Population pharmacokinetics of mizoribine in adult recipients of renal transplantation

Abstract

The present findings suggested that not only the rate of renal excretion but also the extent of intestinal absorption of mizoribine is responsible for the large interindividual pharmacokinetic variability of the drug.

Variability of Bioavailability and Intestinal Absorption Characteristics of Bisoprolol

“…2) Recently, we have reported that the variability of bioavailability (F) is one of the causes of the interindividual pharmacokinetic variability of mizoribine, an immunosuppressive agent. 3,4) That is, we analyzed the serum concentration data of mizoribine in adult and pediatric recipients of renal transplantation using a nonlinear mixed effect model (NONMEM) program. We found a significant positive correlation between CL/F and the apparent volume of distribution (V/F) in both studies.…”

“…We found a significant positive correlation between CL/F and the apparent volume of distribution (V/F) in both studies. 3,4) Since the plasma protein binding of mizoribine is negligible, the systemic clearance (CL) of the drug may not be correlated with the volume of distribution (V). In addition, mizoribine is not subjected to hepatic firstpass metabolism, and is exclusively excreted into the urine as the unchanged form.…”

“…Therefore, interindividual variability in F of mizoribine is one of the causes of the interindividual pharmacokinetic variability of the drug, and the intestinal absorption step is plausibly responsible for the interindividual variability of the F of mizoribine. 3,4) The primary aim of the present study was to evaluate the variability of the F of bisoprolol. That is, we analyzed the plasma concentration data of bisoprolol in 52 Japanese patients using a NONMEM program, and evaluated the correlation between CL/F and V/F of the drug.…”

Advantages and Disadvantages of Conditional Estimation Methods for Population Pharmacokinetic Analysis of Mizoribine

“…We have recently performed population pharmacokinetic analysis of mizoribine in adult and pediatric recipients of renal transplantation with a nonlinear mixed effects model (NONMEM) program, and reported that the pharmacokinetics of mizoribine was described well by the 1-compartment model with absorption lag time (ALAG) and rst-order absorption. 7,8) In addition, there was a positive correlation between the apparent volume of distribution (V/F) and oral clearance (CL/F).…”

“…Therefore, the positive correlation between V/F and CL/F can be due to the variability of F. The variable F of mizoribine reflects the extent of intestinal absorption of the drug, because there is no rst-pass metabolism of mizoribine in the liver and intestine. 7,8) On the other hand, we previously performed population pharmacokinetic analysis of mizoribine in healthy adult men. 9) In this analysis, we assumed that the variability of F was negligible in healthy subjects, and omitted the correlation between V/F and CL/F.…”