Exposure-response relationships and drug interactions of sirolimus
Journal Title: The AAPS Journal - Year 2004, Vol 6, Issue 4
Abstract
Sirolimus (rapamycin, RAPAMUNE, RAPA) is an immunosuppressive agent used for the prophylaxis of renal allograft rejection and exhibits an immunosuppressive mechanism that is distinct from that for cyclosporine and tacrolimus. The purpose of this manuscript is to discuss the exposure-response relationships and drug interactiosn of sirolimus. The various factors affecting sirolimus whole blood exposure included first-pass extraction, formulation, food, demographics, liver disease, assay method, and interacting drugs. Clinically significant effects caused by food, pediatric age, hepatic impairment, and interacting drugs require recommendations for the safe and efficacious use of sirolimus in renal allograft patients. An exposure-response model based on multivariate logistic regression was developed using the interstudy data from 1832 renal allograft patients. The analysis revealed an increased probability of acute rejection for sirolimus troughs <5 ng/mL, cyclosporine troughs <150 ng/mL, human leukocyte antigen (HLA) mismatches ≥4, and females. The outcomes suggested that individualization of sirolimus doses immediately after transplantation, based on HLA mismatch and sex, would likely decrease the probability of acute rejections in renal allograft recipients who receive concomitant sirolimus, cyclosporine (full-dose), and corticosteroid therapy. Sirolimus is a substrate for both Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) and undergoes extensive first-pass extraction. Drugs that are known to inhibit or induce these proteins may potentially affect sirolimus whole blood exposure. In healthy volunteers, cyclosporine, diltiazem, erythromycin, ketoconazole, and verapamil significantly increased sirolimus whole blood exposure, and rifampin significantly decreased sirolimus exposure. However, sirolimus whole blood exposure was not affected by acyclovir, atorvastatin, digoxin, ethinyl estradiol/norgestrel, glyburide, nifedipine, or tacrolimus. Among the 15 drugs studied, sirolimus significantly increased the exposures of only erythromycin and S-(−)verapamil.
Authors and Affiliations
James J. Zimmerman
Keywords
Related Articles
- EP ID EP681934
- DOI 10.1208/aapsj060428
- Views 94
- Downloads 0
Statistics on BCS Classification of Generic Drug Products Approved Between 2000 and 2011 in the USA
The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Esse...
Vaccinomics: Current Findings, Challenges and Novel Approaches for Vaccine Development
Recent years have witnessed a growing interest in a field of vaccinology that we have named vaccinomics. The overall idea behind vaccinomics is to identify genetic and other mechanisms and pathways that determine immune...
Evaluation of Methods for Estimating Time to Steady State with Examples from Phase 1 Studies
An overview is provided of the methodologies used in determining the time to steady state for Phase 1 multiple dose studies. These methods include NOSTASOT (no-statistical-significance-of-trend), Helmert contrasts, splin...
Microstructural Analysis of Porous Composite Materials: Dynamic Imaging of Drug Dissolution and Diffusion Through Porous Matrices
Inert matrix tablets (ferrous sulphate-Ferrogradumet®, Abbott Laboratories, Australia) were used as supplied. Each tablet contained 375 mg ± 5% of ferrous sulphate, which is approx...
A semiautomated approach to gene discovery through expressed sequence tag data mining: Discovery of new human transporter genes
Identification and functional characterization of the genes in the human genome remain a major challenge. A principal source of publicly available information used for this purpose is the National Center for Biotechnolog...