Effects of Plasmapheresis on Mycophenolic Acid Concentrations

Abstract

Although plasmapheresis (PP) is a widely used intervention in immunologic disease states, there is an absence of literature on its effects on the pharmacokinetics of mycophenolic acid (MPA) (1). Supplemental dosing is often necessary for highly protein-bound drugs with low volumes of distribution (Vd) as pharmacokinetics can be significantly altered by PP. Based on the pharmacokinetic information on Vd and protein binding provided in mycophenolate mofetil and mycophenolate sodium package inserts, clearance by PP would theoretically be expected to be minimal; however, there exists wide variance in reported Vd and protein binding in the literature with reported unbound free fraction of up to 29%, which suggests that drug removal by PP may be possible (2, 3). This was a prospective case series. Institutional review board approval and written informed consent were obtained before study enrollment. Patient 1 was a 63-year-old white female, weighing 63 kg, with myasthenia gravis admitted for intermittent PP. She had been maintained on mycophenolate mofetil 1000 mg in the morning and 1500 mg in the evening for approximately 1 month before the study. Patient 2 was a 55-year-old, African American female, weighing 71 kg, admitted for three times weekly PP for biopsy-confirmed recurrent focal segmental glomerulosclerosis approximately 9 months after renal transplantation. Her mycophenolate sodium dose of 360 mg twice daily had been stable since the time of transplantation. PP was performed using continuous flow centrifugation to separate red blood cells from plasma. Wasted plasma is referred to as plasmapheresate. For patient 1, three MPA concentrations were obtained during each weekly session for a total of 3 weeks, and for patient 2, three MPA concentrations were obtained during each thrice-weekly session for a total of 1 week. For each patient, 5 mL blood samples were collected immediately preceding and after PP. A 10 mL plasmapheresate sample was collected at the conclusion of PP with MPA concentrations assayed within 24 hr. Concentrations of MPA in serum and plasmapheresate were determined using high-pressure liquid chromatography with diode array detection (Agilent, Santa Clara, CA) and assayed at the hospital laboratory. Duration of PP, total blood volume, hematocrit, plasma volume, and volume of plasma exchanged were collected (Table 1).TABLE 1: Pharmacometrics of MPA with plasmapheresisPharmacometric Analysis The amount of MPA removed by PP was calculated by the equation: The proportion of total body MPA removed by PP was estimated by the equation: To approximate the percentage of daily MPA dose removed by PP, we assumed 94% absorption (4, 5). Using this assumption and knowing that PP was conducted under steady-state conditions, the approximation of daily MPA dose removed by PP was: To evaluate plasma concentration profiles of MPA in the time interval between pre-PP and post-PP, we calculated the elimination rate constant (KE), terminal half-life based on the following equation: Minor variations in serum concentrations between PP sessions was likely due to inherent variability in MPA pharmacokinetics related to secondary peaks as a consequence of enterohepatic circulation, but may also reflect redistribution from tissue. Because of patient constraints, we were unable to assess AUC measurements, and we acknowledge the controversy of utility of trough concentrations compared with AUC measurements as an assessment of total MPA exposure. However, we sought to determine whether PP affected MPA concentrations, and this is the first report to show that exchange of approximately 3 L of plasma did not significantly alter post-PP serum concentrations of MPA during PP sessions in two female patients. Based on typical trough steady-state calculations before initiation of PP of 1 to 5 mg/L, it was estimated that 10.5 to 12 mg of MPA would be removed per PP. This is similar to the average amount actually removed: 11.6 mg per PP, equivalent to approximately 0.5% of the bioavailable daily MPA dose or 2.5% of body stores. Dose escalation was, therefore, unnecessary to counteract the loss of MPA during PP. Angela Q. Maldonado1,2 Neal M. Davies3 Stacy A. Crow1 Cindy Little4 Okechukwu N. Ojogho2 Douglas L. Weeks1 1Department of Pharmacotherapy Washington State University Spokane, WA 2Kidney Transplant Program Providence Sacred Heart Medical Center and Children's Hospital Spokane, WA 3Department of Pharmaceutical Sciences Washington State University Pullman, WA 4Inland Northwest Blood Center Spokane, WA