Published papers

This study evaluated the effects of cytochrome P450 (CYP) 2C19 polymorphisms on tacrolimus pharmacokinetics when coadministered with voriconazole. Eighteen healthy volunteers, including 6 individuals in each CYP2C19 genotype (extensive metabolizers [EMs], intermediate metabolizers [IMs], and poor metabolizers [PMs]), received a single oral dose of 3 mg tacrolimus alone or in combination with 200 mg voriconazole twice daily at steady state. When tacrolimus was coadministered with voriconazole, a significant increase in area under its concentration-time curve (AUC0-24) was observed for all genotypes. AUC0-12 of voriconazole in IMs and PMs were significantly higher than that in EMs (P 0-24 of tacrolimus in combination with voriconazole in IMs and PMs were also significantly higher than that in EMs (P

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m2. A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9–108.8 mL/min as estimated by the Cockcroft–Gault equation. The S-1 dosage formula was derived as follows:(Formula presented.)where AUC is the area under the concentration–time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration–time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

Background: Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD. Methods: The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m2) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m2) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). Results: A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied. Conclusions: Oxaliplatin (85 mg/m2) with weekly bol us 5-FU (400 mg/m2) and high-dose l-LV (250 mg/m2) is recommended for further phase III studies in patients with metastatic colorectal cancer. © 2006 Oxford University Press.

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m2), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate. Copyright © 2006 by Lippincott Williams & Wilkins.

Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen. © 2010 by American Society of Clinical Oncology.

The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (Emax) of olmesartan, whereas azelnidpine Emax was independent of patient background characteristics investigated. No patient was found to have a high Emax to one agent who also had a high Emax to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.

The purpose of this study is to examine the effects of doxazosin, an α-adrenoceptor antagonist, on P-glycoprotein/MDR1-mediated multidrug resistance (MDR) and the transport of anticancer drugs. The effects of doxazosin, prazosin, and terazosin on MDR1-mediated MDR were assessed in human cervical carcinoma HeLa cells and the MDR1-overexpressing derivative Hvr100-6, established by stepwise increases of the vinblastine concentration in the culture medium. The effects of doxazosin on the transcellular transport and intracellular accumulation of [3H]vinblastine, [3H]daunorubicin, and [3H]digoxin, all MDR1 substrates, were evaluated using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. The sensitivity to vinblastine and paclitaxel of Hvr100-6 cells was increased at 3.4- and 17.5-fold, respectively, by the addition of 1 μM doxazosin, whereas prazosin and terazosin had weaker or no such effects. Prazosin at 1 μM had a reversal effect on the sensitivity to vinblastine, whereas terazosin had no effect. In transport experiments, doxazosin concentration dependently increased the apical-to-basal transport of radiolabeled drugs in LLC-GA5-COL150 cells, but did not show remarkable effects on the basal-to-apical transport. In addition, doxazosin restored the intracellular accumulation in a concentration-dependent manner in LLC-GA5-COL150 cells. Doxazosin may partly reverse MDR by inhibiting MDR1-mediated transport, making it a candidate lead compound in the development of a reversing agent for MDR. Copyright © 2009 Cognizant Comm. Corp.

Objective: The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Methods: Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts <0.5 × 109 cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 μg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Results: Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration - time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. Conclusions: A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia. © The Author (2009). Published by Oxford University Press. All rights reserved.

A 69-year-old woman undergoing hemodialysis due to ANCA-associated nephritis and chronic renal failure developed lung adenocarcinoma and underwent radical surgery. Upon recurrence of her cancer, she received combination chemotherapy with carboplatin (CBDCA) 150 mg/m2 and docetaxel 35-70 mg/m2. Concentration of free CBDCA in serum was monitored for 6 days after drug administration. Hemodialysis was performed 1 hour after administration of CBDCA, and on day 4. Despite the lower maximum concentration, serum CBDCA levels 20-24 h after chemotherapy in this patient were 15 to 20 times higher than in subjects with normal renal function who received CBDCA at the area under the curve (AUC) of 5. She experienced moderate to severe nausea and vomiting which persisted for 12 days. During her second course of chemotherapy, hemodialysis was performed for 3 consecutive days after drug administration. The serum CBDCA levels on day 2 or later remained lower than in the first course, and the patient experienced fewer severe side effects. Based on the data from therapeutic drug monitoring of CBDCA, hemodialysis for 3 consecutive days after drug administration has been demonstrated to be useful for treatment of a patient with chronic renal failure receiving chemotherapy with CBDCA.

Background and objective: Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC4 synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC4 synthase gene polymorphisms, were also investigated. Methods: The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV1 after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed. Results: Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC 4 synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05). Conclusions: There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug. © 2009 The Authors.

Landiolol hydrochloride is a newly developed cardioselective, ultra short-acting β1-adrenergic receptor blocking agent used for perioperative arrhythmia control. The objective of this study was to characterize the population pharmacokinetics of landiolol hydrochloride in healthy male subjects. A total of 420 blood concentration data points collected from 47 healthy male subjects were used for the population pharmacokinetic analysis. NONMEM was used for population pharmacokinetic analysis. In addition, the final pharmacokinetic model was evaluated using a bootstrap method and a leave-one-out cross validation method. The concentration time course of landiolol hydrochloride was best described by a two-compartment model with lag time. The final parameters were total body clearance (CL: 36.6 mL/min/kg), distribution volume of the central compartment (V1: 101 mL/kg), inter-compartmental clearance (16.1 mL/min/kg), distribution volume of the peripheral compartment (55.6 mL/kg), and lag time (0.82 min). The inter-individual variability in the CL and V1 were 21.8% and 46.3%, respectively. The residual variability was 22.1%. Model evaluation by the two different methods indicated that the final model was robust and parameter estimates were reasonable. The population pharmacokinetic model for landiolol hydrochloride in healthy subjects was developed and was shown to be appropriate by both bootstrap and leave-one-out cross validation methods.