HIV
Conditions
Brief summary
The purpose of the study is to look at the levels of an HIV medication (raltegravir) in the blood, and how it is affected if raltegravir is taken at the same time as another medicine for high blood pressure (amlodipine). Many patients with HIV will also have high blood pressure, so it is important to know which drugs for each of these conditions can be taken together without affecting how well they work individually. Over a 3 week period, participants took amlodipine for 2 weeks, and raltegravir for 2 weeks, with the middle week being on both drugs. The investigators will look at and compare the levels of these two drugs in the blood after subjects have taken them separately and both together. This study is randomised into two groups with both study medications received by all participants in a three-period crossover pattern; randomisation determined which medication was taken first. Once randomised allocation was performed, medications were administered in an open-label fashion.
Detailed description
HIV-negative male and female volunteers will be enrolled, after written confirmation of informed consent, in a phase I, open-label, cross-over, PK study (approved by Westminster Research Ethics Committee and UK Regulatory Authorities; Eudra number 2012-005400-18). Subjects are randomized to receive either raltegravir 400mg twice-daily (seven days), followed by raltegravir 400mg twice-daily plus amlodipine 5mg once-daily (seven days), followed by amlodipine 5mg once-daily alone (seven days), or the same treatments in the opposite order, in the fasted state (at least eight hours) with 240mL of water. Intensive PK sampling and safety laboratory analysis are performed at the end of each phase (Days 7, 14 and 21). Raltegravir and amlodipine plasma concentrations will be analysed by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. PK parameters are determined by non-compartmental methods \[WinNonlin Phoenix (version 6.1; Pharsight Corp, Mountain View, CA, USA\]. These are the concentrations measured 12 and 24 hours post-dose (C12h, C24h) for raltegravir and amlodipine, respectively; the maximum concentration (Cmax); and the area under the curve over 12 and 24 hours (AUC12h, AUC24h) for raltegravir and amlodipine, respectively.
Interventions
DRUGRaltegravir
Isentress 400mg tablet taken twice daily
DRUGAmlodipine
generic amlodipine 5mg tablets (Accord healthcare Limited, UK)
Sponsors
St Stephens Aids Trust
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects must meet all of the following inclusion criteria within 28 days prior to the baseline visit: * The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements * Male or non-pregnant, non-lactating females * Between 18 to 65 years, inclusive * Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 12 weeks after the study * Willing to consent to their personal details being entered onto The Over-volunteering Prevention Scheme (TOPS) database * Willing to provide photographic identification at each visit. * Registered with a GP in the UK
Exclusion criteria
Subjects who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) of Raltegravir and Amlodipine Without and With Co-administration of the Other Studied Drug. | Day 7 of each intervention (0 (pre-dose), 2, 4, 8 and 12 hours post dose (both drugs) and 24 hours post dose (amlodipine only)) | To investigate the pharmacokinetics of raltegravir and amlodipine co-administration. The pharmacokinetic parameters calculated for raltegravir and amlodipine will be trough concentration (Ctrough), defined as the concentration at 24 hours after the observed drug dose, the maximum observed plasma concentration (Cmax), elimination half-life (t1/2), time point at Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration-time curve from 0-24 hours after dosing (AUC0-24h). All pharmacokinetic parameters will be calculated using non-compartmental modeling techniques (WinNonlin®) and all statistical calculations performed and analyzed using SAS version 9.1 or SPSS V17.0. |
| Raltegravir C12h | 12 hours post-dose on day 7 of daily dosing. | measured concentration 12 hours after dose in the absence, and presence, of amlodipine. |
| Amlodipine C24h | 12 hours post-dose on day 7 of daily dosing. | measured concentration 24 hours after dose in the absence, and presence, of raltegravir |
| Raltegravir AUC(0-12h ) | Post dose after day 7 of daily dosing | AUC0-12h: Area under the concentration time curve over 12 hours in the absence, and presence, of amlodipine. |
| Amlodipine AUC(0-24h) | Post-dose on day 7 of daily dosing | AUC0-24h: Area under the concentration time curve 24 hours in the absence, and presence, of raltegravir |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A DAYS 1 to 7: raltegravir 400 mg BID DAYS 8 to 14: raltegravir 400 mg BID PLUS amlodipine 5 mg OD DAYS 15 to 21: amlodipine 5 mg OD | 11 |
| Group B DAYS 1 to 7: amlodipine 5 mg OD DAYS 8 to 14: raltegravir 400 mg BID PLUS amlodipine 5 mg OD DAYS 15 to 21: raltegravir 400 mg BID | 6 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (Days 1 to 7) | Protocol Violation | 0 | 1 |
| Second Intervention (Days 8 to 14) | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Group A | Group B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 12 | 3 / 7 |
| serious Total, serious adverse events | 1 / 12 | 0 / 7 |
Outcome results
Primary
Amlodipine AUC(0-24h)
AUC0-24h: Area under the concentration time curve 24 hours in the absence, and presence, of raltegravir
Time frame: Post-dose on day 7 of daily dosing
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir PK (Alone) | Amlodipine AUC(0-24h) | 166.0 ng*h/mL |
| Raltegravir PK (Administered With Amlodipine) | Amlodipine AUC(0-24h) | 165.9 ng*h/mL |
Primary
Amlodipine C24h
measured concentration 24 hours after dose in the absence, and presence, of raltegravir
Time frame: 12 hours post-dose on day 7 of daily dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir PK (Alone) | Amlodipine C24h | 4.91 ng/mL |
| Raltegravir PK (Administered With Amlodipine) | Amlodipine C24h | 4.55 ng/mL |
Primary
Maximum Observed Concentration (Cmax) of Raltegravir and Amlodipine Without and With Co-administration of the Other Studied Drug.
To investigate the pharmacokinetics of raltegravir and amlodipine co-administration. The pharmacokinetic parameters calculated for raltegravir and amlodipine will be trough concentration (Ctrough), defined as the concentration at 24 hours after the observed drug dose, the maximum observed plasma concentration (Cmax), elimination half-life (t1/2), time point at Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration-time curve from 0-24 hours after dosing (AUC0-24h). All pharmacokinetic parameters will be calculated using non-compartmental modeling techniques (WinNonlin®) and all statistical calculations performed and analyzed using SAS version 9.1 or SPSS V17.0.
Time frame: Day 7 of each intervention (0 (pre-dose), 2, 4, 8 and 12 hours post dose (both drugs) and 24 hours post dose (amlodipine only))
Population: Data from all enrolled participants who participated in at least two of the three PK assessments were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir PK (Alone) | Maximum Observed Concentration (Cmax) of Raltegravir and Amlodipine Without and With Co-administration of the Other Studied Drug. | 1178 ng/mL |
| Raltegravir PK (Administered With Amlodipine) | Maximum Observed Concentration (Cmax) of Raltegravir and Amlodipine Without and With Co-administration of the Other Studied Drug. | 1866 ng/mL |
| Amlodipine PK (Alone) | Maximum Observed Concentration (Cmax) of Raltegravir and Amlodipine Without and With Co-administration of the Other Studied Drug. | 8.47 ng/mL |
| Amlodipine PK (Administered With Raltegravir) | Maximum Observed Concentration (Cmax) of Raltegravir and Amlodipine Without and With Co-administration of the Other Studied Drug. | 8.49 ng/mL |
Primary
Raltegravir AUC(0-12h )
AUC0-12h: Area under the concentration time curve over 12 hours in the absence, and presence, of amlodipine.
Time frame: Post dose after day 7 of daily dosing
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir PK (Alone) | Raltegravir AUC(0-12h ) | 4600 ng*h/mL |
| Raltegravir PK (Administered With Amlodipine) | Raltegravir AUC(0-12h ) | 6410 ng*h/mL |
Primary
Raltegravir C12h
measured concentration 12 hours after dose in the absence, and presence, of amlodipine.
Time frame: 12 hours post-dose on day 7 of daily dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir PK (Alone) | Raltegravir C12h | 48 ng/mL |
| Raltegravir PK (Administered With Amlodipine) | Raltegravir C12h | 37 ng/mL |