The study will be a randomized, open-label, cross-over clinical pharmacokinetic trial to investigate a strategy for probenecid "boosting" in the setting of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for HIV pre-exposure prophylaxis (PrEP). The study will be conducted at the Indiana University Clinical Research Center. All samples will be processed and the amount of tenofovir/FTC in plasma, blood, and urine, and tenofovir diphosphate and emtricitabine in peripheral blood mononuclear cells will be determined using validated analytical methods developed by the investigators at the University of Colorado. Probenecid plasma and urine concentrations will also be measured using an in-house assay. Following completion of the study, the secondary aim will be accomplished via analysis of selected samples collected at baseline and following treatment. Those selected samples will be assessed for urinary markers of proximal tubulopathy (urine total protein, albumin, creatinine, phosphorus, retinol binding protein, and beta-2-microglobulin) and serum alkaline phosphatase, osteocalcin, procollagen type 1 N propeptide, cystatin C, and creatinine to determine if the probenecid boosting strategy does indeed lead to less potential renal and bone toxicity.

Inclusion Criteria:

1. 18 to 55 years old healthy (as decided from a pre-enrollment screening session described above) male participants within 32% of their ideal body weight.
2. Individuals who agree to refrain from taking any prescriptions medications, over-the-counter medications (including salicylates/aspirin), hormonal agents, and herbal, dietary, and alternative supplements that may interact with the metabolism of those study drugs at least 2 weeks prior to the start of the study and until study completion.
3. Nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at least one month prior to and until the completion of the study (the entire study lasts for approximately 49 days).

Exclusion Criteria:

• 1. Are underweight (weigh less than 52 kg or 114 lb) or overweight [body mass index (BMI) greater than 32].

  2. Females will be excluded to reduce study variability for this first proof of concept study.

  3. Have insufficient renal function (estimated Creatinine Clearance ≤ 90 mL/min).

  4. Have history of current alcohol or drug abuse (more than 4 alcoholic drinks per day on a regular basis).

  5. Have history of intolerance, allergic reactions (e.g. rash) or other forms of hypersensitivities to any of the study medications (tenofovir disoproxil fumarate/ emtricitabine, probenecid).

  6. Have taken TDF or FTC as part of pre-exposure prophylaxis within the past 6 weeks.

  7. Any current major illness or chronic illness such as (but not limited to) kidney disease, hepatic disease, diabetes mellitus, gout, hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, chronic active hepatitis B virus (HBV) infection, or HIV.

  8. History of anemia or any other significant hematologic disorder. 9. Have history or current gastrointestinal disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.

  10. Have a serious infection within the last week before study enrollment. 11. Have donated blood within the past two months. 12. Have blood results that do not fall in a healthy range (e.g., blood hemoglobin less than 12.0 mg/dl).

  13. Are taking on regular basis substances that may interfere with the metabolism (breakdown) of study medications by the body, including prescription medications, over-the-counter, herbal or dietary supplements, alternative medications, or hormonal agents (i.e. oral contraceptives, intra-uterine device with hormones).

  14. Have a life style that places subjects at a higher risk for contracting HIV during the study period (e.g. active illicit drug use, excessive alcohol drinking, sexually transmitted infection (including gonorrhea, chlamydia, syphilis, herpes, human papilloma virus) within the past one year, or having more than one sexual partner in the past 6 months).

  15. Positive HIV antibody test. 16. Positive HBV surface antigen test. 17. Have participation in a research study or use of an investigational drug in the last one month.

  18. Are employed or are student under supervision of any of the investigators of this study.

  19. Cannot state a good understanding of this study including risks and requirements; are unable to follow the rules of this study.

  20. Cannot commit the time requested for this study.

Only male healthy volunteers will be enrolled.

We do not plan to share IPD with other researchers.

Adverse events were collected over 1 year during study conduction.

All adverse events reported from participant were included and graded for severity by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Adverse events were reviewed per patient by treatment and was not separated individually.

This will be an open-label study.