Effect of diabetes mellitus on pharmacokinetics and pharmacodynamics of tacrolimus and sirolimus
Chronic hyperglycemia associated with the diabetes may lead to irreversible kidney damage requiring a renal replacement therapy such as kidney transplantation. After the operation, a kidney transplant recipient needs to be maintained either on a tacrolimus or sirolimus based immunosuppressant therapy. ^ Diabetes is known to alter the disposition of drugs. Most importantly, it may alter the expression and activity of drug metabolizing enzymes. These changes may have a significant effect on the drug exposure or elimination. In addition, epidemiological studies have reported higher infection rate in the diabetic population that may indicate compromised immunity among this population. ^ More than 50% of the kidney transplant population in the United States have diabetes mellitus. Several studies have reported inferior patient and graft survival rate in the diabetic transplant population than nondiabetic patients. Currently, they are maintained on the same dosages of immunosuppressant drugs as nondiabetic patients. The objective of this dissertation is to compare the pharmacokinetics of tacrolimus and pharmacokinetics-pharmacodynamics (PKPD) of sirolimus in between diabetic and nondiabetic kidney transplant patients. ^ Through this dissertation, we have observed that, diabetic transplant patients exhibit significantly higher exposure to tacrolimus and its metabolites. We have also assessed the combined effect of diabetes and genetic-polymorphism associated with CYP3A4 and 3A5 gene on tacrolimus and metabolites levels. We have observed that nondiabetic patients that have CYP3A4*1B allele and are CYP3A5 expresser have significantly lower levels of tacrolimus and metabolites. ^ Moreover, sirolimus PKPD investigation indicated that diabetic kidney transplant patients present with significantly higher exposure to parent drug as well as its major metabolite. The pharmacodynamic analysis of sirolimus performed using B-cell surface markers expression in the diabetic and nondiabetic kidney transplant patients showed that CD95 expression on B-cell surface markers is significantly lower in the diabetic transplant patients as compared to nondiabetic counterpart. ^ We have also conducted sirolimus PKPD analysis using a population pharmacokinetics approach. Sirolimus concentration-time data was modeled using a two compartmental pharmacokinetic model, whereas CD95 expression data was modeled using sigmoidal inhibitory Emax model. ^ Collectively our data suggests that diabetic kidney transplant patients may need lower dosages of immunosuppressant drugs as compared to nondiabetic patients. Although further clinical studies are warranted to confirm these observations in a larger patient population.^
Health Sciences, Pharmacology
Shripad D Chitnis,
"Effect of diabetes mellitus on pharmacokinetics and pharmacodynamics of tacrolimus and sirolimus"
Dissertations and Master's Theses (Campus Access).