A5223-SEX DIFFERENCES IN LOPINAVIR/RITONAVIR PHARMACOKINETICS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DESIGN: Pharmacokinetic (PK) evaluations will be performed on plasma samples obtained prior to and up to 12 hours after the administration of the morning dose of lopinavir/ritonavir (LPV/RTV) in 78 evaluable subjects (39 men and 39 women) currently managed on LPV/RTV as part of their antiretroviral regimen. DURATION: A screening visit will occur within 30 days prior to the PK visit. Upon confirmation of eligibility, subjects will return for a registration/entry visit to enroll into the study and will be given a 48 hour medication diary to complete. Subjects will be required to spend approximately 13 hours at a general clinical research center (GCRC) or a similar research clinic setting for the intensive PK blood sampling. POPULATION: Seventy-eight HIV-infected subjects, 39 men and 39 women, age 18 years currently receiving LPV/RTV (lopinavir 400 mg/ritonavir 100 mg po bid) plus one or more of the following: nucleoside reverse transcriptase inhibitors (NRTIs), tenofovir (a nucleotide RTI), and enfuvirtide (a fusion inhibitor). Subjects must be on the same regimen for at least 14 days prior to screening. STRATIFICATION: Subjects to be stratified by race/ethnicity. REGIMEN: Subjects will be on LPV/RTV and one or more of the following: NRTIs, tenofovir (TDF), and enfuvirtide (ENF). These drugs will not be provided by this study. 1.0 HYPOTHESIS AND STUDY OBJECTIVES 1.1 Hypothesis Women achieve higher LPV drug levels than do men on similar doses of LPV/RTV. 1.2 Primary Objective To compare the PK parameter, area under the concentration-time curve (AUC) of LPV between HIV-1-infected men and women currently receiving similar doses of LPV/RTV. 1.3 Secondary Objectives 1.3.1 To compare the PK parameters: the maximum concentration (Cmax), 12 hour post- dose concentration (C12h), and the apparent oral clearance (CL/F) of LPV between HIV-1-infected men and women currently receiving similar doses of LPV/RTV. 1.3.2 To evaluate the effect of race/ethnicity on the PK parameters of LPV in HIV-1- infected subjects. 1.3.3 To identify factors associated with differences in the AUC of LPV. Covariates of interest include age, weight, body mass index (BMI), and the use of TDF. 1.3.4 To examine the relationship of LPV PK parameters with self-reported signs and symptoms of LPV/RTV toxicity. 1.3.5 To evaluate the association between the LPV PK parameters listed above and gastrointestinal signs and symptoms. Gastrointestinal signs and symptoms are defined as Grade 3 nausea, vomiting, diarrhea, abdominal pain, and bloating. 1.3.6 To evaluate differences in ritonavir (RTV) PK parameters between HIV-1- infected men and women. This study will look at drug levels in the blood in both men and women taking Kaletra¿ (also known as lopinavir/ritonavir) to see if they are different. This study will also try to find out how factors such as age, weight, race/ethnicity, and other medications may affect these drug level results. Recent scientific studies have suggested that more and more women are being infected with the HIV virus. It is thought that half of all the people in the world living with HIV/AIDS are women. However, most of the initial research studies on the safety and effectiveness of drugs used for treatment of HIV infection did not include a lot of women. Recent research suggests that HIV medications may affect men and women differently. The anticipated outcome of the pharmacologic studies for A5223 is to provide estimates of the PK characteristics of LPV/RTV to assess whether these parameters are different between men and women.