title: Bioavailability versus bioequivalence: the cyclosporine model.
abstract: The quest for a fixed-dose immunosuppressive drug continues. Experience with cyclosporine, tacrolimus and mycophenolate mofetil has taught us that there is no correlation between dose and clinical events. These data indicate that the concentration of the drug at the site of action (bioavailability) of each of these agents differs from one patient to the next. In addition, the bioequivalence (concentration of intact drug at the site of action resulting in a measurable response [effect]) may differ among individuals. Technically, it is very difficult to measure the drug concentration at a particular site, especially in organs or tissues that are not directly accessible. Therapeutic drug-blood-level monitoring is a simple indirect method that is used to estimate both bioavailability and bioequivalence. However, the immunosuppressive effect of all these drugs is initiated by binding to receptors on the surface of lymphocytes, which leads to inhibition of cytokine production and proliferation of activated lymphocytes. Thus, it would be more advantageous to monitor the level and effect of these drugs at the site of action (bioequivalence), the lymphocyte. This report describes an assay of this type that was developed for monitoring transplant patients at one center. The assay is based on measuring drug levels in the cytoplasm of lymphocytes. It is quick and easy to perform (20 samples per hour), inexpensive, and reproducible. The between-run Coefficient of Variance (CV) is 5.4 and a within-run CV is 3.1. For this study, blood and lymphocyte drug levels in transplant patients were determined and correlated with graft function and clinical events (biopsy-proven rejection and/ or toxicity).
authors.affiliation: Transplant Unit of Rizk Hospital, Beirut, Lebanon. marwan.masri@mysalima.com
authors.forename: Marwan A
authors.initials: MA
authors.lastname: Masri
mesh_terms: D000328:Adult; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003593:Cytoplasm / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods; D006084:Graft Rejection / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015994:Incidence; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000378:metabolism; D008875:Middle Aged; D012189:Retrospective Studies; D013810:Therapeutic Equivalency
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine