Drug-drug Interactions Between Antiretroviral Drugs and Cardiovascular Drugs in Elderly Patients
Drug-drug Interactions Between Antiretroviral Drugs and Cardiovascular Drugs in Elderly Patients
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.
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.
Inclusion Criteria:

 -  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

 Exclusion Criteria:

 -  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