Population Pharmacokinetic Analysis of Vancomycin in Patients with Solid or Hematological Malignancy in Relation to the Quick Sequential Organ Failure Assessment Scores.

BACKGROUND AND OBJECTIVE: It remains unclear whether sepsis in patients with malignancy interferes with the predictive performance of the dose-estimation formulas. The quick sequential organ failure assessment (qSOFA) score can help identify patients with poor outcomes because of sepsis-associated organ damage. Vancomycin, an important antibiotic, treats systemic infections (sepsis) caused by methicillin-resistant Staphylococcus aureus. We aimed to clarify whether including the qSOFA score in a standard population pharmacokinetic (PopPK) assessment may improve the predictive performance of vancomycin doses in patients with malignancy. METHODS: This was a retrospective, observational study. Serum vancomycin concentration-time datasets were obtained from the therapeutic drug monitoring records of St. Luke's International Hospital (Tokyo, Japan) from January 2011 to August 2016. Clinical and laboratory data of the relevant patients were retrieved from electronic health records. PopPK analysis was performed using the NONMEM program, which includes creatinine clearance (CLCr), blood neutrophil counts, qSOFA scores, and type of malignancy as covariates. We examined the validity of the final PopPK model using bootstrapping, goodness-of-fit plots, and prediction-corrected visual predictive checks. RESULTS: Six hundred and eight blood samples were obtained from 325 patients. In the final PopPK model, the CLCr and qSOFA scores were selected as covariates of systemic vancomycin clearance (p < 0.05): the population mean value was 2.8 (L/h). Regardless of the CLCr, a qSOFA score of greater than 1 was associated with an approximately 10% reduction in vancomycin clearance. CONCLUSIONS: qSOFA scores might be an additional covariate to CLCr for estimating vancomycin concentrations with a PopPK model in patients with malignancy.

[Analysis of Information on Drug Adverse Reactions Using U.S. Food and Drug Administration Adverse Event Reporting System (FAERS)].

Nowadays, medical big data has been developed and made available in a variety of fields such as epidemiology and pharmacovigilance. Spontaneous reporting databases are one category of medical big data and that has been adequate for analysing events related to side effects that rarely occur in general practice. These data are freely available in several countries. In Japan, the Pharmaceuticals and Medical Devices Agency has developed the Japanese Adverse Drug Event Report (JADER), and the Food and Drug Administration (FDA) developed the FDA Adverse Events Reporting System (FAERS) in the United States. Since the release of these medical big data, many researchers in academic and research setting have accessed them, but it is still difficult for many medical professionals to analyse these data due to costs and operation of requisite statistical software. In this section, we give some tips to study spontaneous reporting databases resulting from our learning experiences.

Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass in adult patients undergoing cardiac surgery.

PURPOSE: The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin. METHODS: Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated. RESULTS: A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (Bmax). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8 mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16 mg/L was proposed. CONCLUSION: PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.

Comparisons between dipeptidyl peptidase-4 inhibitors and other classes of hypoglycemic drugs using two distinct biomarkers of pancreatic beta-cell function: A meta-analysis.

BACKGROUND AND OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-ß). However, whether HOMA-ß is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-ß and proinsulin-to-insulin ratio (PIR). METHODS: We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-ß or PIR during study periods were calculated for pairwise comparisons. RESULTS: Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-ß and PIR, respectively. HOMA-ß and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-ß showed no significant differences between DPP-4 inhibitors and the two other agents. CONCLUSION: DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-ß or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-ß and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.

[A Retrospective Evaluation of the Impact of Multi-disciplinary Approach for Improving the Quality of Anticoagulation Therapy in Ambulatory Patients with Non-valvular Atrial Fibrillation Receiving Warfarin].

While percent time within therapeutic range (%TTR) of international normalized ratio of prothrombin time (PT-INR) represents the quality of anticoagulation therapy with warfarin, it is often maintained less than 50% in patients with non-valvular atrial fibrillation (NVAF). We aimed to study if implementation of a multi-disciplinary ambulatory anticoagulation service (MAAS) may improve %TTR. Collaborating with cardiologists at Kanto Rosai Hospital, we conducted a MAAS for NVAF patients receiving warfarin from April 2013 to December 2015. Patients who agreed to utilize the service in addition to their appointments with cardiologists visited pharmacists to have counseling about diet, concomitant medications, and lifestyle. According to a protocol, pharmacists made dose adjustment proposals to cardiologists, if necessary. Upon approval by cardiologists, dose modifications were made. We retrospectively reviewed medical records of the patients who participated in the MAAS before and during the service. The study protocol was approved by the institutional review board. We identified 78 eligible patients (44 males and 34 females, aged 51 to 91 years). Their median %TTR increased significantly (p<0.05) from 57% during the pre-MAAS period to 77% during the MAAS period. In addition, the median percent time below therapeutic range (%TBTR) decreased significantly (p<0.05) from 35% during the baseline period to 11% during the MAAS period. The present study indicates that MAAS improves the quality of anticoagulation therapy with warfarin in ambulatory patients with NVAF. Further prospective, randomized studies with a greater number of patients are required to confirm the results of the present study.

Vancomycin Pharmacokinetics in Patients with Advanced Cancer Near End of Life.

BACKGROUND AND OBJECTIVE: The effect of cancer cachexia on the pharmacokinetics of vancomycin remains unclear. We investigated whether the pharmacokinetics of vancomycin and the risk of kidney injury are altered with the development of cancer cachexia. METHODS: A retrospective analysis was conducted using therapeutic drug monitoring data obtained from 86 cancer patients who received vancomycin intravenously for infection. The patients were classified into four groups according to the stage of cachexia defined by international consensus-non-cachexia (n = 26), pre-cachexia (n = 10), cachexia (n = 21) and refractory cachexia (n = 29). Vancomycin pharmacokinetics were analyzed by a traditional one-compartment model and Bayesian method using plasma concentrations measured in these patients. Renal function and pharmacokinetic parameters were compared between the non-cachexia patients (n = 26) and total cancer cachexia patients (n = 60). RESULT: No significant difference in estimated glomerular filtration rate was observed between the non-cachexia and the total cancer cachexia patients. In contrast, systemic clearance of vancomycin was significantly lower in the total cancer cachexia patients compared with the non-cachexia patients when analyzed by the traditional one-compartment model [median (range)-49.7 (9.8‒98.7) vs 70.2 (12.5‒211.8) mL/min, p < 0.01] and by the Bayesian method [45.6 (12.5-84.7) vs 63.3 (12.2-102.5) mL/min, p < 0.05]. None of the non-cachexia patients developed kidney injury, whereas 15% (9 of 60 patients) of the total cancer cachexia patients developed kidney injuries (p = 0.052). CONCLUSIONS: The present study revealed that cancer patients with cachexia may have reduced vancomycin clearance compared with those without cachexia. Cancer cachexia may be a risk factor of vancomycin-associated kidney injury, independent of renal function.

Analysis of the Association of Administration of various glucocorticoids with development of acute pancreatitis using US Food and Drug Administration adverse event reporting system (FAERS).

BACKGROUND: There have been debates about the association between the administration of glucocorticoids and the development of acute pancreatitis, since many anecdotal cases of this adverse event were affected either by concomitant diseases (such as systemic lupus erythematosus, SLE) that may develop acute pancreatitis without glucocorticoid treatment or by co-administered drugs with high risk for the event. The aim of the present study was to explore whether disproportionally elevated signals of developing acute pancreatitis may be detected in patients receiving glucocorticoids as compared those receiving other drugs. METHODS: We retrieved spontaneously reported cases of acute pancreatitis and clinically related adverse events (target events) from the US Food and Drug Administration Adverse Event Reporting System (FAERS) using 18 preferred terms (PTs). Target drugs studied were cortisol, cortisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, and betamethasone. After cleaning the data, we calculated reporting odds ratios (RORs) and 95% confidence intervals (CIs) of acute pancreatitis in patients who received one of the glucocorticoids. RORs were calculated for each glucocorticoid using all reported cases irrespective of reporters' judgement about the contribution of the target drugs to events [i.e., primary suspected medication (PS), secondary suspected medication (SS), concomitant medication (C) and interacting (I)] and using cases with higher certainty of contribution (PS and SS), separately. When the lower limit of 95% CI of a ROR signal exceeded 1.0, the signal was considered statistically significant. RESULTS: The RORs (95% CIs) calculated using all reported cases (PS, SS, C, and I) for cortisol (1.68; 1.43-1.98), prednisolone (1.33; 1.19-1.47), methylprednisolone (1.77; 1.55-2.02) were significant, whereas those for other target drugs were insignificant. Using the cases in which target drugs were considered to contribute the events with higher certainty (PS or SS), RORs for prednisolone (1.31; 1.10-1.55), methylprednisolone (1.62; 1.30-2.01), and dexamethasone (1.27; 1.10-1.47) were considered significant, whereas those for others were insignificant. Regarding the performance of PTs for detecting signals (RORs) associated with acute pancreatitis from FAERS database, "pancreatitis acute" gave RORs with higher significance than others, whereas more specific PTs, "haemorrhagic necrotic pancreatitis", "ischaemic pancreatitis", "pancreatic necrosis" and "pancreatitis necrotising", gave RORs with greater magnitude. CONCLUSION: The present study demonstrated that the overrepresentation of signals for acute pancreatitis may be detected for prednisolone, methylprednisolone, and some others in the FAERS database.(372 words).

Reduced Clearance of Phenobarbital in Advanced Cancer Patients near the End of Life.

BACKGROUND AND OBJECTIVES: Little is known about the pharmacokinetics of phenobarbital in terminally ill cancer patients. We investigated whether phenobarbital clearance alters depending on the length of survival. METHODS: We retrospectively reviewed the clinical, laboratory, and therapeutic drug monitoring (TDM) records of patients who received parenteral or oral phenobarbital for 21 consecutive days or longer between 2000 and 2016. Patients were divided into non-cancer and cancer groups. Cancer patients were further stratified according to the survival interval after TDM: those who survived > 3 months were classified as long-surviving and the remainders short-surviving cancer patients. Phenobarbital clearance (CLPB) was calculated at steady state. Multiple comparisons of median CLPB were conducted among the three groups. RESULTS: Data were collected from 44 non-cancer patients and 34 cancer patients comprising 24 long-surviving and 10 short-surviving cancer patients. Among 10 short-surviving cancer patients, 4 had hepatic metastasis. Median CLPB (range) in short-surviving cancer patients [0.076 (0.057‒0.114) L/kg/day] was significantly (p < 0.05) lower than that in non-cancer patients [0.105 (0.060‒0.226) L/kg/day] and in long-surviving cancer patients [0.100 (0.082‒0.149) L/kg/day]. CONCLUSION: Terminally ill patients with advanced cancer may have reduced CLPB, thereby TDM is recommended for these patients particularly near the end of life.

Effects of cardiopulmonary bypass on the disposition of cefazolin in patients undergoing cardiothoracic surgery.

The aim of the study was to evaluate the disposition of plasma unbound cefazolin in patients undergoing cardiothoracic surgery with cardiopulmonary bypass (CPB). Adult patients undergoing cardiothoracic surgery with CPB were enrolled in the study. Cefazolin sodium was given intravenously before skin incision (1 g) and at the beginning of CPB (2 g). Thereafter, an additional dose (1 g) was given every 4 hours. Seven to ten blood samples were collected before and during surgery. Plasma total and unbound (ultrafiltrated) cefazolin concentrations were analyzed using an HPLC-UV method. Plasma protein binding was analyzed with the Langmuir model. Twenty-seven patients (aged 70 ± 12 years, body weight 62 ± 12 kg, mean ± SD) with GFR >30 mL min-1 completed the study. There was a significant (P < 0.001) increase in median plasma unbound fraction of cefazolin from 21% before skin incision to 45% during CPB (P < 0.001), which was accompanied by a significant (P < 0.001) reduction in median plasma albumin concentration from 36 to 27 g L-1. Plasma concentrations of unbound cefazolin exceeded the assumed target thresholds of 2 µg mL-1 in all samples and of 8 µg mL-1 in all but one of 199 samples. The increased plasma unbound fraction of cefazolin would be attributable to dilutional reduction of serum albumin at the beginning of CPB and to saturable plasma protein binding of cefazolin. These data reveal CPB may alter the plasma protein binding and possibly distribution of cefazolin. Further studies are warranted to reappraise the protocol of antimicrobial prophylaxis with cefazolin in patients undergoing surgery with CPB.

Evaluation of a pharmacokinetic-pharmacodynamic model for hypouricaemic effects of febuxostat using datasets obtained from real-world patients.

AIM: Febuxostat is an active xanthine oxidase (XO) inhibitor which is widely used in the treatment of hyperuricaemia. We aimed to evaluate the predictive performance of a pharmacokinetic-pharmacodynamic (PK-PD) model of the hypouricaemic effects of febuxostat. METHODS: Previously, we formulated a PK-PD model for predicting the hypouricaemic effects of febuxostat as a function of baseline serum urate levels, body weight, renal function and drug dose, using datasets reported in preapproval studies. Using an updated model with a sensitivity analysis, we examined the predictive performance of the PK-PD model, using datasets obtained from the medical records of patients who received febuxostat from March 2011 to December 2015 at Tokyo Women's Medical University Hospital. Multivariate regression analysis was performed to explore clinical variables to improve the predictive performance of the model. RESULTS: A total of 1199 serum urate values were retrieved from 168 patients (age: 60.5 ± 17.7 years; 71.4% male) who were receiving febuxostat as a treatment for hyperuricaemia. There was a significant correlation (r = 0.68; P < 0.01) between the serum urate levels observed and those predicted by the modified PK-PD model. A multivariate regression analysis revealed that the predictive performance of the model could be improved further by considering comorbidities (such as diabetes mellitus), estimated glomerular filtration rate (eGFR) and the coadministration of loop diuretics (r = 0.77, P < 0.01). CONCLUSIONS: The PK-PD model may be useful for predicting individualized maintenance doses of febuxostat in real-world patients.

Causal relationship between acute pancreatitis and methylprednisolone pulse therapy for fulminant autoimmune hepatitis: a case report and review of literature.

BACKGROUND: A causal relationship between acute pancreatitis and administration of glucocorticoids remains a matter of debate, since most of the reported cases were diagnosed with systemic vascular diseases (including systemic lupus erythematosus and polyarteritis nodosa) that may be responsible for the pancreatitis. CASE PRESENTATION: We report a case of a 51-year-old woman who developed acute pancreatitis after receiving methylprednisolone pulse therapy for the treatment of fulminant autoimmune hepatitis (AIH). She was admitted to our hospital because of overt jaundice and back pain. Since her liver dysfunction deteriorated progressively, a liver biopsy was performed and a diagnosis of AIH was established. She was given intravenous methylprednisolone pulse therapy at 1000 mg/day for 3 days, and oral prednisolone at 40 mg/day thereafter. While her liver function improved rapidly, she started complaining of mild back pain and serum amylase and lipase levels were elevated from 5 days after the initiation of steroid therapy. A CT scan revealed mildly edematous changes around the pancreas, leading to a diagnosis of acute pancreatitis. After tapering off prednisolone, back pain disappeared, and elevated serum amylase was normalized without exacerbation of AIH. A systematic literature review identified 8 cases of acute pancreatitis developing after administration of corticosteroid pulse therapy with a median latent period of 5 days. CONCLUSIONS: The present case and reports in the literature suggest that steroid pulse therapy may cause acute pancreatitis in patients having no signs of systemic vasculitis.

Developmental changes of fluconazole clearance in neonates and infants in relation to ontogeny of glomerular filtration rate: literature review and data analysis.

BACKGROUND: Fluconazole is frequently prescribed for the treatment of systemic fungal infection in neonates and infants. At present, prediction of fluconazole doses according to developmental changes in fluconazole clearance is not being done in these patients. We aimed to formulate a developmental model of fluconazole clearance taking into account the ontogeny of renal function, since the drug is largely eliminated renally. METHODS: We systematically retrieved the data of fluconazole pharmacokinetics and renal function in children and adults from databases (MEDLINE and Japan Medical Abstracts Society). Datasets were retrieved from individual children or groups from 9 studies comprising 55 neonates or infants at postmenstrual age (PMA) 27-58 weeks. Datasets were retrieved from 5 studies comprising 60 children and from 13 studies comprising 152 adults. Datasets of glomerular filtration rate (GFR) for individual pediatric subjects were retrieved from 4 studies comprising 187 neonates or infants. RESULTS: Fluconazole clearance normalized to body surface area (BSA) (CLBSA) in neonates was 1/3 to 1/4 of adult values, but CLBSA increased rapidly during the neonatal and infantile periods and attained near adult values at PMA 60 weeks. A significant correlation between CLBSA and PMA was observed in neonates and infants: CLBSA (mL/min/m2) = 0.26・ PMA (weeks) - 4.9 (r = 0.68, p < 0.001). In addition, the developmental time course of GFR normalized to BSA (GFRBSA) was fitted well to a sigmoidal model with the maximum GFRBSA of 149 mL/min/1.73m2, PMA associated with 50% of GFRBSA,max (PMA50) of 54 weeks, and the Hill coefficient of 3.7. A significant correlation between fluconazole clearance and GFR was found in neonates and infants: CL (mL/min) = 0.34・GFR (mL/min) - 0.53 (r = 0.84, p < 0.001). Assuming that plasma drug concentrations required for treating fungal infection are comparable between children and adults, fluconazole doses for pediatric patients with given PMAs may be predicted from adult doses (such as 100 mg/day) using size-normalized clearance as a scaling factor. The predicted doses for neonates and infants were largely within the ranges recommended in the prescribing information. CONCLUSIONS: The present study indicates that fluconazole doses for neonates and infants may be predicted from developmental change of systemic clearance, the ontogeny of which parallels the maturation of nephron function.

Consequences of Different Corticosteroids on Serum Potassium and Prostate-Specific Antigen in Patients Receiving Abiraterone for Castration-Resistant Prostate Cancer: A Retrospective Observational Study.

BACKGROUND: Abiraterone acetate is an androgen synthesis inhibitor approved for the treatment of castration-resistant prostate cancer (CRPC). Although co-administration of either prednisone or prednisolone at 10 mg/d has been recommended to reduce the risk of abiraterone-induced hyperaldosteronism (notably hypokalemia) and to give adjunctive pain relief effects, whether these glucocorticoids can be substituted by dexamethasone remains unknown. METHODS: We performed a retrospective review of medical records of patients who were given abiraterone for the treatment of CRPC with either prednisolone (ABI/PSL) 10 mg/d or dexamethasone (ABI/DEX) 0.5 or 1 mg/d between 2014 and 2017 in Juntendo University Nerima Hospital. Demographic and biochemical data including prostate-specific antigen (PSA) level were retrieved from the electronic medical records. RESULTS: Fifty-three eligible patients (27 in ABI/PSL group and 26 in ABI/DEX group) were extracted from the records. Both groups showed no significant changes in serum potassium level before and after starting treatment. In the ABI/PSL group, 12 patients (46%) showed elevations of PSA and 7 patients (27%) discontinued treatment within 3 months. In contrast, in the ABI/DEX group, only 6 patients (25%) showed elevations of PSA and 3 patients (13%, all were given dexamethasone 1 mg/d) discontinued treatment. CONCLUSIONS: Dexamethasone and prednisolone may be equally effective in preventing abiraterone-induced hypokalemia.

Induration at Injection or Infusion Site May Reduce Bioavailability of Parenteral Phenobarbital Administration.

BACKGROUND: Phenobarbital is well tolerated and effective for controlling agitation or preventing convulsion at the end of life. No information is available concerning parenteral bioavailability of phenobarbital when induration develops at the injection or infusion site. We investigated whether induration at injection or infusion site is related to phenobarbital bioavailability via parenteral routes of continuous subcutaneous infusion and intermittent subcutaneous or intramuscular injection. METHODS: A retrospective analysis was conducted on the medical data obtained from 18 patients who received chronic subcutaneous or intramuscular injections of phenobarbital for the prevention of convulsions and underwent plasma concentration monitoring of the drug. Patients whose concomitant medications were altered during the observation periods were excluded from the analysis. Comparisons were performed for concentration/dose (C/D) ratios obtained from patients with induration at injection or infusion sites (induration group, n = 6) and those without induration (noninduration group, n = 12). P < 0.05 was considered statistically significant. RESULTS: The induration group showed significantly reduced C/D ratio compared with the noninduration group [median (range): 0.131 (0.114-0.334) versus 0.219 (0.180-0.322) d/L, P < 0.05). Assuming that systemic clearance was constant in our patients, changes in the C/D ratio would have contributed to 40% (median) reduction in bioavailability of the drug from the injection or infusion site. CONCLUSIONS: Our data suggest that absolute bioavailability of phenobarbital may be reduced when induration develops at the injection or infusion site in patients treated parenterally by continuous subcutaneous infusion or intramuscular injection.

Delayed de-induction of CYP2C9 compared to CYP3A after discontinuation of rifampicin: Report of two cases
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OBJECTIVE: Timely dose reduction of concomitant medications is important after withdrawal of rifampicin, a CYP inducer. However, little is known about the differences in the time course of deinduction for various CYP isoforms. To clarify the time courses of deinduction of CYP2C9 and -CYP3A activities after rifampicin withdrawal, we monitored these enzyme activities in 2 patients over time after discontinuing rifampicin. MATERIALS AND METHODS: Two patients (aged 70 and 80 years) received warfarin and rifampicin for anticoagulation and antituberculosis therapy, respectively. Warfarin doses were increased due to rifampicin-induced CYP activity. Upon completion of antituberculosis therapy, rifampicin was discontinued and warfarin doses were titrated downward according to prothrombin time. We monitored CYP2C9 and CYP3A activities over their clinical courses by measuring the metabolic clearance of S-warfarin to S-7-hydroxywarfarin and that of cortisol to 6ß-hydroxycortisol, respectively. RESULTS: In both patients, the time courses of CYP2C9 deinduction appeared to be delayed compared to CYP3A. CONCLUSION: Our findings suggest that a uniform dose reduction protocol for drugs metabolized by different CYP isoforms may be unsafe after rifampicin withdrawal.
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Impact of Pharmacists' audit on improving the quality of prescription of dabigatran etexilate methanesulfonate: a retrospective study.

BACKGROUND: Appropriate prescription of dabigatran etexilate methanesulfonate (JAN) is more complicated than assumed, because there are totally 10 items of contraindications and instructions for dosage reduction depending on patients' characteristics. We aimed to study whether the routine audit of first-time prescriptions of dabigatran performed by pharmacists is effective in improving the quality of prescription. METHODS: A retrospective re-audit was performed on all the prescriptions of dabigatran issued at Kitahara International Hospital, Tokyo between March 2011 and February 2014, by evaluating the prescriptions rigorously against the approved prescribing information of the drug. The original routine audit of the prescriptions for inpatients was performed by hospital pharmacists using electronic medical records (EMR), whereas the audit for ambulant patients receiving external prescriptions was performed by community pharmacists using information obtained mainly by questioning patients. The frequencies of inappropriate prescriptions detected by the re-audit in the two groups were compared. RESULTS: Two hundred and twenty-eight patients (131 ambulant patients and 97 inpatients) were prescribed dabigatran for the first time during the study period. All patients met the approved indications. While 33% of the prescriptions for ambulant patients showed at least one violation of the approved usage, only 11% of the prescriptions for inpatients showed violations (p < 0.001). Two ambulant patients with creatinine clearance < 30 mL/min were dispensed dabigatran, whereas no such case was found among inpatients. A significantly greater proportion of ambulant patients aged ≥70 years showed violation of the instruction for dosage reduction compared to inpatients of the same age group (18 and 4%, respectively). CONCLUSION: The present study suggests that pharmacists may achieve better performance in auditing prescriptions of dabigatran when medical records are fully available than when information is available mainly by questioning patients. Further large-scale studies are required to clarify whether the audit of dabigatran prescriptions improves ultimate therapeutic outcomes or complications.

Whole genome analysis on the genetic backgrounds associated with the secondary failure to etanercept in patients with rheumatoid arthritis.

OBJECTIVES: Etanercept is effective for the treatment of rheumatoid arthritis (RA). However, some of the patients eventually lose efficacy (secondary failure) despite the absence of neutralizing antibodies. We aimed to explore single nucleotide polymorphisms (SNPs) associated with secondary failure. METHODS: We recruited RA patients given etanercept at 50 mg/week for ≥6 months from the Matsubara Mayflower Hospital RA registry. They were assigned to responders, secondary failure patients, and non-responders according to Disease Activity Score. Genome-wide association study (GWAS) was performed using Illumina HumanHAP300k BeadChips and the results were analyzed with Plink software. Clinical backgrounds were compared by ANOVA and contingency table analysis. The protocol was approved by IRB and written informed consent was obtained. RESULTS: Ninety, 27 and 17 patients were assigned to responders, secondary failure patients, and non-responders, respectively. No significant differences were observed regarding clinical backgrounds among the groups. GWAS revealed that six and 37 SNPs may be associated with secondary failure to etanercept with p< 10-6 and <10-5, respectively. CONCLUSION: While our preliminary results with borderline significance should be validated by studies with a greater population size, some of the SNPs detected by our GWAS may be involved in the development of secondary failure to etanercept.

Correlations between the enantio- and regio-selective metabolisms of warfarin.

AIM: To clarify whether the activities of multiple CYPs associated with warfarin metabolism would be correlated with each other. METHODS: Oral clearances (CLpo) of warfarin enantiomers were estimated in 378 Chinese, Caucasians and African-Americans. The partial metabolic clearances (CLm) for 7-hydroxywarfarin enantiomers were also measured. In addition, CLpo and CLm were determined in a patient on warfarin and rifampicin. RESULTS: Correlations between CLpo for warfarin enantiomers existed across the three populations. In addition, there was a significant correlation between the CLm for 7-hydroxylation of warfarin enantiomers. Under induced conditions by rifampicin, there were significant correlations between the enantio- and regio-selective metabolisms of warfarin. CONCLUSION: Metabolic activities of CYP2C9, CYP1A2 and CYP3A4 may be regulated by common transcriptional mechanism(s).