory investigations)
- treatment with one or eventually 2 of the comedications of interest, i.e. amlodipine, atorvastatin or rosuvastatin (or any drug potentially involved in clinically relevant DDI for the exploratory investigations).
- Ability to comply with the study requirements
Who cannot join
- Presence of severe comorbidities (i.e. cirrhosis (Child-Pugh score C), heart failure (NYHA 3-4), advanced kidney impairment (KDOQI 4-5)) which can substantially impact the pharmacokinetic of drugs and significantly confound the study results.
- Presence of interacting non HIV comedications (i.e comedications with known, strong inhibitory or inducing effects on drug metabolizing cytochromes and drug transporters, which might significantly confound the study results)
- Participants incapable of jugement or participants under tutelage
- Known or suspected non-compliance, drug or alcohol abuse considered at risk to significantly confound the study results
- Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia of the participant,
- Enrolment of the investigator, his/her family members, employees and other dependent persons.
- Women who are pregnant or breastfeeding
Trial locations and contacts
2 sites in 1 country.
Switzerland2 sites
Universitätsspital Basel
Basel, 4031
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, 1011
About this study
Official title: Drug-drug Interactions Between Antiretroviral Drugs and Cardiovascular Drugs in Elderly Patients From the Swiss HIV Cohort Study
Ageing is characterized by physiological changes, which can impact drug pharmacokinetics and thereby cause drug-drug interactions. This study aims to assess the pharmacokinetics of amlodipine, atorvastatin and rosuvastatin in the presence of darunavir/ritonavir (inhibitor of drug metabolizing enzymes and drug transporters), by comparison with dolutegravir (no inhibitory effects on cytochromes or transporters involved in the disposition of the evaluated co-medications), in order to characterize the importance of drug-drug interactions in elderly individuals.
Read the detailed description
HIV-infected individuals live longer, making the proportion of older individuals within the HIV infected population constantly growing. Thus, the management of HIV infection is becoming more complex as patients encounter more age related chronic ailments such as hypertension, diabètes and tumors, or acute diseases, sometimes severe, leading to polypharmacy and consequently to potential drug-drug interactions (DDI). In addition, aging is characterized by a decline in the function of elimination organs, which may impact the pharmacokinetics of drugs and thereby the magnitude of DDI.
The principal aim of the study is to determine the importance of DDIs between antiretroviral drugs and commonly prescribed co-medications (namely amlodipine, rosuvastatin and atorvastatin) in HIV-infected patients of the Swiss HIV Cohort Study (SHCS). The investigation will include a majority of patients over 60 years old, yet without excluding younger patients. Pharmacokinetic investigations will be primarily conducted in patients treated with darunavir/ritonavir- or dolutegravir-containing regimens, and who receive one of the cardiovascular drug of interest. The objective is to contrast the effects of darunavir/ritonavir (strong inhibitor of drug metabolizing cytochromes) and dolutegravir (devoid of inhibitory effects on these enzymes), in order to determine the magnitude of the interaction with the co-medication. Besides their common use in elderly HIV-infected patients, amlodipine, atorvastatin and rosuvastatin were primarily selected due to their predisposition to become victims of drug-drug interactions. In addition, the same study framework will possibly serve to examine further drug combinations susceptible to interact, whose exploration could be of interest from a clinical point a view to stimulate future confirmatory research. It will thus be open to investigate associations of other cardiovascular agents with the antiretroviral drugs defined above, or with other antiretroviral drugs.
On a morning selected for investigation, the patient will take the antiretroviral medications together with the comedication of interest with a standard breakfast. Serial blood samples will be collected into EDTA-K monovettes (2.7 ml) from a catheter positioned in the forearm at the following time-points: t = 0 (just before the drug intake) and 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 12 hours after drug intake (a certain flexibility in sampling times is allowed, provided that dosing and sampling times are carefully recorded). The patient will then spend the night at home and return the following morning to provide the last sample of blood 24 hours after drugs intake. In total, 30 ml of blood will be required for a full pharmacokinetic investigation).
A second full pharmacokinetic investigation will be performed for patients undergoing antiretroviral treatment change for clinical reasons. The investigation will be scheduled two weeks after switching treatment, so that a steady-state is reached, and will be performed as described above.
The blood samples will be centrifuged and the separated plasma will be frozen at -80°C until analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters will be first estimated by classical non-compartmental approaches: Maximal concentration (Cmax), minimal concentration (Cmin), Area Under the Curve (AUC), slope of the terminal phase (Lambda_z), clearance (Cl), half-life (t1/2). These parameters will be compared according to the co-prescription of darunavir/ritonavir versus dolutegravir, using a variance analysis on log-transformed values. The analysis will accommodate partial pairing of parameter values obtained in patients investigated in cross-over, through the inclusion of a random patient factor (assumed to take independent values only between patients). PK parameters of antiretroviral drugs will be simply described.
- Conditions
- HIV Infections, Drug Interactions, Cardiovascular Diseases
- Being tested
- Co-administration of darunavir with a cardiovascular drug
- Keywords
- dolutegravir, darunavir, amlodipine, rosuvastatin, atorvastatin
- Medical subject headings
- HIV Infections, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Co-administration of darunavir with a cardiovascular drugDrug
Co-administration of darunavir, an HIV agent considered prone to induce drug interactions, with a cardiovascular drug (amlodipine, atorvastatin or rosuvastatin). Note that a patient will be able to participate in the intervention group and the control group if a change in his/her anti-HIV treatment occurs (study partly parallel and partly in cross-over).
| Study group | Role | What they receive |
|---|---|---|
| Amlodipine with Dolutegravir | This is the "control" group regarding HIV drug interaction potential on amlodipine | |
| Amlodipine with Darunavir | This is the "case" group regarding HIV drug interaction potential on amlodipine Receives: Drug: Co-administration of darunavir with a cardiovascular drug | |
| Atorvastatin with Dolutegravir | This is the "control" group regarding HIV drug interaction potential on atorvastatin | |
| Atorvastatin with Darunavir | This is the "case" group regarding HIV drug interaction potential on atorvastatin Receives: Drug: Co-administration of darunavir with a cardiovascular drug | |
| Rosuvastatin with Dolutegravir | This is the "control" group regarding HIV drug interaction potential on rosuvastatin | |
| Rosuvastatin with Darunavir | This is the "case" group regarding HIV drug interaction potential on rosuvastatin Receives: Drug: Co-administration of darunavir with a cardiovascular drug |
What is being measured
The primary outcome is the main question the study is designed to answer.
Circulating exposure (AUC) to cardiovascular agent amlodipine
Area under the curve (AUC) of the cardiovascular drug, namely amlodipine, in the presence of darunavir/ritonavir (inhibitory effect hypothesized) or dolutegravir (no inhibitory effect predicted).
Measured: 2 weeks
Circulating exposure (AUC) to cardiovascular agent atorvastatin
Area under the curve (AUC) of the cardiovascular drug, namely atorvastatin in the presence of darunavir/ritonavir (inhibitory effect hypothesized) or dolutegravir (no inhibitory effect predicted).
Measured: 2 weeks
Circulating exposure (AUC) to cardiovascular agent rosuvastatin
Area under the curve (AUC) of the cardiovascular drug, namely rosuvastatin in the presence of darunavir/ritonavir (inhibitory effect hypothesized) or dolutegravir (no inhibitory effect predicted).
Measured: 2 weeks
Secondary outcomes (1)
Circulating exposure (AUC) to another cardiovascular agent, if one appears frequently associated with HIV agents
Area under the curve (AUC) of the cardiovascular drug in the presence of darunavir/ritonavir (inhibitory effect hypothesized) or dolutegravir (no inhibitory effect predicted).
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 May 2018
- Study start23 Apr 2018
- Primary completion29 Aug 2019
- Study completion29 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by Centre Hospitalier Universitaire VaudoisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre Hospitalier Universitaire Vaudois
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Thierry Buclin, Centre Hospitalier Universitaire Vaudois
- Investigators
- Thierry Buclin, Prof., Principal investigator, Service of Clinical Pharmacology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03515772
- Sponsor's protocol ID
- HIV-Interactions
- Status last verified
- Jul 2020
- First submitted
- 23 Apr 2018
- Last updated
- 28 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The investigators will share anonymized IPD with colleagues interested upon motivated request
Publications
Courlet P, Guidi M, Alves Saldanha S, Stader F, Traytel A, Cavassini M, Stoeckle M, Buclin T, Marzolini C, Decosterd LA, Csajka C; and the Swiss HIV Cohort Study. Pharmacokinetic/Pharmacodynamic Modelling to Describe the Cholesterol Lowering Effect of Rosuvastatin in People Living with HIV. Clin Pharmacokinet. 2021 Mar;60(3):379-390. doi: 10.1007/s40262-020-00946-3. Epub 2020 Oct 29.
PubMed 33124006
Study at a glance
From the registry record, last updated by the sponsor on 28 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Drug-drug Interactions Between Antiretroviral Drugs and Cardiovascular Drugs in Elderly Patients From the Swiss HIV Cohort Study
- ClinicalTrials.gov ID
- NCT03515772
- Acronym / sponsor ID
- HIV-Interactions
- Conditions
- HIV Infections, Drug Interactions, Cardiovascular Diseases
- Keywords
- dolutegravir, darunavir, amlodipine, rosuvastatin, atorvastatin
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Centre Hospitalier Universitaire VaudoisUniversity, hospital or other
- Study start
- 23 Apr 2018 (actual)
- Primary completion
- 29 Aug 2019 (actual)
- Study completion
- 29 Aug 2019 (actual)
- First posted
- 4 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Ageing is characterized by physiological changes, which can impact drug pharmacokinetics and thereby cause drug-drug interactions. This study aims to assess the pharmacokinetics of amlodipine, atorvastatin and rosuvastatin in the presence of darunavir/ritonavir (inhibitor of drug metabolizing enzymes and drug transporters), by comparison with dolutegravir (no inhibitory effects on cytochromes or transporters involved in the disposition of the evaluated co-medications), in order to characterize the importance of drug-drug interactions in elderly individuals.
Detailed description
HIV-infected individuals live longer, making the proportion of older individuals within the HIV infected population constantly growing. Thus, the management of HIV infection is becoming more complex as patients encounter more age related chronic ailments such as hypertension, diabètes and tumors, or acute diseases, sometimes severe, leading to polypharmacy and consequently to potential drug-drug interactions (DDI). In addition, aging is characterized by a decline in the function of elimination organs, which may impact the pharmacokinetics of drugs and thereby the magnitude of DDI.
The principal aim of the study is to determine the importance of DDIs between antiretroviral drugs and commonly prescribed co-medications (namely amlodipine, rosuvastatin and atorvastatin) in HIV-infected patients of the Swiss HIV Cohort Study (SHCS). The investigation will include a majority of patients over 60 years old, yet without excluding younger patients. Pharmacokinetic investigations will be primarily conducted in patients treated with darunavir/ritonavir- or dolutegravir-containing regimens, and who receive one of the cardiovascular drug of interest. The objective is to contrast the effects of darunavir/ritonavir (strong inhibitor of drug metabolizing cytochromes) and dolutegravir (devoid of inhibitory effects on these enzymes), in order to determine the magnitude of the interaction with the co-medication. Besides their common use in elderly HIV-infected patients, amlodipine, atorvastatin and rosuvastatin were primarily selected due to their predisposition to become victims of drug-drug interactions. In addition, the same study framework will possibly serve to examine further drug combinations susceptible to interact, whose exploration could be of interest from a clinical point a view to stimulate future confirmatory research. It will thus be open to investigate associations of other cardiovascular agents with the antiretroviral drugs defined above, or with other antiretroviral drugs.
On a morning selected for investigation, the patient will take the antiretroviral medications together with the comedication of interest with a standard breakfast. Serial blood samples will be collected into EDTA-K monovettes (2.7 ml) from a catheter positioned in the forearm at the following time-points: t = 0 (just before the drug intake) and 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 12 hours after drug intake (a certain flexibility in sampling times is allowed, provided that dosing and sampling times are carefully recorded). The patient will then spend the night at home and return the following morning to provide the last sample of blood 24 hours after drugs intake. In total, 30 ml of blood will be required for a full pharmacokinetic investigation).
A second full pharmacokinetic investigation will be performed for patients undergoing antiretroviral treatment change for clinical reasons. The investigation will be scheduled two weeks after switching treatment, so that a steady-state is reached, and will be performed as described above.
The blood samples will be centrifuged and the separated plasma will be frozen at -80°C until analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters will be first estimated by classical non-compartmental approaches: Maximal concentration (Cmax), minimal concentration (Cmin), Area Under the Curve (AUC), slope of the terminal phase (Lambda_z), clearance (Cl), half-life (t1/2). These parameters will be compared according to the co-prescription of darunavir/ritonavir versus dolutegravir, using a variance analysis on log-transformed values. The analysis will accommodate partial pairing of parameter values obtained in patients investigated in cross-over, through the inclusion of a random patient factor (assumed to take independent values only between patients). PK parameters of antiretroviral drugs will be simply described.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Amlodipine with Dolutegravir | – | –This is the "control" group regarding HIV drug interaction potential on amlodipine |
| Amlodipine with Darunavir | – | Drug: Co-administration of darunavir with a cardiovascular drugThis is the "case" group regarding HIV drug interaction potential on amlodipine |
| Atorvastatin with Dolutegravir | – | –This is the "control" group regarding HIV drug interaction potential on atorvastatin |
| Atorvastatin with Darunavir | – | Drug: Co-administration of darunavir with a cardiovascular drugThis is the "case" group regarding HIV drug interaction potential on atorvastatin |
| Rosuvastatin with Dolutegravir | – | –This is the "control" group regarding HIV drug interaction potential on rosuvastatin |
| Rosuvastatin with Darunavir | – | Drug: Co-administration of darunavir with a cardiovascular drugThis is the "case" group regarding HIV drug interaction potential on rosuvastatin |
Who may qualify
- Sex
- All
- Age groups
- Child, Adult, Older adult
- Study population
- HIV patients treated with the anti-HIV agents dolutegravir or darunavir, while simultaneously receiving cardiovascular agents, namely amlodipine, atorvastatin or rosuvastatin
Key inclusion criteria (6 listed)
- documented HIV-infection
- informed consent as documented by signature (Appendix Informed Consent Form)
- included in the SHCS and followed-up in the HIV Clinic in Lausanne or in Basel
- treatment with a HIV therapy including either once-daily ritonavir-boosted darunavir or dolutegravir (or others ARV drugs for the exploratory investigations)
- treatment with one or eventually 2 of the comedications of interest, i.e. amlodipine, atorvastatin or rosuvastatin (or any drug potentially involved in clinically relevant DDI for the exploratory investigations).
Key exclusion criteria (7 listed)
- Presence of severe comorbidities (i.e. cirrhosis (Child-Pugh score C), heart failure (NYHA 3-4), advanced kidney impairment (KDOQI 4-5)) which can substantially impact the pharmacokinetic of drugs and significantly confound the study results.
- Presence of interacting non HIV comedications (i.e comedications with known, strong inhibitory or inducing effects on drug metabolizing cytochromes and drug transporters, which might significantly confound the study results)
- Participants incapable of jugement or participants under tutelage
- Known or suspected non-compliance, drug or alcohol abuse considered at risk to significantly confound the study results
- Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia of the participant,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Co-administration of darunavir with a cardiovascular drugCo-administration of darunavir, an HIV agent considered prone to induce drug interactions, with a cardiovascular drug (amlodipine, atorvastatin or rosuvastatin). Note that a patient will be able to participate in the intervention group and the control group if a change in his/her anti-HIV treatment occurs (study partly parallel and partly in cross-over). | Drug | Amlodipine with Darunavir, Atorvastatin with Darunavir, Rosuvastatin with Darunavir |
Primary outcome
Circulating exposure (AUC) to cardiovascular agent amlodipine
Time frame: 2 weeks
Area under the curve (AUC) of the cardiovascular drug, namely amlodipine, in the presence of darunavir/ritonavir (inhibitory effect hypothesized) or dolutegravir (no inhibitory effect predicted).
Circulating exposure (AUC) to cardiovascular agent atorvastatin
Time frame: 2 weeks
Area under the curve (AUC) of the cardiovascular drug, namely atorvastatin in the presence of darunavir/ritonavir (inhibitory effect hypothesized) or dolutegravir (no inhibitory effect predicted).
Circulating exposure (AUC) to cardiovascular agent rosuvastatin
Time frame: 2 weeks
Area under the curve (AUC) of the cardiovascular drug, namely rosuvastatin in the presence of darunavir/ritonavir (inhibitory effect hypothesized) or dolutegravir (no inhibitory effect predicted).
1 secondary outcome
Circulating exposure (AUC) to another cardiovascular agent, if one appears frequently associated with HIV agents
Time frame: 2 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jul 2020.
- Derived from this study: PubMed 33124006Courlet P, Guidi M, Alves Saldanha S, Stader F, Traytel A, Cavassini M, Stoeckle M, Buclin T, Marzolini C, Decosterd LA, Csajka C; and the Swiss HIV Cohort Study. Pharmacokinetic/Pharmacodynamic Modelling to Describe the Cholesterol Lowering Effect of Rosuvastatin in People Living with HIV. Clin Pharmacokinet. 2021 Mar;60(3):379-390. doi: 10.1007/s40262-020-00946-3. Epub 2020 Oct 29.
- Website of the Service of Clinical Pharmacology at CHUV, LausanneLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. The investigators will share anonymized IPD with colleagues interested upon motivated request
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thierry Buclin, Prof. principal investigator
Service of Clinical Pharmacology
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of HIV Infections and Drug Interactions, run by Centre Hospitalier Universitaire Vaudois at 2 sites in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Circulating exposure (AUC) to cardiovascular agent amlodipine (time frame: 2 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03515772, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jul 2020.