Pharmacokinetic Interactions Between DMPA and LPV/r Among HIV-Infected Women

Study Overview
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Brief Summary
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This study was done to look at the level of Depo-Provera, an injectable birth control, in the blood to see whether it is affected by the anti-HIV drug Kaletra (lopinavir/ritonavir [LPV/r]). It is not known whether taking Depo-Provera together with Kaletra changes the amount of Kaletra in blood. Therefore, this study also looked at the levels of HIV and Kaletra before and after receiving a shot of Depo-Provera. This study evaluated the safety of Depo-Provera and Kaletra when they are used together. In addition to what is stated above, this study also explored any effect of Depo-Provera on the immune system.

Detailed Description
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The primary study objective was addressed by calculating the Area Under the Concentration-Time Curve (AUC) from week 0 (prior to DMPA injection) to week 12 (twelve weeks after DMPA injection) in our study participants. DMPA was supplied and administered as part of the protocol, however Kaletra was not. It was required that participants already be on a Kaletra based regimen prior to entering the study, as described in the eligibility criteria. Arm A of AIDS Clinical Trial Group (ACTG) A5093, which consisted of 14 participants who were administered DMPA without Kaletra, was used as reference data.

Official Title
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An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Between Depo-Medroxyprogesterone Acetate (DMPA) and Lopinavir/Ritonavir (LPV/r) and of the Effects of DMPA on Cellular Immunity and Regulation in HIV-Infected Women

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: depo-medroxyprogesterone acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection Documentation of plasma HIV-1 RNA </= 400 copies/mL within 30 days prior to study entry. Last menstrual period </= 35 days prior to study entry. If last menstrual period >35 days prior to study entry, serum follicle-stimulating hormone (FSH) must be </= 40 Milli-International units per Milliliter (MIU/mL) Stable anti-retroviral (ARV) regimen consisting of BID LPV/r plus 2 or more nucleoside reverse transcriptase inhibitors (NRTIs) for at least 30 days if postpartum or for at least the previous 14 days if on a previously stable antiretroviral regimen without modifications prior to study entry Cluster of Differentiation 4 (CD4+) cell count ≥200 cells/mm^3 within 30 days prior to study entry Certain laboratory values within 30 days prior to study entry Premenopausal females with normal ovarian function Negative serum or urine-Human Chorionic Gonadotropin (HCG) pregnancy test within 72 hours prior to study entry All subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or in vitro fertilization) for the duration of the study.Subjects of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use an additional reliable method of contraception while in the study. Ability and willingness to give written informed consent Documentation of Pap smear within one year prior to study entry. Documentation of hepatitis B (surface antigen) and hepatitis B (core antibody) and hepatitis C (antibody) status prior to study entry. Documentation of varicella-zoster virus (VZV) status by history of varicella or herpes zoster, or history of varicella or herpes zoster vaccination or documentation of anti-VZV antibodies. Willingness to abstain from alcohol 24 hours prior to and during the 10-hour pharmacokinetic (PK) specimen draws. Willingness to abstain from any grapefruit product or supplement for 24 hours prior to entry and for the duration of the study. Exclusion Criteria: Received DMPA within 180 days prior to study entry. Received other hormonal therapies within the 30 days prior to study entry. Concurrent dual nucleoside therapy of zidovudine (ZDV) and stavudine (d4T) within 30 days prior to study entry. Use of any prohibited medications within 30 days prior to study entry. Prohibited Medications were: amiodarone (Cordarone) astemizole (Hismanal) bepridil (Vascor) carbamazepine (Tegretol) cisapride (Propulsid) clarithromycin (Biaxin) cyclosporine (Sandimmune, Neoral) dihydroergotamine (Migranal and others) ergotamine (Ergostat, Gotamine, and others) erythromycin (E-mycin, erythromycin ethylsuccinate (EES) and others) flecainide (Tambocor) glucocorticoids Hypericum perforatum (St. John's wort) itraconazole (Sporanox) ketoconazole (Nizoral) lovastatin (Mevacor) midazolam (Versed) nefazadone (Serzone) phenobarbital (Luminal) phenytoin (Dilantin) pimozide (Orap) pioglitazone (Actos) propafenone (Rythmol) propofol (Diprivan) quinidine (Quinidex) rifabutin (Mycobutin) rifampin (Rifadin, Rifamate, Rifater, Rimactane) rosiglitazone (Avandia) simvastatin (Zocor) tacrolimus (Prograf) terfenadine ticlopidine (Ticlid), and triazolam (Halcion) Breastfeeding. Less than 30 days postpartum at study entry. Bilateral oophorectomy. Hypersensitivity to DMPA, MPA, or any of the other ingredients in DMPA. More than a 50% change in tobacco smoking within the 30 days prior to study entry or plans to significantly change tobacco use during the study. Invasive cancer of the reproductive tract; known or suspected malignancy of the breast, or known increased risk for breast cancer; undiagnosed vaginal bleeding; liver tumors; or serious ocular disorders at any time prior to study entry. Uncontrolled hypothyroidism or hyperthyroidism within 30 days of study entry. Acute infections or other opportunistic diseases requiring medication within 14 days prior to study entry. Receipt of any immunizations within 2 weeks prior to enrollment. Use of any immunosuppressant medication including systemic corticosteroids within 30 days prior to study entry. Chronic immunosuppressive conditions other than HIV. Initiated, discontinued, or changed doses of drugs that are cytochrome P450 3A4 (CYP3A4) substrates within 30 days of study entry. History of deep venous thrombosis or pulmonary emboli.

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Depo-medroxyprogesterone acetate (DMPA)<br>At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose. | Drug: depo-medroxyprogesterone acetate<br>* At study entry/ Day 0, participants will receive Depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.<br>* Other names: Depo-Provera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Medroxyprogesterone Acetate (MPA) Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-12weeks) | This evaluates the effect of lopinavir/ritonavir (LPV/r) on pharmacokinetic parameter AUC of MPA by looking at the MPA AUC from day 0 to week 12. AUC0-12weeks was calculated using single MPA concentrations sampled immediately prior to DMPA administration on day 0, and at 2, 4, 6, 8, 10 and 12 weeks after administration of the single DMPA dose. | Day 0, Weeks 2, 4, 6, 8, 10 and 12 | 
| AUC0-12hour for LPV at Baseline (Day 0) Before DMPA Administration and at Week 4 (Four Weeks After DMPA Administration) | This evaluates the effect of DMPA on LPV PK parameter AUC by comparing PK AUCs of LPV from 0 to 12 hours obtained at study Day 0 (before DMPA was administered) with PK AUCs of LPV from 0 to 12 hours at study Week 4 (4 weeks after DMPA was administered). Blood samples were drawn for LPV concentration levels at time zero (before LPV/r dosing) and at 30 minutes and 1, 2, 3, 4, 5, 6, 8 and 10 hours after LPV/r dosing at day 0 and week 4. | Day 0 and Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). | This evaluates the suppression of ovulation due to the potential PK interaction between DMPA and LPV/r. The LLQ of progesterone is 0.5ng/mL. The threshold for suppression of ovulation is 5ng/mL. | 0, 2, 4, 6, 8, 10, and 12 weeks | 
| MPA PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on MPA Levels. | This evaluates the effect of LPV/r on the secondary MPA PK parameter Cmin based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12. | 0, 2, 4, 6, 8, 10, and 12 weeks | 
| MPA PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on MPA Levels. | This evaluates the effect of LPV/r on the secondary MPA PK parameter Cmax based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12. | 0, 2, 4, 6, 8, 10, and 12 weeks | 
| MPA PK Parameter Time to Cmax (Tmax) Determined Based on MPA Levels. | This evaluates the effect of LPV/r on the secondary MPA PK parameter Tmax based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12. | 0, 2, 4, 6, 8, 10, and 12 weeks | 
| MPA PK Parameter Clearance (CL/F) Determined Based on MPA Levels. | This evaluates the effect of LPV/r on the secondary MPA PK parameter CL/F based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12. | 0, 2, 4, 6, 8, 10, and 12 weeks | 
| MPA PK Parameter Half-Life (T1/2) Determined Based on MPA Levels. | This evaluates the effect of LPV/r on the secondary MPA PK parameter T1/2 based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12. | 0, 2, 4, 6, 8, 10, and 12 weeks | 
| LPV PK Parameter Cmin. | This evaluates the effect of MPA on the secondary LPV PK parameter Cmin obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4. | Day 0 and Week 4 | 
| LPV PK Parameter Cmax. | This evaluates the effect of MPA on the secondary LPV PK parameter Cmax obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4. | Day 0 and Week 4 | 
| LPV PK Parameter Tmax. | This evaluates the effect of MPA on the secondary LPV PK parameter Tmax obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4. | Day 0 and Week 4 | 
| LPV PK Parameter CL/F. | This evaluates the effect of MPA on the secondary LPV PK parameter CL/F obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4. | Day 0 and Week 4 | 
| LPV PK Parameter T1/2. | This evaluates the effect of MPA on the secondary LPV PK parameter T1/2 obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4. | Day 0 and Week 4 | 
| Ritonavir (RTV) PK Parameter AUC0-12h. | This evaluates the effect of MPA on the PK parameter AUC0-12h of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. Blood samples were drawn for RTV concentration levels at time zero (before LPV/r dosing) and at 30 minutes and 1, 2, 3, 4, 5, 6, 8 and 10 hours after LPV/r dosing at day 0 and week 4. | Day 0 and Week 4 | 
| RTV PK Parameter Cmin. | This evaluates the effect of MPA on the PK parameter Cmin of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. | Day 0 and Week 4 | 
| RTV PK Parameter Cmax. | This evaluates the effect of MPA on the PK parameter Cmax of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. | Day 0 and Week 4 | 
| RTV PK Parameter Tmax. | This evaluates the effect of MPA on the PK parameter Tmax of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. | Day 0 and Week 4 | 
| RTV PK Parameter CL/F. | This evaluates the effect of MPA on the PK parameter CL/F of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. | Day 0 and Week 4 | 
| RTV PK Parameter T1/2. | This evaluates the effect of MPA on the PK parameter T1/2 of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. | Day 0 and Week 4 | 
| Percentage of Participants With Menstrual Irregularities of Grade 1 and Higher Deemed Possibly, Probably or Definitely Related to Study Treatment. | This evaluates toxicity and safety of concomitant medication of DMPA and LPV/r, focusing specifically on the adverse event (AE) menstrual irregularities with abnormal vaginal bleeding. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the study's co-chairs. | From day 0 to week 12 | 
| Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. | This evaluates the short-term impact of MPA on virologic suppression in participants taking LPV/r who have received a dose of DMPA by measuring percentage of participants with HIV-1 RNA levels <400 copies/mL at day 0 (prior to DMPA injection) and at weeks 2, 4, 8 and 12 (after DMPA injection). An FDA-approved HIV-1 RNA assay with a lower limit of detection of 75 copies/mL or less was required and the same HIV-1 RNA assay was required to be performed for each participant across all study visits. The Roche COBAS AmpliPrep/TaqMan HIV-1 and Abbott RealTime HIV-1 tests were used. | Day 0, Weeks 2, 4, 8, and 12 | 
| Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. | This evaluates the effect of MPA on CMI to HIV and VZV at baseline before DMPA (day 0) and after DMPA (weeks 4 and 12) . Cytokines are interferon-gamma (IFN-gamma) and interleukin 2 (IL-2), and Stimuli are HIV and VZV. Summary of adjusted ELISPOT assay results is in spot forming cells (SFC)/10^6 peripheral blood mononuclear cells (PBMC) by study weeks 0, 4 and 12. The outcome measures of IFN-gamma and IL-2 measured for HIV and VZV are presented here together to provide all results pertaining to the same objective in a single data table. | Day 0, Weeks 4 and 12 | 
| CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). | This evaluates the effect of MPA on CMI to HIV and VZV. This outcome was measured at Baseline Before DMPA (Day 0) and After DMPA (Weeks 4 and 12) using the Lymphocyte Proliferation Assay (LPA). The data table shows a summary of LPA assay results by study week with stimuli HIV and VZV. Proliferation results are reported as a stimulation index (SI) which represents the ratio of the stimulated counts per minute to unstimulated control counts per minute. | Day 0, Weeks 4 and 12 | 
| Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. | This evaluates the effect of MPA on Tregs at baseline (Day 0), week 4 and week 12 using flow cytometry in freshly thawed PBMCs. A summary of CD4+ and cluster of differentiation 8 (CD8+) anchored T-cell subsets by study week, in percent that express the marker of interest, is presented here together to provide all results pertaining to this objective in a single data table. | Day 0, Weeks 4 and 12 |