Population Pharmacokinetics of Higher-Dose Mizoribine in Healthy Male Volunteers

Abstract

Mizoribine is an orally available immunosuppressive agent, which has been on the market since 1984 in Japan for the prevention of rejection in renal transplantation.1) In contrast to other immunosuppressive agents (e.g., azathioprine), mizoribine has been shown in animal experiments to lack oncogenicity and has shown clinically a low incidence of severe adverse drug reactions (such as myelosuppression and hepatotoxicity), making it useful in long-term immunosuppressive therapy.2) After oral administration, mizoribine is absorbed rapidly from the gastro-intestinal tract and distributed into living cells according to a concentration gradient between the extracellular and intracellular environment. It is completely eliminated from blood circulation within 24 h, and is excreted in urine (85%), feces (9.7%), and bile (Ͻ1%). 1,3) As elimination rate of mizoribine is highly dependent on renal function, low-dose mizoribine (1 to 3 mg/kg/d) was administered to patients whose renal function did not return soon after transplantation. However, renal function returns much earlier following transplantation due to the concomitant use of calcineurin inhibitors. High-dose mizoribine (5 mg/kg/d) has been administered since 1998 to a number of patients, and has been shown to be safe and well tolerated in renal transplant patients at doses up to 5 mg/kg/d. 4,5) In addition, Akiyama et al. reported that patients treated with Ն5 mg/kg/d of mizoribine showed about 20% fewer acute rejection episodes at 3 months post-transplantation than those with Ͻ5 mg/kg/d of mizoribine.4) Recently, phase 1 single-and multiple-dose studies have been carried out to confirm the safety, tolerability, and pharmacokinetics of higher-dose (up to 12 mg/kg/d) mizoribine.5) In the phase 1 study, no notable or clinically relevant abnormality was observed in the clinical laboratory values except for transient elevation in serum uric acid at the highest dose level (multiple dose of 12 mg/kg/d). 5)In the present study, to evaluate the pharmacokinetic characteristics of mizoribine in subjects with normal renal function, we estimated the population pharmacokinetic parameters of mizoribine using a nonlinear mixed effects model (NONMEM) program.6) Pharmacokinetic data for population analysis were obtained in the previous phase 1 study, where 24 healthy Caucasian male subjects participated in a singledose (3, 6, 9, 12 mg/kg) study, and 12 subjects participated in a multiple-dose (6, 12 mg/kg/d) study.5) In addition, to assess linearity and constancy in the pharmacokinetics of mizoribine, the pharmacokinetic parameters in individual 36 subjects were obtained from the population estimates according to Bayes' theorem using the NONMEM post-hoc option.6) We further evaluated the precision of Bayesian analysis in the sparse sampling protocol by using pharmacokinetic data obtained from 24 subjects in the single-dose study. 5) MATERIALS AND METHODSPharmacokinetic Data Serum mizoribine concentration data for population pharmacokinetic analysis were obtained in the previous stu...

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

“…16,17) In the single-dose (protocol 1) trial, each subject received a single dose of 6 mg aripiprazole (ABILIFY ® tablet) under a fasting condition. Blood samples were collected for the analysis of aripiprazole at 1, 2, 3, 4, 5, 6,8,12,24,48,72, and 168 h after the dose. In the multiple-dose (protocol 2) trial, each subject received a once-daily dose of 3 mg aripiprazole at 30 min after breakfast for 14 consecutive days.…”

“…Blood samples were collected at 1, 2, 3, 4, 6, 8, and 12 h after the first dose on Day 1, at predose on Day 2-7, at 1, 2, 3, 4, 6, 8, and 12 h after the dose on Day 7, and at predose on Day 8-14. After the last dose on Day 14, blood samples were collected at 1, 2, 3, 4,6,8,12,24,48,72,96,120,168,216, and 288 h. In the protocol-3 trial, each subject first received a single dose of aripiprazole alone at 3 mg once under a fasting condition. After a 5-week washout period, the subjects were administrated itraconazole at 100 mg once daily for 21 consecutive days.…”

“…12) In the case of aripiprazole, large interindividual variability was observed not only for KA, but also for CL/F, V 1 /F, and V 2 /F ( Table 2). Since absolute bioavailability (F) of aripiprazole was reported to be 87%, its absorption from the gastrointestinal tract should be almost complete.…”

“…The FOCE method needs much (20-40-fold) longer computational time than the first-order method, but generally gives precise parameter estimates, especially for the analysis of multiple-dose pharmacokinetic data with multiple compartment models. [9][10][11][12] In the present study, therefore, we used the FOCE method to estimate the population pharmacokinetic parameters of aripiprazole, where a two-compartment model with first-order input was applied for data obtained from single-and multiple-dose clinical trials. …”

Simulation for Clinical Repeated-Dose Pharmacokinetic Trials Applying a Peak-and-Trough Sampling Design to Estimate Oral Clearance

“…[2][3][4][5][6][7] The area under the concentration-time curve (AUC ) and/or oral clearance (CL/F) of orally administered drugs is a key pharmacokinetic parameter to evaluate drug exposure in the patient population. In the present study, we evaluated the usefulness of clinical repeated-dose pharmacokinetic trials, applying a simple peak-and-trough sampling design in order to estimate the CL/F value.…”