A novel antiretroviral medication, Drug X, is being developed for treating patients with HIV infection. Initial studies show a high rate of treatment failure due to continued viral proliferation in the brain. However, treatment success rates improve when Drug X is combined with an adjuvant agent. Data comparing the two medication regimens is shown in the table below. Based on the data, the adjuvant agent most likely improves viral control through which of the following mechanisms?

Question

A novel antiretroviral medication, Drug X, is being developed for treating patients with HIV infection.  Initial studies show a high rate of treatment failure due to continued viral proliferation in the brain.  However, treatment success rates improve when Drug X is combined with an adjuvant agent.  Data comparing the two medication regimens is shown in the table below.  Based on the data, the adjuvant agent most likely improves viral control through which of the following mechanisms?

Quizplus · Accepted Answer

The study results show that the cerebral spinal fluid (CSF) viral load level remains elevated when subjects are treated with Drug X alone but becomes undetectable when Drug X is combined with the adjuvant agent. Because average serum levels are relatively equal between the 2 groups, it is likely that the adjuvant improves the efficacy of Drug X by increasing its ability to penetrate the blood-brain barrier (BBB). Many drugs have a difficult time crossing the BBB due to the presence of specialized endothelial cells with very tight intercellular junctions that form a physical barrier separating the CNS from the circulation. In addition, multidrug transport proteins, particularly p-glycoprotein, are highly expressed on the luminal membrane of brain capillary endothelial cells. P-glycoprotein is an ATP-driven efflux pump that actively removes a wide range of substrates from cells, including many commonly prescribed drugs (eg, antibiotics, immunosuppressant agents, HIV protease inhibitors). In HIV infection, poor penetration of antiretroviral medications allows the brain to act as an anatomical sanctuary where viral replication can proceed unchecked, facilitating the development of resistant strains. Methods of bypassing the BBB (eg, disruption of tight junctions, p-glycoprotein inhibition) can improve drug delivery to the CNS. P-glycoprotein transporters are also found on the apical surface of enterocytes and can limit drug bioavailability by pumping the drug back into the intestinal lumen. However, inhibition of p-glycoprotein can have a variable effect on serum drug levels, as increased bioavailability is often countered by increased drug distribution (eg, into the CSF or intracellular compartments). (Choices A, B, and E) Reduced drug metabolism or decreased excretion could potentially improve drug efficacy by increasing average serum drug levels. However, in this experiment, serum drug levels increased by only 10 ng/ml (~2%) with coadministration of the adjuvant. This minimal increase in drug concentration is not representative of a significant change in drug metabolic/clearance parameters and is unlikely to lead to increased BBB penetration. (Choice C) The choroid plexus is the site of CSF production and can function as an alternate entryway into the CNS. However, the excretion of a substance by the choroid plexus is directly dependent on choroidal blood flow; diminished blood flow would reduce the excretion of a particular substance into the CSF. Educational objective: P-glycoprotein is an efflux pump found on brain capillary endothelial cells (part of the blood-brain barrier) that inhibits a wide range of substrates from entering the brain. Inhibition of p-glycoprotein can improve drug delivery to the CNS.

A Novel Antiretroviral Medication, Drug X, Is Being Developed for Treating