A clinical trial is being conducted to evaluate the safety and efficacy of a novel therapy to treat refractory Crohn disease. The medication is a monoclonal antibody against the α4β7 integrin, which inhibits migration of T-lymphocytes into the intestinal parenchyma and produces a gut-selective anti-inflammatory effect. Patients who have active, moderate to severe Crohn disease and have failed conventional therapy are enrolled in the study. Many of these patients have renal or hepatic dysfunction, and some take other medications that affect cytochrome P450 enzymes. Which of the following is the most appropriate dose adjustment in this patient population to decrease drug toxicity?
Monoclonal antibodies (mAbs) are used to treat a growing variety of malignant (eg, leukemia/lymphoma, melanoma) and autoimmune diseases (eg, Crohn disease, rheumatoid arthritis). The therapeutic effect of mAbs is achieved by binding to their target antigen in the plasma or on the cell surface and blocking deleterious receptor interactions or triggering a cytotoxic immune response against abnormal cells.
Because of their large molecular size, mAbs cannot be administered orally and must be given via intravenous or subcutaneous/intramuscular routes. Unlike most other drugs, mAbs are not eliminated by hepatic or renal clearance, but are instead removed from the body in 2 primary ways:
Target-mediated drug clearance: mAbs directed against cell surface antigens undergo internalization (receptor-mediated endocytosis) upon binding to their targets, removing them from the circulation
Nonspecific clearance: Immunoglobulins are constitutively taken up by reticuloendothelial macrophages (via binding to Fc receptors) and vascular endothelial cells (via pinocytosis)
Once internalized, immunoglobulins are catabolized into amino acids within lysosomes.
(Choices A and C) Many drugs undergo modifications by the cytochrome P450 system and subsequent conjugation reactions within hepatocytes that help facilitate excretion of the drug into the urine or bile. In contrast, immunoglobulins are not metabolized by these systems, but rather broken down by proteolytic enzymes.
(Choices B and D) Immunoglobulins are too large to undergo substantial filtration at the glomerular basement membrane and are not secreted by the renal tubules. Therefore, renal dysfunction does not significantly affect monoclonal antibody clearance.
Educational objective:
Monoclonal antibodies (mAbs) are not eliminated by hepatic or renal clearance. Therefore, no dose adjustment is necessary with impaired hepatic/renal function or use of cytochrome P450 inducers or inhibitors.