Impact of Severe Hypothyroidism on Cyclophosphamide Disposition and Routes of Metabolism and Transport in a Patient with Treatment-Resistant Lupus Nephritis

Abstract

To report what we believe to be the first case of severe hypothyroidism with reduced drug metabolism and transport activity. A 32-year-old African American woman with a history of treatment-resistant lupus nephritis and concurrent hypothyroidism was participating in a clinical study to evaluate cyclophosphamide pharmacokinetics in patients with glomerulonephritis due to lupus nephritis and small-vessel vasculitis. Thyroid-stimulating hormone levels ranged from 60 to 300 μIU/mL, despite high doses of thyroid replacement hormone (levothyroxine 400 μg twice weekly). The pharmacokinetics of the probe drug cocktail (flurbiprofen/fexofenadine) were altered, with formation clearance of flurbiprofen (CYP2C9 function) lower in our patient versus the average value in our study cohort, suggesting a reduction in activity. The area under the concentration-time curve from 0 to 24 hours for fexofenadine (transporter function) was 2-fold higher in our patient compared to that of other study patients. Pharmacokinetic data showed markedly decreased cyclophosphamide clearance and exposure to 4-hydroxycyclophosphamide, as well as a reduced metabolic ratio of 4-hydroxycyclophosphamide to cyclophosphamide. Previous cases of altered pharmacokinetics and toxicity of medications in patients with mild to moderate thyroid dysfunction have been published. Our case evaluated the impact of a severe form of hypothyroidism on cyclophosphamide pharmacokinetics and probe drug metabolism and transport. If changes were not demonstrated at the extreme spectrum of hypothyroidism, there would be little concern for changes in patients with less severe disease. Profound hypothyroidism likely contributed to the patient's poor response to cyclophosphamide treatment through its influence on CYP isoenzymes responsible for the activation to 4-hydroxycyclophosphamide and possibly through reduced transport function. Clinicians should monitor for significant hypothyroidism in patients who are prescribed drugs (eg, cyclophosphamide) that require metabolic conversion to form active therapeutic moieties.