Yuichi Muraki

Japanese antimicrobial consumption surveillance: First report on oral and parenteral antimicrobial consumption in Japan (2009–2013)

No reliable national antimicrobial consumption data have been available in Japan. The Japanese antimicrobial consumption surveillance (JACS) project started to collect data nationwide on antimicrobial consumption. This paper provides the first sales data from the JACS project on oral and parenteral antimicrobial consumption in Japan as well as the trends for the years from 2009 to 2013. The population-weighted total consumption was expressed as defined daily doses (DDDs) per 1000 inhabitants per day (DID). The value of DID increased from 14.7 in 2009 to 15.8 in 2013. Notably, oral antimicrobials accounted for 92.6% (mean of 2009, 2011 and 2013) of total consumption. Oral third-generation cephalosporins, macrolides and fluoroquinolones accounted for 77.1% (mean of 2009, 2011 and 2013) of oral consumption. Consumption of antimicrobials has increased during the years 2009 and 2013 regardless of the dosage form. This is the first report regarding the population-weighted consumption of oral and parenteral antimicrobials in Japan during the years 2009 and 2013. These results provide useful information for combating the menace of antimicrobial resistance in Japan.

Changes in the pharmacokinetics of teicoplanin in patients with hyperglycaemic hypoalbuminaemia: Impact of albumin glycosylation on the binding of teicoplanin to albumin.

There is large interindividual variability in serum teicoplanin (TEIC) concentrations after administration of a loading dose, and the factors that influence the pharmacokinetics of TEIC are disputed. The aim of this study was to clarify changes in the pharmacokinetics of TEIC that occur in patients with hyperglycaemia as well as the impact of albumin glycosylation on the pharmacokinetics of TEIC. This study consisted of retrospective and prospective investigations. The pharmacokinetic parameters of TEIC were retrospectively compared between patients receiving TEIC treatment. Ninety-four patients were divided into four groups according to their serum albumin and blood glucose concentrations [(i) hyperglycaemic hypoalbuminaemia (albumin<3.0g/dL) (n=16); (ii) non-hyperglycaemic hypoalbuminaemia (n=29); (iii) hyperglycaemic normoalbuminaemia (albumin≥3.0g/dL) (n=9); and (iv) non-hyperglycaemic normoalbuminaemia (n=40)]. In addition, the concentration of glycosylated albumin was prospectively determined in 28 patients. At 12h after administration of a loading dose, patients with hyperglycaemic hypoalbuminaemia displayed significantly lower serum TEIC concentrations (P<0.05) and higher TEIC volume of distribution (Vd) (P<0.05) than the other three groups, whereas TEIC clearance did not differ significantly among the groups. In addition, the percentage of glycosylated albumin was significantly correlated with the association constant (Ka) of TEIC for albumin (r=0.53, P=0.004) and the Vd (r=0.41, P=0.031). These results suggest that hyperglycaemic hypoalbuminaemia lowers the serum TEIC concentration, which is attributable to the decreased Ka and increased Vd of TEIC by albumin glycosylation.

Immunological aspects in late phase of living donor liver transplant patients: usefulness of monitoring peripheral blood CD4+ adenosine triphosphate activity.

Aim. To evaluate whether the combination of the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (ImmuKnow assay: IMK assay) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for monitoring of immunological aspects in the patient followup of more than one year after living donor liver transplantation (LDLT). Methods. Forty-nine patients, who underwent LDLT more than one year ago, were randomly screened by using IMK assay from January 2010 to December 2011, and the complete medical records of each patient were obtained. The CYP3A5 genotypes were examined in thirty-nine patients of them. Results. The mean ATP level of the IMK assay was significantly lower in the patients with infection including recurrence of hepatitis C (HCV) (n = 10) than in those without infection (n = 39): 185 versus 350 ng/mL (P < 0.001), while it was significantly higher in the patients with rejection (n = 4) than in those without rejection (n = 45): 663 versus 306 ng/mL (P < 0.001). The IMK assay showed favorable sensitivity/specificity for infection (0.909/0.842) as well as acute rejection (1.0/0.911). CYP3A5 genotypes in both recipient and donor did not affect incidence of infectious complications. Conclusions. In the late phase of LDLT patients, the IMK assay is very useful for monitoring immunological aspects including bacterial infection, recurrence of HCV, and rejection.

Combination assays for evaluation of immune function and CYP3A5 genotype to identify the risk of infectious complications and mortality in living donor liver transplant patients.

BACKGROUND The aim of this study is to evaluate whether the combination of the ImmuKnow assay (IMK) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for identifying the risk of morbidity and mortality in living donor liver transplantation (LDLT) patients, and also to investigate the optimal cutoff value of IMK level of immune status. MATERIAL AND METHODS Sixty six LDLT patients, who were randomly screened by using IMK between March 2002 and June 2011, were divided into 2 groups: patients in whom at least 1 IMK value was <175 ng/mL (Group A, n=16) and patients in whom all IMK values were >175 ng/mL (Group B, n=50). Both donors and recipients were evaluated for the CYP3A5 genotype. RESULTS The frequencies of cytomegalovirus and bacterial infection in Group A were significantly higher than those in Group B (P<0.001). The short term mortality was 4 (25.0%) in Group A and none in Group B, and the IMK level in all four cases became <100 ng/mL at least one time before death. The rate of CYP3A5*1 allele (expressors) among recipients was significantly higher in Group A than in Group B (63.6% vs. 22.2%, P=0.0147). The rates of CMV infection and bacterial infection, and the IMK levels was significantly higher in recipients with expressors (p=0.0216, p=0.0332, and p=0.0433, respectively). CONCLUSIONS The combination of the IMK and CYP3A5 genotype assay is useful for monitoring immune status after LDLT, and the IMK level <100 ng/ml might be the critical level to make a recovery from the severe immunesupressive condition.

Co-administration of proton pump inhibitors ameliorates nephrotoxicity in patients receiving chemotherapy with cisplatin and fluorouracil: a retrospective cohort study

PurposeThe nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP-induced nephrotoxicity.MethodsWe analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury.ResultsThe rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan–Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033).ConclusionsThese findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy.

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non–small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

Long-Term Influence of CYP3A5 Gene Polymorphism on Pharmacokinetics of Tacrolimus and Patient Outcome After Living Donor Liver Transplantation.

BACKGROUND We investigated a long-term association between donor/recipient CYP3A5 polymorphisms, pharmacokinetics of tacrolimus, and recipient outcomes in settings of living donor liver transplantation (LDLT). METHODS From February 2002 to November 2009, 67 couples of donor/recipients with tacrolimus administration, who could be genotyped for CYP3A5*3 and *1, were eligible in this study. We compared the dose-adjusted trough levels (C/D ratio) and dose/weight ratio of tacrolimus at 1 to 36 months postoperatively and recipient prognosis according to donor/recipient CYP3A5 polymorphisms; *1*1 in 7, *1*3 in 15, and *3*3 in 45, based on recipient genotype, and *1*1 in 1, *1*3 in 28, and *3*3 in 38, based on donor genotype. RESULTS On the basis of the data from C/D ratio and dose/weight ratio of tacrolimus, the recipients who had *1 allele and/or whose donor had *1allele required significantly high doses of tacrolimus with, compared with those without, all through 3 years after transplantation. These data allowed us to show the importance of not only recipient CYP3A5 polymorphisms but also donor polymorphisms to obtain the target tacrolimus blood concentration. The overall survival rates of the recipients with *1*1 (5-year survival rate: 28.6%) were significantly unfavorable, which might have been caused by over-immunosuppression, compared with those with *1*3 (5-year survival rate: 78.8%) and *3*3 genotype (5-year survival rate: 84.3%). CONCLUSIONS Immune suppressive therapy with the use of tacrolimus should be tailored on the basis of CYP3A5 genotype, which may reduce the adverse effects and improve graft outcome.

Immune Response following Liver Transplantation Compared to Kidney Transplantation: Usefulness of Monitoring Peripheral Blood CD4+ Adenosine Triphosphate Activity and Cytochrome P450 3A5 Genotype Assay

Seventy living donor liver transplantation (LDLT) and 39 kidney transplantation (KT) patients were randomly screened by using the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (IMK assay). The patients were divided into 2 groups in each organ transplantation with low IMK ATP level (<225 ng/mL) or high (>225) (LT-L: n = 23, KT-L: n = 19, LT-H: n = 47, and KT-H: n = 20, resp.). The incidence of bacterial and/or viral infection was significantly higher in LT-L group than in LT-H group (74.0 versus 8.5%: P < 0.001). Occurrence of total viral infection in KT-L was also significantly higher than that in KT-H (36.8 versus 10%: P = 0.046). The sensitivity and specificity of the IMK assay for identifying risk of infection was 0.810 and 0.878 in LDLT patients and 0.727 and 0.607 in KT patients. The percentage of LDLT patients with cytochrome P450 3A5 (CYP3A5) *1/*1 or *1/*3 genotype (expressors) was significantly higher in LT-L group than in LT-H group (53.8 versus 20.7%: P = 0.032). In both LDLT and KT patients, the IMK assay can be useful for monitoring immunological aspects of bacterial and/or viral infection. CYP3A5 expressors in LT-L group are related to postoperative infections.

Monitoring of peripheral blood cluster of differentiation 4+ adenosine triphosphate activity and CYP3A5 genotype to determine the pharmacokinetics, clinical effects and complications of tacrolimus in patients with autoimmune diseases

A total of 25 patients with autoimmune diseases receiving tacrolimus were screened using a peripheral blood cluster of differentiation 4+ adenosine triphosphate (ATP) activity assay (IMK assay) between October 2013 and July 2014. The autoimmune diseases of patients were as follows: Rheumatoid arthritis (n=15), lupus nephritis (n=6), ulcerative colitis (n=2) and myasthenia gravis (n=2). Patients were divided into two groups based on CYP3A5 genotype [expression of *1 allele: Expressor (EX; n=6) and non-expressor (NEX; n=19)]. The tacrolimus concentration and concentration/dose ratio was significantly lower in the EX group compared with the NEX group (P=0.0108 and 0.0056, respectively). In addition, all enrolled patients that presented with adverse effects belonged to the NEX group. No significant associations were observed between IMK ATP levels and the concentration or dose of tacrolimus (P=0.1092 and 0.6999, respectively). However, the IMK ATP high-level group exhibited a significantly higher occurrence rate of insufficient effect when compared with the normal and low-level groups (P=0.0014). In conclusion, the clearance of tacrolimus in patients with autoimmune diseases was affected by the CYP3A5 genotype, as previously reported in organ transplant patients. The IMK ATP level may indicate the clinical response irrespective of tacrolimus concentration.

Effect of lipid emulsion infusion on paliperidone pharmacokinetics in the acute overdose rat model: A potential emergency treatment for paliperidone intoxication

&NA; Paliperidone prolongs cardiac repolarization in a concentration‐dependent manner. Meanwhile, continuous infusion of intravenous lipid emulsion (ILE) has been established as a detoxification therapy for lipophilic drugs. However, this change in pharmacokinetics of various drugs following ILE administration remains to be clarified. Our objective is to clarify the effect of continuous infusion of ILE on the pharmacokinetics of overdosed paliperidone in rats. Paliperidone (20 mg/kg) was administered orally to free‐moving male Wistar rats. Continuous infusion (initial loading dose: 4 ml/kg for 10 min, followed by 4 ml/kg/h for 12 h) of ILE or acetated Ringers solution (AR) was initiated 30 min after paliperidone administration. Plasma concentration profile of paliperidone was monitored for 12 h after administration. The plasma concentration and tissue/plasma concentration ratios of paliperidone were compared between ILE and AR groups. The rat group infused with ILE showed a higher area under the concentration–time curve (mean [S.D.]: 6102 [900.9] vs. 3407 [992.1] ng h ml−1, p = 0.02) and longer elimination half‐time (t1/2) (4.1 [0.9] vs. 2.2 [0.4] h, p = 0.02) compared with the AR group. Tissue/plasma concentration ratios of paliperidone were lower in ILE rats than in AR rats (1.98 [0.70] vs. 3.82 [1.47] in the heart, p = 0.04; 0.28 [0.29] vs. 1.27 [0.58] in the brain, p < 0.001). In conclusion, continuous infusion of ILE would reduce tissue distribution and prolonged the t1/2 of paliperidone in rats. These results suggest that continuous infusion of ILE has potential as an emergency treatment for acute paliperidone intoxication. Graphical abstract Figure. No caption available.