lammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy. In addition, use of warfarin in patients with blood dyscrasias is contraindicated. Therefore, to minimize the bleeding risk, warfarin should be used cautiously in patients receiving antineoplastic agents that cause myelosuppression or blood dyscrasias.
PREGNANCY AND LACTATION
Pregnancy
Siltuximab is pregnancy risk category C. The FDA-labeling suggests that use during pregnancy should be weighed against the potential risk to the fetus. There are no adequate or well-controlled studies in pregnant women. Animal studies suggest siltuximab may cross the placenta. Babies born to pregnant women treated with siltuximab may be at increased risk of infection and caution is advised in the administration of live vaccines to these babies. Patients of childbearing potential should avoid pregnancy and women of childbearing potential should use contraception during use and for the 3 months after treatment.
FDA-labeling states that it is not known whether siltuximab is excreted in human milk or is absorbed systemically after ingestion. However, because many immunoglobulins are excreted in human milk and due to the potential for adverse reactions in the nursing baby, the manufacturer recommends that a decision be made whether to discontinue nursing or to discontinue siltuximab. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
MECHANISM OF ACTION
Siltuximab is a chimeric monoclonal antibody that binds human interleukein-6 (IL-6) and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. Overproduction of IL-6 has been linked to systemic manifestations in patients with multicentric Castleman's disease (MCD)
PHARMACOKINETICS
Siltuximab is administered intravenously. The pharmacokinetic profile is a linear two-compartment intravenous model with first-order elimination. Based on population pharmacokinetic analysis, the volume of distribution in a male patient weighing 70 kg is 4.5 L (20% CV). Body weight has been identified as the only statistically significant covariant for siltuximab clearance. The clearance in patients during a population pharmacokinetic analysis is 0.23 L/day (51% CV). The mean terminal half-life after the first intravenous infusion is 20.6 days (range 14.2—29.7 days).
Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. When siltuximab is initiated or discontinued in patients being treated with CYP450 substrates with a narrow therapeutic index, monitor appropriately for effect and drug concentrations as necessary. Caution is warranted in patients with co-administer |
