Effect of pharmacokinetic profile on the pancreatic toxicity and efficacy of tacrolimus in rats

Abstract

ABSTRACTmg/kg/day were given once daily for 8 days in the bolus intravenous injection groups. In the continuous intravenous infusion groups, tacrolimus was infused using an Alzet ® osmotic mini-pump for 9 days at the same doses. Pancreatic insulin content decreased dose-dependently in both the bolus intravenous injection -es caused by the two dosing regimens. At 0.03 mg/kg, continuous intravenous infusion did not cause glu--erance. The pharmacokinetic data indicated that continuous intravenous infusion resulted in a sustained blood drug concentration with an area under the curve (AUC) similar to that obtained with the bolus thoraxes of recipients. Tacrolimus doses of 0.01, 0.1, or 1 mg/kg/day were administered from day 0 to day 13. Both bolus intramuscular administration and continuous intravenous infusion prolonged skin allograft groups given the same doses. To summarize, the sustained-release of tacrolimus resulted in a steady blood drug concentration with an AUC similar to that of the bolus administration. In rats, it was better tolerated -tion (Cmax). These results indicate that the sustained-release formulation has the potential to improve the safety of tacrolimus.

Comparison of Pharmacokinetics and Pathology for Low-Dose Tacrolimus Once-Daily and Twice-Daily in Living Kidney Transplantation

“…The main measure to prevent nephrotoxicity is to reduce the systemic exposure levels and keep the local renal exposure levels to CNI and its metabolites at the lowest possible (18). We have hypothesized that the C max may be closely related to its toxicity, and the use of once-daily tacrolimus would be less toxicity by the lower C max (12). In an experimental animal model, avoidance of high peak concentrations has been associated with a reduced incidence of hyperglycemia (19).…”

“…A prolonged-release formulation of tacrolimus (Graceptor or Advagraf, Astellas Pharma; referred to as Tacrolimus QD) was developed to allow once-daily dosing and to have similar safety and efficacy profiles to Tacrolimus BID with the potential for improving patient's drug adherence and quality of life (10,11). Furthermore, the use of once-daily tacrolimus may decrease the toxicity of the drug by the low maximal blood concentration (C max ) (12). However, tacrolimus has a narrow therapeutic window and highly individual variable pharmacokinetic (PK) characteristics, monitoring of drug exposure is strongly recommended, but limited data are available on the kinetics of Tacrolimus QD in de novo transplanted kidney recipients (11).…”

Pharmacokinetics of prolonged‐release tacrolimus and implications for use in solid organ transplant recipients

“…The focus on equivalence in AUC 24 was based on pre‐clinical and clinical data that showed this to be a significant variable associated with efficacy, while C max was not a significant variable. Therefore, the same efficacy could be presumed if the total daily AUC was maintained . This is discussed further in a review by Barraclough et al…”

Sub-Maximal Exercise Altered the Prednisolone Absorption Pattern.

“…Previous studies showed the efficacy of drug depends on total exposure rather than C max . (26,27). On the other hand, a study demonstrated that drug side effects may be reduced by lowering the peak blood level of drug concentration (27).…”

“…(26,27). On the other hand, a study demonstrated that drug side effects may be reduced by lowering the peak blood level of drug concentration (27). The increased exposure to prednisolone increased side effects may be apparent at low dosage (28).…”