Practical approach to the use and monitoring of dofetilide therapy.

FDA's requirements for the use of dofetilide are described, and one hospital's strategy for meeting the requirements is discussed. Dofetilide is a specific class III antiarrhythmic agent approved for use in the conversion of atrial fibrillation and atrial flutter and the maintenance of normal sinus rhythm. It is available as an option for highly symptomatic patients who fail to respond to or do not tolerate other antiarrhythmic agents and patients with structural heart disease. Because of the risk of torsade de pointes associated with dofetilide, FDA has mandated in-hospital initiation of dofetilide therapy and has restricted its availability to hospitals and prescribers who have received appropriate education on dofetilide treatment initiation and dosing. Control of the drug's distribution is limited to a single wholesaler and a single mail-order pharmacy. These restrictions, along with the FDA labeling and the inherent risks associated with dofetilide use, have made this drug a complicated agent to use within an institution. When dofetilide was added to the formulary at Harper University Hospital, policies and procedures were developed to ensure appropriate use and monitoring. The use of dofetilide within health systems requires detailed procedures for prescribing, dispensing, and monitoring and thorough education of caregivers about those procedures. Pharmacists have a pivotal role in ensuring the appropriate use of dofetilide.

A urine metabolic ratio of dextromethorphan and 3-methoxymorphinan as a probe for CYP3A activity and prediction of cyclosporine clearance in healthy volunteers.

Dextromethorphan (DM) is metabolized in the body to dextrophan (DT) and 3-methoxymorphinan (3-MM) by cytochrome P450 (CYP) 2D6 and 3A4, respectively, and cyclosporine (CsA) is a known substrate of CYP3A4. We attempted to determine if the urine metabolic ratio of DM:3-MM at various time intervals during 24 hours is predictive of CsA clearance in 11 healthy volunteers. Each subject took DM 30 mg orally, and serial urine samples were collected at 0-4, 4, and 4-24, and 0-24 hours. Subjects then were randomly assigned to receive either oral microemulsion CsA 5 mg/kg or intravenous CsA 1.5 mg/kg in a crossover fashion in a two-sequence pharmacokinetic study with a wash-out period of at least 7 days. A total of 17 blood samples were collected from each subject in the CsA pharmacokinetic study over 24 hours. Urinary DM, DT, and 3-MM were quantified by high-performance liquid chromatography (HPLC) with a fluorescence detector, and blood CsA concentrations were analyzed by HPLC with ultraviolet detection. All subjects were extensive metabolizers of CYP2D6 as determined by metabolic ratios of DM:DT (mean+/-SD 0.0255+/-0.048). There was no correlation between CYP2D6 and CYP3A4 (p=0.38). The metabolic ratios of DM:3-MM in any urine samples during the 24-hour collection period did not predict CsA pharmacokinetics, although the 0-24 hour sample had an unexpected positive correlation with CsA clearance (r2 = 0.38, p<0.0001). The correlation was similar for metabolic ratios of DM:3-MM with intravenous CsA clearance (r2 = 0.5, p<0.0001). Metabolic ratios of DM:3-MM based on 24-hour cumulative urine collection did not appear to have clinical utility in predicting CYP3A activity measured by CsA clearance.