Assessment of Blood Prostaglandin E2 Metabolite Levels among Infants Born Preterm with Patent Ductus Arteriosus: A Prospective Study.

OBJECTIVE: To assess the role of prostaglandin E2 by measuring blood prostaglandin E2 metabolite (PGEM) concentrations in preterm infants with patent ductus arteriosus (PDA). STUDY DESIGN: A prospective observational study of preterm infants born before 32 weeks of gestational age (GA) was performed in a single tertiary hospital in Japan. Blood samples were collected to measure serum concentrations of PGEM, ibuprofen (IBU), and cytokines. Multiple regression analyses assessed associations between blood PGEM levels and perinatal factors, development of hemodynamically significant PDA (hsPDA), and IBU treatment response of hsPDA. RESULTS: Seventy-nine infants (median GA 28 weeks) were enrolled in this study. Forty-seven received IBU for hsPDA treatment 1 d after birth in median. PDA closure occurred in 25 infants after a single IBU treatment. Serum PGEM concentrations were associated with histologic chorioamnionitis (P < .01), but not with GA, respiratory distress syndrome, or serum IL-6 concentrations. Serum PGEM concentrations decreased after initial IBU treatment; however, they were not associated with hsPDA development (P = .39). IBU concentrations correlated with IBU treatment response (aOR 1.29, P < .01). However, pre-IBU serum PGEM levels and PGEM reduction ratio did not (P = .13, .15, respectively). CONCLUSIONS: Serum PGEM concentrations in preterm infants were associated with maternal histologic chorioamnionitis, but not hsPDA development. IBU treatment response was associated with higher blood IBU concentrations, but not PGEM concentrations.

Naldemedine for Opioid-Induced Constipation in Patients With Cancer: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

PURPOSE: Opioid-induced constipation is the most frequent and non-self-limiting adverse effect of opioid analgesia, reducing adherence and interfering with pain relief. This clinical trial aimed to clarify the preventive effect of naldemedine versus placebo for constipation in patients with cancer starting regularly dosed strong opioids therapy. METHODS: This multicenter, double-blinded, randomized, placebo-controlled, confirmatory trial was conducted between July 2021 and May 2023 at four academic hospitals in Japan (ClinicalTrials.gov identifier: jRCTs031200397). Patients with cancer starting a first-time regularly dosed strong opioid for cancer pain and age 20+ years were included. Eligible patients were randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio for 14 days with protocol treatment. The primary end point was the proportion of patients with a Bowel Function Index (BFI) of <28.8 on day 14. The secondary end points included frequency of spontaneous bowel movements (SBM), quality of life (QOL), and frequency of opioid-induced nausea and vomiting (OINV). RESULTS: Of the 103 patients assessed for eligibility, 99 received either naldemedine (n = 49) or placebo (n = 50). A BFI of <28.8 on day 14 was significantly more likely to occur in the naldemedine group (64.6%; 95% CI, 51.1 to 78.1) versus placebo (17.0%; 95% CI, 6.3 to 27.8), and the difference between groups was 47.6% (95% CI, 30.3 to 64.8; P < .0001). The frequency of SBM, QOL, and the severity of OINV were nominally significant in the naldemedine group than in the control group. CONCLUSION: Naldemedine prevented constipation and improved constipation-related QOL, with possible preventive effect on OINV in patients with cancer starting regularly dosed opioids therapy.

External Validation of a Limited Sampling Strategy for the Estimation of Mycophenolic Acid Exposure Between Different Assay Methods: PETINIA and HPLC Methods.

INTRODUCTION: A limited sampling strategy (LSS) for estimating the area under the plasma concentration-time curve (AUC0-12) of the immunosuppressant mycophenolic acid (MPA) is used for therapeutic drug monitoring (TDM) in clinical practice. Our study delves into the applicability of the MPA AUC0-12 LSS, originally developed using particle-enhanced turbidimetric inhibition immunoassay (PETINIA) measurements, to those obtained via high-performance liquid chromatography with ultraviolet detection (HPLC-UV). METHODS: We developed an LSS for estimating MPA AUC0-12 based on PETINIA measurements in 32 adult kidney transplant patients who were receiving mycophenolate mofetil. Validation of this strategy was conducted in an additional 14 adult kidney transplant patients (validation sets) through measurements obtained by both PETINIA and HPLC-UV. Predictive performance was assessed using mean absolute error (MAE), root mean squared error (RMSE), and "good guess" defined as predicted AUC within observed AUC ± 15%. RESULTS: The three time point equation (0, 2, and 6 h) emerged as optimal for estimating MPA AUC0-12, balancing predictive performance and usefulness in clinical settings. In validation sets, the coefficient of determination for observed versus predicted AUC0-12 was consistent between PETINIA (0.978) and HPLC-UV (0.958) measurements. Comparable MAE, RMSE, and "good guess" outcomes were observed for PETINIA (6.4%, 8.1%, and 85.7%, respectively) and HPLC-UV (7.6%, 9.4%, and 85.7%, respectively) measurements. CONCLUSION: Our findings support the application of the MPA AUC0-12 LSS, originally developed using PETINIA measurements, to those obtained via HPLC-UV.

An analytical method using salting-out assisted liquid-liquid extraction to quantify ceftriaxone from micro volumes of human serum.

Ceftriaxone (CTRX) is a commonly used cephalosporin antibiotic. It is suggested that monitoring plasma/serum concentrations is helpful for its safe use. This study aimed to develop and validate an analytical method for measuring CTRX concentrations in human serum according to International Conference on Harmonization guideline M10. Ten microliters of serum sample was purified using a salting-out assisted liquid-liquid extraction procedure with magnesium sulfate. The upper layer was then diluted threefold and analyzed using a liquid chromatography-tandem mass spectrometry-based method with a total run time of 12 min. The linear calibration curve was obtained over the concentration range 5-500 µg/ml. The within-run accuracy varied from 0.2 to 6.5%, and the precision was ≤8.0%. The between-run accuracy and precision ranged from 0.7% to 5.6% and ≤6.4%, respectively. Significant carryover was resolved by injecting four blanks after high-concentration CTRX samples. The recovery rates from spiked serum at low and high concentrations were 44.4 and 43.4%, respectively. Other factors, including selectivity, matrix effects, stability, dilution integrity and reinjection reproducibility also met the acceptance criteria. Serum concentrations in 14 samples obtained from two participants receiving 2 g/day of CTRX were successfully determined using this method.

Impact of Hepatitis B Surface and Core Antibody Levels on Hepatitis B Virus Reactivation.

Hepatitis B virus reactivation (HBV-R) is a serious complication that can occur in patients with resolved HBV infection during cancer chemotherapy. We examined the levels of HBV surface antibody (HBsAb) and HBV core antibody (HBcAb) to assess the incidence of HBV-R in cancer patients including hematopoietic stem cell transplantation (HSCT) and rituximab administration. This retrospective cohort study included 590 patients with resolved HBV infection. The incidence of HBV-R was evaluated 761.5 (range, 90-3898) days after the inititiation of chemotherapy. Of the patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All 13 patients exhibited lower HBsAb (<100 mIU/mL) levels at baseline. A higher level of HBcAb (≥100 cut off index (C.O.I.)) was a possible risk factor for HBV-R as well as HSCT and rituximab administration. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab were at a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results suggest that assessment of HBsAb and HBcAb levels prior to the chemotherapy is important for identifying patients at high risk of HBV-R, especially in solid cancers without HSCT and rituximab administration.

Implications of Incorporating Plasma Lipoprotein Binding into a Physiologically-Based Pharmacokinetic Model: A Simulation Study with Amiodarone.

Although various lipophilic drugs are bound to lipoproteins, lipoprotein binding in plasma is not usually considered in current physiologically-based pharmacokinetic (PBPK) models. Amiodarone is extensively bound to serum triglyceride-rich lipoproteins. Total plasma amiodarone concentration, which is the sum of both unbound and bound concentrations, increases with increasing serum triglyceride levels. We investigated the impact of lipoprotein binding on amiodarone pharmacokinetics using PBPK modeling and simulations. An amiodarone PBPK model that incorporates plasma lipoprotein binding (LPP model) was developed based on the correlation between serum triglyceride levels and lipoprotein-bound amiodarone. The predicted unbound fraction of amiodarone in plasma and systemic clearance in the LPP and base models (with albumin binding only) were similar, but the coefficients of variation for the LPP model were greater than those for the base model and were closer to the observed data. The total plasma amiodarone concentration predicted using the LPP model increased with higher levels of plasma lipoprotein binding and serum albumin. In contrast, changes in plasma lipoprotein binding and serum albumin levels did not influence the predicted unbound plasma amiodarone concentration at steady-state. This study demonstrates that incorporating plasma lipoprotein binding into a PBPK model improves the accuracy of predicting interindividual variabilities in amiodarone clearance by more reliably predicting the interindividual variability in the plasma unbound fraction of amiodarone. Plasma lipoprotein binding should be considered in PBPK modeling and simulations for lipoprotein-associated drugs if there is available information on the relationship between plasma lipoprotein binding and hyperlipidemia.

Effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers: a population pharmacokinetic analysis.

PURPOSE: Considerable amounts of injected immunoglobulin G-based therapeutic monoclonal antibodies, such as ramucirumab, are distributed into ascites. This study aimed to examine the effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers. METHODS: Population pharmacokinetic analysis of ramucirumab was performed using data on serum ramucirumab concentrations of 52 patients with gastrointestinal cancers, including 8 patients with massive ascites. The Bayesian method using the final population pharmacokinetic model was utilized to estimate trough ramucirumab concentrations after the first dose and at steady state. RESULTS: Population pharmacokinetic analysis revealed that massive ascites as well as body weight were influencing factors for ramucirumab clearance. The estimated ramucirumab clearance was significantly higher in patients with massive ascites than in those with no/mild ascites (0.020 ± 0.004 versus 0.013 ± 0.004 L/h, P < 0.001). The estimated trough ramucirumab concentrations were significantly lower in patients with massive ascites than in those with no/mild ascites after the first dose (26.4 ± 6.8 versus 36.1 ± 7.1 µg/mL, P < 0.001) and at steady state (41.4 ± 16.3 versus 65.9 ± 18.0 µg/mL, P < 0.001). CONCLUSION: In the present study, the presence of massive ascites affected the pharmacokinetics of ramucirumab in patients with gastrointestinal cancers. Our results suggest that dose optimization of ramucirumab may be necessary in patients with massive ascites due to higher ramucirumab clearance.

Distribution of therapeutic monoclonal antibodies into ascites in advanced gastric cancer patients with peritoneal metastasis: case reports and literature review.

BACKGROUND: Therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are used to treat advanced gastric cancer (AGC). Malignant ascites is often accompanied by peritoneal metastasis in AGC patients. However, the distribution of therapeutic monoclonal antibodies into ascites has yet to be adequately investigated. METHODS: We determined serum and ascites concentrations of ramucirumab or nivolumab and total IgG in three AGC patients with massive ascites. When serum and ascites samples were obtained on the same day, the ascites-to-serum ratio (A/S ratio) of the concentration of monoclonal antibodies was evaluated. The relationship between time after last infusion and the A/S ratio of therapeutic monoclonal antibodies was examined using 15 datasets from the present study and the literature. RESULTS: Ramucirumab and nivolumab were detected in massive ascites at considerable amounts (A/S ratios of 0.24-0.35 for ramucirumab and 0.17-0.55 for nivolumab). A positive correlation was detected between the A/S ratios of the therapeutic monoclonal antibodies and the time after last infusion (r = 0.747). Removal of ascites using paracentesis eliminated at least 15.3%-30.3% and 5.2-27.4% of the injected ramucirumab and nivolumab, respectively. Endogenous IgG, as well as therapeutic monoclonal antibodies, were distributed into ascites; the A/S ratios for IgG were 0.22-0.45. CONCLUSION: Our results suggest that therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are distributed into massive ascites in AGC patients concomitantly with endogenous IgG. In these patients, retention of ascites and its removal may result in decreased systemic drug exposure to ramucirumab and nivolumab.

Rationale and design of a multicenter, double-blinded, randomized, placebo-controlled trial to investigate the effects of naldemedine on opioid-induced constipation for patients with cancer pain: A study protocol.

Background: It is unclear which laxatives are appropriate to prevent opioid-induced constipation (OIC). This study will evaluate whether prophylactic use of naldemedine prevents OIC in patients with cancer who start opioid administration. Methods: This study is a multicenter, double-blinded, randomized, placebo-controlled trial. Patients who meet the eligibility criteria and give consent will be randomly assigned to the naldemedine or placebo group. Both groups will take each drug once a day after breakfast for 14 days. Results: The primary endpoint is the proportion of patients with a Bowel Function Index of less than 28.8 on Day 14. The secondary endpoints include assessment scales of the impact of constipation on comprehensive quality of life. Conclusions: This is the first study proposed to assess the superiority of naldemedine over placebo in the prevention of OIC. If naldemedine is found to be effective in reducing OIC compared with the placebo, it will be regarded as a new standard for OIC prophylaxis at opioid initiation. Trial registration: jRCT identifier: jRCTs031200397. Registered March 5, 2021, https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs031200397.

Increased serum amiodarone concentration in hypertriglyceridemic patients: Effects of drug distribution to serum lipoproteins.

Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration-to-dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (rs  = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (rs  = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high-density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (rs  = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein-binding and decreased metabolism of amiodarone.

A simple HPLC assay for determining eltrombopag concentration in human serum.

Eltrombopag, a thrombopoietin receptor agonist, is used for the treatment of idiopathic thrombocytopenic purpura (ITP) and aplastic anemia. We developed a HPLC assay for the determination of serum eltrombopag concentration in ITP patients. An aliquot of a serum sample spiked with diclofenac as the internal standard (IS) was treated with acetonitrile to precipitate the proteins. Eltrombopag and the IS were separated on an octadecylsilyl silica-gel column using a mobile phase consisting of 10 mM 1-pentanesulfonic acid sodium salt, acetonitrile, and acetic acid. The detection wavelength was set at 265 nm. The calibration curve was linear at the concentration range of 0.15-12.5 µg/mL for eltrombopag (r = 0.9987). The recoveries of eltrombopag from the serum samples were greater than 95.9% with coefficients of variation (CVs) being less than 2.8%. The CVs for the intra-day and inter-day assays were 1.9-11.8% and 1.0-11.8%, respectively. This assay method could be used for therapeutic drug monitoring of eltrombopag in ITP patients.

Effect of CYP2D6 genetic polymorphism on peak propafenone concentration: no significant effect of CYP2D6*10.

Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.

A Follow-Up Report of an Infant Born to a Mother Receiving Tamoxifen.

Tamoxifen, an estrogen receptor antagonist, is contraindicated in pregnant women due to its teratogenic activity. In the present study, we report the case of an infant whose mother received tamoxifen for breast cancer while unaware of the pregnancy. The infant, born at 29 weeks and 6 days of gestational age with a birth weight of 1664 g, had no congenital anomalies. This case presents detailed information on the development of an infant with placental transfer of tamoxifen. The infant has grown and developed normally throughout a 5-year follow-up period, but long-term vigilance continues.

High-Performance Liquid Chromatography for Therapeutic Drug Monitoring of Serum Lenvatinib.

BACKGROUND: Therapeutic drug monitoring (TDM) and dose adjustment of lenvatinib may be beneficial in the treatment of radioiodine-refractory thyroid cancer, by maximizing antitumor effects and minimizing adverse drug reactions. The aim of this study was, therefore, to develop and validate a high-performance liquid chromatography method using an ultraviolet detection system for routine serum lenvatinib detection in patients with thyroid cancer. METHODS: Serum specimens, spiked with an internal standard, were treated by a solid-phase extraction through an octadecylsilyl silica cartridge. Lenvatinib and internal standard were concomitantly separated from serum using a conventional octadecylsilyl silica column through isocratic elution, using a mobile phase consisting of 0.02 mol/L sodium phosphate (pH 6.7) and acetonitrile (50/50, vol/vol) at a flow rate of 1.0 mL/min. The detection wavelength was set at 244 nm. Serum samples from 5 patients were used for clinical validation of the method. RESULTS: The calibration curve for lenvatinib was linear (Pearson correlation coefficient, r = 0.9998) over the concentration range of 6.25-400 ng/mL, with a lower limit of quantification of 6.25 ng/mL. Extraction recoveries for lenvatinib were 97% or more, with coefficients of variation less than 2.2%. The coefficients of variation for intraday and interday assays were less than 4.7% and 6.0%, respectively. CONCLUSIONS: This sensitive high-performance liquid chromatography method can be used for lenvatinib therapeutic drug monitoring when liquid chromatography-tandem mass spectrometry facilities are unavailable.

Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis.

PURPOSE: Higher drug concentrations in complex clinical scenarios in which multiple factors such as drug-drug interactions (DDIs) and comorbidities are simultaneously present are not necessarily rationalized in prospective clinical studies. Physiologically based pharmacokinetic (PBPK) modeling and simulation of the anti-arrhythmic drug flecainide, as an example, were utilized to quantitatively rationalize the higher flecainide concentration in a complex clinical case involving end-stage renal disease (ESRD), cirrhosis, and the co-administration of mexiletine, a CYP1A2 inhibitor. METHODS: The developed flecainide PBPK model was used to evaluate the DDI effect (as measured by AUC ratio before and after inhibition) of mexiletine and the combined disease effects of ESRD and cirrhosis on flecainide exposure. RESULTS: The predicted DDI effect of mexiletine was negligible or weak in anuric hemodialysis with cirrhosis population (mean [5th/95th percentiles], 1.23 [0.97-1.67]), although it was negligible in healthy volunteers (1.03 [1.02-1.05]). The predicted flecainide concentrations after multiple flecainide doses (50 mg BID) in the anuric hemodialysis with cirrhosis population were comparable with the observed value (3602 ng/mL), which fell between the predicted concentrations in the absence and presence of mexiletine (3043 [718-8499] and 5914 [880-20,624] ng/mL, respectively). CONCLUSIONS: The PBPK simulation proposed a likely explanation that the observed higher flecainide concentration could be attributed to the combined effects of ESRD, cirrhosis, and a potential DDI with mexiletine. This approach provides quantitative insight into theoretically conceivable extremes in drug exposure occurring in complex clinical situations even if uncommon.

Involvement of Renal Efflux Transporter MATE1 in Renal Excretion of Flecainide.

Flecainide, an anti-arrhythmic drug, undergoes renal excretion through active renal tubular secretion in addition to passive glomerular filtration. The contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide remains unclear except that flecainide is a substrate of human multidrug resistance protein 1 (MDR1). To elucidate renal efflux and uptake transporters involved with active renal tubular secretion of flecainide, we conducted in vitro interaction studies of flecainide using organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, and MATE2-K. Uptake transporter inhibition assays using hOCT2-Chinese hamster ovary (CHO), hMATE1-CHO, and hMATE2-K-Madin Darby canine kidney strain II (MDCKII) cells revealed that flecainide (2.5 µM) inhibited hMATE1-mediated transport by 40% with an IC50 value of 6.7 µM; however, it showed no or weak inhibitory effects on hOCT2- and hMATE2-K-mediated transport. For investigating flecainide as a substrate of hMATE1, the accumulation of flecainide in hMATE1-CHO was compared with that in control cells. Uptake transporter substrate assay revealed that flecainide (1 µM) showed 1.11-fold accumulation though the hMATE1-related active transport was significantly decreased in the presence of quinidine (42.0 ± 23.9 vs. 11.8 ± 4.1 pmol/mg in transfected cells; p < 0.05). These results suggest that flecainide is a weak substrate of hMATE1, which is involved in the renal tubular secretion of cationic drugs, and hMATE1 may be less important in the pharmacokinetic drug-drug interaction for renal excretion of flecainide. However, in vivo drug-drug interaction studies of flecainide with substrates of hMATE1 may be needed because flecainide has the potential to inhibit hMATE1.

Interior Temperature and Relative Humidity of an Envelope During Mail Transport by the Japan Post in the Summer: Preliminary Study for a Stability Test of Dried Blood Spot Samples Sent as Regular Mail.

BACKGROUND: The dried blood spot (DBS) is well studied and has been considered a useful technique for collecting biological specimens for therapeutic drug monitoring. Since DBS cards are transported as regular mail, these samples can be exposed to various climatic conditions while in transit. However, there have been limited amounts of data regarding interior temperature and relative humidity (RH) of the envelope during mail transport of DBS samples. This study investigated the interior temperature and RH during the transport of regular mail by Japan Post during the summer and assessed the effect of the gas permeability of zip lock bags on the interior temperature and RH when used as containers for the DBS card. METHODS: Either an aluminum zip lock bag, gas-impermeable, or a plastic zip lock bag, gas-permeable, containing a desiccant pouch (10 g) and a data logger was packed in an envelope and then transported by mail between Sapporo and Tsukuba/Kagoshima. The ambient temperature and RH in the above cities during the mail transport were obtained from the website of the Japan Meteorological Agency. RESULTS: The envelope was exposed to ≥30°C for up to 22 hours during the mail transport. Differences in the temperature between the interior and exterior of the envelope were almost completely within a range of ±4°C regardless of the gas permeability of the zip lock bags. Although the ambient RH was sometimes over 90% during mail transport, the mean interior RHs of the envelope containing the aluminum or plastic zip lock bag throughout the transport process were 13% and 17%, respectively. CONCLUSIONS: Both zip lock bags provided comparable results in relation to the interior temperature and RH of the envelope. Our results suggest that a stability test at 40°C and 90% RH for at least 24 hours is recommended as a validation process if DBS samples are transported as regular mail in Japan. However, conditions may need to be modified depending on the regions.