論文

Thrombomodulin alfa is the recombinant extracellular domain of human thrombomodulin, which shows anticoagulation activity. To elucidate the pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation (DIC), population pharmacokinetic (PPK) analysis was performed using plasma concentration data obtained in phase 1 (20 patients, 348 time points) and phase 2 (116 patients, 305 time points) clinical trials. The actual and predicted plasma concentrations of thrombomodulin alfa based on the final PPK model showed a good linear correlation (R = 0.9504), and the pharmacokinetics of thrombomodulin alfa in DIC patients were affected by body weight, age, renal dysfunction, and hematocrit value. The distribution volume and clearance (CL) were proportional to body weight and were significantly increased in patients with lower hematocrit value (male <40%, female <35%). Furthermore, CL was decreased in patients with renal dysfunction and in elderly patients. Based on these results, the standard dose of thrombomodulin alfa is adjusted according to body weight. However, further dose adjustment is not needed based on age and hematocrit value, since these factors did not cause the large changes in plasma concentration that can affect the efficacy or safety. © 2011 The Author(s).

We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Eldecalcitol, which was developed by Chugai Pharmaceutical Co., Ltd. as a treatment with the potential of becoming the drug of first choice for osteoporosis, is a new derivative of active vitamin D3 (1,25(OH) 2D3) with a hydroxypropyloxy group introduced at the 2β position. The clinical development of this product has included a Phase I multiple dose study, early and late Phase II studies, a Phase III study, a clinical pharmacology study to investigate pharmacokinetics in postmenopausal women, a drug interaction study, a bioequivalence formulation study and a clinical pharmacology study to investigate pharmacokinetics in patients with impaired liver function. Using data from all these studies, we sought to characterize the pharmacokinetic profile of eldecalcitol.

Background: Eldecalcitol, which was developed by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan) as a treatment for osteoporosis, is a new derivative of active vitamin D3(1,25 (OH)2D3) with a hydroxypropyloxy group introduced at the 2β position. A Phase III, alfacalcidol-controlled clinical study of eldecalcitol was conducted in primary osteoporosis patients, with the incidence of new, non-traumatic vertebral fractures designated as the primary endpoint. Objectives: The objective of this study was to characterize the pharmacokinetic profile of eldecalcitol, using data obtained from this Phase III clinical study in primary osteoporosis patients. Methods: Patients were randomly assigned to an oral eldecalcitol or alfacalcidol group. Patients in the eldecalcitol group took one capsule each of eldecalcitol 0.75 μg and alfacalcidol placebo, while those in the alfacalcidol group took one capsule each of eldecalcitol placebo and alfacalcidol 1.0 μg, once daily for 144 weeks. Efficacy and safety in patients on eldecalcitol were compared with those in patients on alfacalcidol. For the pharmacokinetic analysis, the serum eldecalcitol concentration was measured at 48, 72, 96 and 144 weeks. Results: In the eldecalcitol group, the mean trough serum eldecalcitol concentrations obtained from patients without dose reduction at the time of blood collection were 286.9, 320.1, 387.3 and 344.0 pg/mL at 48, 72, 96 and 144 weeks, respectively. At all times, the trough serum eldecalcitol concentration remained within the range of values at 72 weeks. It was concluded from these results that the serum eldecalcitol concentration had reached steady state by 48 weeks. Calculation of the trough serum eldecalcitol concentration by baseline characteristic showed that the concentration was in a similar range in all categories of age, renal function and vitamin D supplementation. Conclusions: The trough serum eldecalcitol concentration in patients receiving eldecalcitol 0.75 μg did not change substantially from 48 to 144 weeks after starting treatment, suggesting that the pharmacokinetics of eldecalcitol do not vary with long-term treatment. Analysis using trough serum eldecalcitol concentrations revealed that age, renal function and vitamin D supplementation had no substantial effect on pharmacokinetics.

We developed a population pharmacokinetic (PPK) model of S-1 including the cytochrome P450 (CYP) 2A6 genotype and then used this PPK model to assess the influence of the CYP2A6 genotype on PK parameters of S-1 and the relationship between toxicity and the individual maximum concentrations (Cmax) or the area under the concentrationtime curve (AUC) of 5-fluorouracil (5-FU) in Japanese patients with advanced cancer. Fifty-eight patients with advanced cancer were assessed. A dose of 80 mg/m2/day of S-1 was given orally. On the basis of the CYP2A6 genotypes (*1, *4, *7 and *9), all patients were classified as having the wildtype, 1 variant allele or 2 variant alleles. The PPK model was established with plasma concentration data for tegafur (FT), 5-chloro-2,4-performed dihydroxypyridine (CDHP) and 5-FU. In patients with 2 variant alleles of CYP2A6, the clearance of FT was 58% less than in patients with the wildtype or 1 variant allele. The AUC of 5-FU correlated with the AUC of CDHP, but not with the AUC of FT. Therefore, the CYP2A6 genotype did not affect the AUC of 5-FU. The individual AUC or Cmax of 5-FU did not differ significantly between patients with grade 3 or 4 toxicities and patients with grade 0-2 toxicities. In conclusion, the CYP2A6 genotype did not affect the AUC of 5-FU, although the clearance of FT was lower in patients with 2 variant alleles of CYP2A6 than in patients with the wild-type or 1 variant allele.

Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. Case presentation: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. Conclusion: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

Background: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. Our recent proteomics studies have demonstrated that intracellular protein expression levels of S100A10 are significantly correlated with the sensitivity of colorectal cancer (CRC) cells to L-OHP, but not 5-FU, suggesting that S100A10 is a candidate predictive marker for the response to L-OHP. In this study, we investigated whether S100A10 is involved in L-OHP sensitivity or not.Results: Forced expression of S100A10 in COLO-320 CRC cells significantly increased the 50% inhibitory concentration (IC50) for L-OHP (P = 0.003), but did not change that for 5-FU, indicating that S100A10 is more specific to L-OHP than 5-FU. Silencing of the S100A10 gene showed no apparent effect on sensitivity to L-OHP in HT29 cells. Silencing of the annexin A2 (a binding partner of S100A10) gene alone downregulated both annexin A2 and S100A10 protein levels, with no change in S100A10 gene expression. However, original levels of intact S100A10 protein in CRC cells positively correlated with S100A10 mRNA levels (P = 0.002, R = 0.91).Conclusions: The present results have shown that protein expression of S100A10 was associated with resistance to L-OHP, but not 5-FU, supporting the hypothesis that S100A10 expression may predict L-OHP sensitivity. Thus, our present study provides basic findings to support that S100A10 expression can be used as a predictive marker for tumor sensitivity to L-OHP. © 2014 Suzuki and Tanigawara; licensee BioMed Central Ltd.

The multidrug transporter MDR1 (P-glycoprotein)-mediated interaction between digoxin and 29 antihypertensive drugs of various types was examined by using the MDR1 overexpressing LLC-GA5-COL150 cells, which were established by transfecting MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. These cells construct monolayers with tight junctions, and enable the evaluation of transcellular transport. The MDR1 was highly expressed on the apical membrane (urine side). The basal-to-apical and apical-to-basal transcellular transport of [3H]digoxin in LLC-GA5-COL150 cells was time- and temperature-dependent. The basal-to-apical transport of [3H]digoxin was markedly increased, whereas the apical-to-basal transport was decreased in LLC-GA5-COL150 cells, compared with the host LLC-PK1 cells, suggesting that [3H]digoxin was a substrate for MDR1. Most of the Ca2+ channel blockers used here markedly inhibited basal-to-apical transport and increased apical-to-basal transport. Exceptions were diltiazem, nifedipine and nitrendipine, which hardly showed inhibitory effects on transcellular transport of [3H]digoxin. α-Blocker doxazosin and β-blocker carvedilol also inhibited transcellular transport of [3H]digoxin, but none of the angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists used here were active. These observations will promote understanding of the digoxin-drug interactions resulting from their actions on MDR1, and which may aid in avoiding these unexpected effects of digoxin. © 2002 Elsevier Science Inc. All rights reserved.

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations ≤1000 ng/ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg/kg for both LD and CD with 30 mg/m2 doxorubicin; these dosages were increased to 2 and 10 mg/kg and 50 mg/m2, respectively. Thirty-one patients were treated. Nausea/ vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > 1000 ng/ml were achieved at a 2 mg/kg LD and a 10 mg/kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC50 of P-glycoprotein expressing 8226/Dox6 in patients' serum was decreased from 5.9 to 1.3 μg/ml (P<0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3±13.7 (mean±SD) liter/h/m2, which was lower than the 49.0±16.9 liter/h/m2 without PSC-833 (P<0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg/kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg/m2, not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

Purpose: KRN5500, a novel spicamycin derivative, shows the greatest activity against a human tumor xenograft model and the highest therapeutic index among spicamycin derivatives. KRN5500 is currently under clinical development in Japan and the United States. The objective of this study was to develop a population pharmacokinetic model that describes the KRN5500 plasma concentration versus time data. Methods: Data were collected from 18 patients entered in a phase 1 study. These patients received KRN5500 3-21 mg/m2 as a 2-h infusion. A total of 219 concentration measurements were available. The data were analyzed using the nonlinear mixed effect model (NONMEM) program. In addition, the basic and final population pharmacokinetic models were evaluated using bootstrapping resampling. Results: The basic model selected was a two-compartment model with a combination of additive and constant coefficient of variation error models. The basic model fitted well not only the original data, but also 100 bootstrap replicates generated from the original data set. With regard to the effect of covariates selected by generalized additive modeling analysis, gender (SEX) and performance status were found to be possible determinants of the volume of central compartment by NONMEM analysis. The final regression model for V1 was V1 = θV1(1 - SEX × θSEX), where V1 is the typical population value of the volume of central compartment, and SEX = 0 if the patient is male, otherwise SEX = 1. The final model was fitted to the 200 bootstrapped samples. The mean parameter estimates were within 15% of those obtained with the original data set. Conclusions: The KRN5500 plasma concentration versus time data obtained from the phase 1 study were well described by the population pharmacokinetic model. Further evaluation by bootstrapping showed that the population pharmacokinetic model was stable.