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Plasma daptomycin has not been fully characterized in diabetic and obese patients. This study aimed to evaluate the associations of plasma daptomycin with glycation of serum albumin and obesity.Infectious patients (n = 70) receiving intravenous daptomycin were enrolled. The plasma concentration of total and free daptomycin were determined using liquid chromatograph-tandem mass spectrometer. The associations of the plasma concentrations of daptomycin with clinical factors including serum albumin fractionations and physical status (obese including overweight, body mass index ≥ 25.0) were investigated. Daptomycin doses were adjusted using total body-weight.The serum albumin level was positively and negatively correlated with the plasma concentration of total daptomycin and its free fraction proportion, respectively. The serum non-glycated albumin was negatively correlated with the free fraction proportion. The dose-normalized plasma concentration of total daptomycin was higher in the obese patients than in non-obese patients when the body-weight was corrected with total and adjusted values. For the dose adjustment with lean body-weight, no difference was observed in the dose-normalized plasma concentration of total daptomycin between the physical statuses. For each body-weight correction method, physical status did not affect the dose-normalized plasma concentration of free daptomycin.The glycation of serum albumin and obesity did not associate with dose-normalized plasma free daptomycin. In obese patients, daptomycin dosage adjustment with total body-weight and adjusted body-weight may lead to an apparent excessive exposure resulting in overdosage compared to lean body-weight.

Rotator cuff retear is a major concern after arthroscopic rotator cuff repair (ARCR); however, the effects of retear remain unclear. Therefore, the purpose of this study was to assess the clinical outcomes of postoperative retear and intact tendons after ARCR.We searched PubMed, Cochrane Library, Scopus, and PEDro databases for studies performed from January 2000 to June 2020. Clinical outcomes included the Constant score, American Shoulder and Elbow Surgeons (ASES) score, University of California Los Angeles shoulder (UCLA) score, pain score, range of motion, and muscle strength. Meta-analysis using random-effects models was performed on the pooled results to determine significance.The initial database search yielded 3141 records. After removal of duplicates, 26 of which met the inclusion criteria. Patients in the retear group had significantly lower Constant score [- 8.51 points (95% CI, - 10.29 to - 6.73); P 0.001], ASES score [- 12.53 points (95% CI, - 16.27 to - 8.79); P 0.001], UCLA score [- 3.77 points (95% CI, - 4.72 to - 2.82); P 0.001], and significantly higher pain score [0.56 cm (95% CI, 0.10 to 1.01); P = 0.02] than the intact group. In addition, the retear group had significantly lower flexion [- 10.46° (95% CI, - 19.86 to - 1.07); P = 0.03], abduction [- 14.84° (95% CI, - 28.55 to - 1.14); P = 0.03], and external rotation [- 7.22° (95% CI, - 13.71 to - 0.74); P = 0.03] range of motion, and flexion [- 1.65 kg·f (95% CI, - 2.29 to - 1.01); P 0.001], abduction [- 1.87 kg·f (95% CI, - 3.02 to - 0.72); P = 0.001], and external rotation [- 1.66 kg·f (95% CI, - 3.25 to - 0.07); P = 0.04] muscle strength.Our results suggest that retear after ARCR leads to poor clinical outcomes after surgery.

The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients.Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism.The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5.This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.

Wheelchair basketball athletes have increased upper limb stress, which frequently leads to shoulder pain.The purpose of this scoping review was to summarize the existing literature on shoulder pain in wheelchair basketball athletes.We searched PubMed, Cochrane Library, Scopus, and PEDro databases for studies performed between January 1990 and February 2021. Two independent reviewers screened the studies according to the inclusion and exclusion criteria. Participants' characteristics and results were extracted from the study.The initial database search yielded 2455 articles, 11 of which met the inclusion criteria. This review included seven studies in its final analysis; among them, seven determined the prevalence and incidence of shoulder pain, five investigated the factors and mechanisms contributing to shoulder pain, and two reported the treatment and preventive measures. The prevalence of shoulder pain in wheelchair basketball players ranged from 38%-75%, and the incidence of shoulder pain was 14%. Factors/mechanisms included overuse, decreased trunk control, and driving posture. Treatment/preventive measures consisted of shoulder and scapular muscle strengthening and stretching exercises. However, the literature on treatment/prevention was scarce, and its effectiveness was unclear.This scoping review confirmed the high prevalence of shoulder pain in wheelchair basketball players; despite this, studies regarding treatment or preventive measures remain lacking. Further studies investigating the mechanism of onset of shoulder pain and the effectiveness of therapeutic and preventive measures are needed in the future.

Serum nivolumab concentrations exhibit a large variation in cancer patients. Cancer cachexia inducing systemic inflammation promotes the elimination of endogenous proteins, while its association with serum nivolumab remains unclear. The present study aimed to evaluate the impacts of cachexia progression in addition to blood components on serum nivolumab in cancer patients. Thirty-eight non-small-cell lung cancer or renal cell cancer patients receiving biweekly intravenous nivolumab were enrolled. Blood samples were collected just before dosing at the 7th administration of nivolumab or later. Serum nivolumab together with serum proteins, inflammatory markers, and peripheral blood leukocytes were determined. Cancer cachexia was classified using the Glasgow Prognostic Score (GPS). Immune-related adverse events (irAEs) were monitored during the study period. Cancer patients had a large variation in serum nivolumab concentrations (interquartile range, 12–21 µg/mL per mg/kg). The serum nivolumab concentration was positively correlated with serum albumin, while negatively associated with serum globulin and immunoglobulin G (IgG). A negative correlation was observed between serum nivolumab and blood lymphocytes. Regarding cachexia progression, the patients with GPS 2 had a higher serum interleukin-6 concentration and a lower serum nivolumab concentration than those with GPS 0 or 1. The GPS, serum IgG, and blood lymphocytes were identified as independent variables for serum nivolumab. The incidence of irAEs was not associated with the nivolumab dose or serum nivolumab. Cachexia progression had a negative impact on serum nivolumab in cancer patients. The interindividual variation in serum nivolumab was characterized by cachexia progression in addition to blood components.

Long-term use of itraconazole (ITZ) is associated with a risk of inducing hepatotoxicity. This study aimed to evaluate the associations of plasma concentrations of ITZ and its hydroxylated metabolite (OH-ITZ) with endogenous markers of hepatic function.Thirty six patients treated with oral ITZ solution for prophylaxis of deep mycosis were enrolled. Plasma concentrations of ITZ and OH-ITZ were determined on the 14th day or later after administration of ITZ. Their associations with endogenous marker levels of hepatic function including plasma coproporphyrin (CP)-I and OATP1B1 genotypes were assessed.The serum level of total bilirubin (T-Bil) was moderately correlated with the plasma concentration of total ITZ (tITZ) and OH-ITZ (tOH-ITZ). T-Bil elevation above 0.3 mg/dL was observed in 19% of patients, although statistically significant difference was not identified. The plasma concentration of tITZ had no correlation with other endogenous markers levels including AST, ALT, albumin, and plasma CP-I. The serum AST and plasma CP-I levels were correlated with the plasma concentration of free OH-ITZ (fOH-ITZ). T-Bil and plasma CP-I, a marker of OATP1B1 activity, were not correlated with each other, and neither was associated with the OATP1B1 genotypes.Plasma ITZ and OH-ITZ had a positive association with T-Bil. The patients with a higher fOH-ITZ level had lower OATP1B1 activity on the basis of plasma CP-I level. ITZ and OH-ITZ have the potential to slightly increase endogenous marker levels of hepatic function, although most likely by different mechanisms.

Oral aprepitant has a large interindividual variation in clinical responses in advanced cancer. This study aimed to characterize plasma aprepitant and its N-dealkylated metabolite (ND-AP) based on the cachexia progression and clinical responses in head and neck cancer patients. Fifty-three head and neck cancer patients receiving cisplatin-based chemotherapy with oral aprepitant were enrolled. Serum albumin level was negatively correlated with the plasma concentrations of aprepitant at 24 hours after a 3-day aprepitant treatment. The patients with Glasgow Prognostic Score (GPS) 1 or 2 had higher plasma concentrations of total and free aprepitant than those with GPS 0. No difference was observed in the plasma concentration of ND-AP between the GPS classifications. The plasma interleukin-6 level was higher in patients with GPS 1 or 2 than 0. The absolute plasma concentration of free ND-AP was higher in patients without the delayed nausea, and its concentration to determine the occurrence was 18.9 ng/mL. The occurrence of delayed nausea had no relation with absolute plasma aprepitant. In conclusion, cancer patients with a lower serum albumin and progressive cachectic condition had a higher plasma aprepitant level. In contrast, plasma free ND-AP but not aprepitant was related to the antiemetic efficacy of oral aprepitant.

Purpose: Cetuximab inhibits epidermal growth factor receptor (EGFR) signaling in cancer and skin cells, thereby inducing anti-cancer effects and skin disorders. The present study aimed to evaluate the relationships between serum cetuximab and EGFR-related markers, and adverse effects in head and neck cancer patients.Methods: Thirty-four head and neck cancer patients receiving weekly intravenous cetuximab were enrolled. Serum cetuximab levels were determined just before dosing. Blood samples for determination of serum EGFR-related markers including soluble epidermal growth factor receptor (sEGFR) and interleukin-6 (IL-6) were obtained. The severities of skin disorders, their medications, and hypomagnesemia treatment were also assessed.Results: Serum levels of cetuximab and sEGFR were negatively and positively correlated with that of IL-6, respectively. The serum cetuximab level was 2-fold higher in the patients with a grade 2–3 skin rash than with a grade 0–1 rash. The serum cetuximab cut-off value related to severe skin rash was 71 μg/mL (sensitivity, 59%; and specificity, 94%). The use of a strong topical corticosteroid for skin rash was also associated with a higher serum cetuximab level. Serum levels of sEGFR and IL-6 had no correlations with the skin disorder severities or their medications. Hypomagnesemia treatment using intravenous magnesium sulfate was not related to serum cetuximab and EGFR-related markers.Conclusions: Head and neck cancer patients with a higher serum IL-6 level tended to have a lower serum cetuximab level. Serum cetuximab had positive correlations to skin rash severity and its medication in the study population.

Several risk factors for postoperative retear after arthroscopic rotator cuff repair (ARCR) have been cited in a large number of reports; various combinations of these seem to be present in the clinical setting.Using a combination model for decision tree analysis, we aimed to investigate the combination of risk factors that affect postoperative retear the most.A total of 286 patients who underwent magnetic resonance (MR) imaging at 6 months after surgery were included in this study. Based on the structural integrity of the MR images taken 6 months after surgery, the patients were divided into a healed group (intact tendon, 254 patients) and a retear group (ruptured tendon, 32 patients). Using univariate and decision tree analyses, we selected a combination of 11 risk factors that drastically affected postoperative retear.The mean age was 64.9 ± 7.1 years, and the mean symptom duration was 9.7 ± 11.6 months. The tear was small/medium in 177 patients and large/massive in 109 patients. The technique for surgical repair was single row in 42 patients, double row in 60 patients, and suture bridging in 216 patients. On univariate analysis, both groups had significant differences in the anteroposterior (AP) tear size (P.0001), mediolateral tear size (P.0001), hyperlipidemia (P = .0178), global fatty degeneration index (P.0001), supraspinatus fatty degeneration stage (P.0001), and critical shoulder angle (CSA) (P = .0015). All of these 5 risk factors, except for mediolateral tear size, were selected as candidates for the decision tree analysis. Eight combination patterns were determined to have prediction probabilities that ranged from 4.3% to 86.1%. In particular, the combination of an AP tear size of ≥40 mm, hyperlipidemia, and a CSA of ≥37° affected retear after ARCR the most.Decision tree analysis lead to the extraction of different retear factor combinations, which were divided into 5 retear groups. The worst combination was of AP tear size ≥40 mm, hyperlipidemia, and CSA ≥37°, and the prediction probability of this combination was 86.2%. Therefore, our data may offer a new index for the prediction of retear after ARCR.

This study aimed to evaluate the influence of CYP2D6 activity and cachexia progression on the enantiomeric alteration of plasma tramadol and its demethylated metabolites in head and neck cancer patients. Fifty-three head and neck cancer patients receiving oral tramadol were enrolled. The plasma concentrations of tramadol, O-desmethyltramadol (ODT), and N-desmethyltramadol (NDT) enantiomers were determined. The CYP2D6 activity score (AS) and degree of cachexia progression were assessed according to genotype and the Glasgow Prognostic Score (GPS), respectively. The enantiomeric ratio of NDT was (+)-form dominant in all patients. CYP2D6 AS had negative correlations with the plasma concentrations of (+)-NDT and (−)-NDT. The plasma concentrations of (+)-tramadol and (+)-ODT were higher in patients with GPS 1 or 2 than in those with GPS 0. Lower metabolic ratios to NDT enantiomers were observed in patients with GPS 1 or 2. In patients with GPS 1 or 2, the plasma (−)-tramadol was associated with the incidence of central nervous system symptoms. In conclusion, CYP2D6 AS partially explained the contribution of CYP2D6 activity to plasma tramadol and its demethylated metabolite enantiomers. Additionally, cachexia progression elevated the plasma (+)-tramadol and (+)-ODT levels through the reduction of N-demethylation of (+)-tramadol.

Background: The difference in type of antibiotics and susceptibility of Bacteroides fragilis to antibiotics may influence warfarin anticoagulation. However, these influences have not been clarified in clinical settings. Objectives: This study aimed to investigate association the between the prothrombin time–international normalized ratio (PT-INR) and concomitant use of antibiotics in a real-world population of warfarin users. Methods: This was a single-center cohort study using data from health records and included patients who received β-lactams (BLs)/fluoroquinolones (FQs) during ongoing warfarin treatment (2011-2015) at Hamamatsu University Hospital in Japan. Antibiotics were categorized into those to which B fragilis is susceptible (BLsus, FQsus) and those to which it is not (BLnon, FQnon) and into those given orally (BLpo, FQpo) or intravenously (BLiv, FQiv). Outcomes were excessive PT-INR and changes in PT-INR, defined as the ratio (INR ratio) and difference (ΔINR) of maximum PT-INR and baseline PT-INR. Excessive PT-INR was graded as INR ratio of >1.5 or >2.5. Results: A total of 1185 warfarin users were included. The proportion of INR ratio >2.5 in FQiv was higher than in BLiv (95% CI: 1.59-46.5). The proportions with an INR ratio of >1.5 in BLsus and FQsus were higher than in BLnon (1.72-14.1) and FQnon (1.05-9.36), respectively. ΔINR values in FQpo, FQiv, and FQsus were higher than those in BLpo, BLiv, and FQnon, respectively. Conclusions and Relevance: Concomitant use of FQs, or of antibiotics to which B fragilis is susceptible is associated with higher risk of excessive anticoagulation. These findings would contribute to safe and proper antibiotic treatment in warfarin users.

Background Itraconazole (ITZ), a triazole antifungal agent, is metabolized to hydroxy-ITZ (OH-ITZ), keto-ITZ (KT-ITZ), and N-desalkyl ITZ (ND-ITZ) by cytochrome P450 3A4. The pharmacokinetics of ND-ITZ remain largely unknown due to the lack of an accurate and reliable determination method. This study aimed to develop a simultaneous determination method for ITZ and its three major metabolites including ND-ITZ in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and then apply the method in a clinical setting. Methods Plasma specimens were pretreated by protein precipitation with acetonitrile. The supernatant was separated on a 3-μm particle octadecyl silane column (75 × 2.0 mm I.D.) in an isocratic elution of acetonitrile and 5 mM ammonium acetate (pH 6.0) (57:43, v/v). The method was applied to 10 patients treated with oral ITZ. Results The calibration curves of ITZ, OH-ITZ, KT-ITZ, and ND-ITZ were linear over the concentration ranges of 15–1500, 15–1500, 1–100, and 1–100 ng/mL, respectively. The pretreatment recoveries and matrix factors were 90.1–102.2% and 99.1–102.7%. Their intra- and inter-assay accuracies and imprecisions were 94.1–106.7% and 0.3–4.4%. The plasma concentrations of ITZ, OH-ITZ, KT-ITZ, and ND-ITZ 12 h after dosing ranged from 32.5–1127.1, 19.0–1166.7, 1.1–5.4, and 3.5–28.3 ng/mL, respectively, in immunocompromised patients. Conclusions This study developed a simultaneous determination method for concentrations of ITZ and its three metabolites including ND-ITZ in a clinical setting.

Tolvaptan efficacy for heart failure has a large interindividual variation. This study aimed to evaluate the influence of CYP3A5 and ABCB1 genotypes on tolvaptan pharmacokinetics and their relationships with plasma markers of CYP3A activity and laboratory test values in heart failure patients. Fifty-eight heart failure patients receiving oral tolvaptan for volume overload were enrolled. Blood samples for determination of pre-dose plasma concentrations of tolvaptan and its metabolites were collected. CYP3A5 and ABCB1 genotypes, plasma 4β-hydroxycholesterol/total cholesterol ratio (4β-OHC/TC) and 25-hydroxyvitamin D (25-OHD), and serum laboratory test values were evaluated. The CYP3A5*3/*3 genotype was associated with a higher plasma concentration of tolvaptan but not with its metabolic ratios. The ABCB1 3435C > T, 2677G > T/A and 1236C > T polymorphisms affected neither tolvaptan pharmacokinetics nor its metabolism. Plasma 4β-OHC/TC and 25-OHD concentration were not correlated with plasma tolvaptan concentration. In a stratified analysis based on CYP3A5 genotype, plasma 4β-OHC/TC had a negative correlation with plasma tolvaptan concentration in the patients with the CYP3A5*1 allele, while the plasma concentration of 25-OHD did not. The CYP3A5*3/*3 genotype was associated with a higher serum sodium level in the patients with volume overload. The plasma concentration of 25-OHD had a positive correlation with the serum total bilirubin level. In conclusion, CYP3A5*3 but not ABCB1 genotypes elevated tolvaptan plasma exposure in heart failure patients. CYP3A5-deficient patients treated with tolvaptan had a higher serum sodium level. The CYP3A5 genotype altered the relationship between plasma tolvaptan and 4β-OHC.

A liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method is a novel approach for the quantification of therapeutic monoclonal antibody. However, this method has severe ionization suppression and time-consuming sample preparation. In the present study, we developed a simple and rapid LC-MS/MS method for quantifying serum nivolumab with good analytical performance using immunoglobulin G (IgG) purification and immobilized tryptic digestion. Surrogate peptide derived from nivolumab was identified by a hybrid quadrupole-Orbitrap mass spectrometer. IgG purification and immobilized tryptic digestion were completed within 25 minutes. The chromatographic separation was completed in 10 minutes with stepwise-gradient elution. Chromatographic peaks interfering with the surrogate peptide and its stable isotope-labeled peptide as an internal standard were not observed from serum digests. The dynamic range of the calibration curve was 2–200 μg mL−1. The intra- and inter-assay accuracies and imprecisions were 92.2–104.5% and less than 10.0%, respectively. Serum nivolumab concentrations ranged from 12–112 μg mL−1 in 14 cancer patients. The measured concentrations in the LC-MS/MS method were strongly correlated with those in the ELISA method (r = 0.92, P < 0.01). In conclusion, a simple and rapid LC-MS/MS method for quantifying serum nivolumab using immobilized tryptic digestion coupled to IgG purification was found to be acceptable for clinical settings.

Dacarbazine (DTIC) is converted to the photo-degradation product 4-diazoimidazole-5-carboxamide (Diazo-IC) by light. Diazo-IC production is often responsible for the pain reactions observed during peripheral intravenous infusion of DTIC in clinical settings. Although light shielding during infusion decreases the photo-degradation of DTIC, its usefulness for the preparation of DTIC has not yet been fully clarified. The aim of this study was to investigate the light conditions during the preparation of DTIC solution in the compounding room from the viewpoint of the production amount of Diazo-IC. DTIC solution was prepared in the compounding room. Various light and temperature conditions and dissolving solutions during the preparation were investigated. The amounts of DTIC and Diazo-IC in solutions were determined using an HPLC coupled to UV detection. The photo-degradation of DTIC was estimated by the amount of Diazo-IC. Diazo-IC production in the dissolving solutions increased in a time-dependent manner at 4 and 25°C under light shielding. Light exposure during the dissolving process did not affect the DTIC and Diazo-IC concentrations. Light shielding during dissolution did not alter the Diazo-IC production until 4 h after dilution. In conclusion, short duration light exposure did not affect Diazo-IC production. These findings suggest that light shielding is not needed in the preparation of DTIC in the compounding room from the viewpoint of Diazo-IC production.

Flavin-containing monooxygenase (FMO) 3 together with cytochrome P450 (CYP) 2C19 play a significant role in voriconazole N-oxidation. This study aimed to evaluate the influence of FMO3 and CYP2C19 genotypes on the plasma disposition and adverse effects of voriconazole in immunocompromised patients. Sixty-five Japanese immunocompromised patients receiving oral voriconazole were enrolled. Predose plasma concentrations of voriconazole and N-oxide were determined at day 5 or later. The adverse effects of voriconazole and the FMO3 and CYP2C19 genotypes were investigated. The patients with FMO3 E158K/E308G had a lower plasma concentration of voriconazole. The metabolic ratio to N-oxide was significantly higher in the FMO3 E158K/E308G group than in the wild group. In contrast, FMO3 V257M was not associated with the plasma concentration of voriconazole. No significant difference was observed in the saturation index, defined as a correlation coefficient of the regression line between the absolute plasma concentration of voriconazole and the inverse value of the metabolic ratio to N-oxide, between the FMO3 genotypes. CYP2C19 phenotype did not affect the plasma concentration and metabolic ratio of voriconazole. The saturation index of voriconazole rose in the order of CYP2C19 extensive, intermediate, and then poor metabolizer groups. However, the FMO3 and CYP2C19 genotypes and their associated voriconazole pharmacokinetics did not have an effect on the incidence of adverse effects. In conclusion, FMO3 E158K/E308G decreased the plasma concentration of voriconazole through its higher metabolic activity. The FMO3 genotype altered the plasma exposure of voriconazole, while the CYP2C19 phenotype affected the metabolic capacity in immunocompromised patients.

Patients with cancer receiving pregabalin potentially have a high incidence of central nervous system (CNS) symptoms. The purpose of this study was to explore clinical factors influencing the incidence of CNS symptoms, including plasma pregabalin exposure, cancer cachexia, and opioid analgesic cotreatment.Sixty-eight patients with cancer receiving twice-daily pregabalin were enrolled. Plasma concentrations of pregabalin, clinical laboratory data, opioid analgesic cotreatment, and the Glasgow Prognostic Score, which is an inflammation-based cachexia score, were considered as clinical factors. The incidence of CNS symptoms was collected from the patients' medical records. The predose plasma concentrations of pregabalin at steady state were determined by ultra-high-performance liquid chromatography.The steady-state trough plasma pregabalin concentrations showed a large variability with an interquartile range of 0.43-1.2 mg/L per mg/kg and were negatively correlated with an estimated glomerular filtration rate (eGFR). C-reactive protein (standardized partial regression coefficient, β = 0.31) and opioid analgesic cotreatment (β = 0.24) were also identified in addition to eGFR (β = -0.60) in the multiple regression analysis. The incidence of CNS symptoms was significantly increased with opioid analgesic cotreatment and a higher Glasgow Prognostic Score but not with the absolute value of plasma pregabalin concentrations, eGFR, or other clinical laboratory data.In patients with cancer, steady-state trough plasma pregabalin concentrations were altered with renal function, systemic inflammation, and opioid analgesic cotreatment. However, a higher incidence of CNS symptoms observed in patients with cancer on pregabalin was more related to cachexia and opioid analgesic cotreatment than to altered pregabalin concentrations.

A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were

Serum nivolumab concentrations exhibit a large variation in cancer patients. Cancer cachexia inducing systemic inflammation promotes the elimination of endogenous proteins, while its association with serum nivolumab remains unclear. The present study aimed to evaluate the impacts of cachexia progression in addition to blood components on serum nivolumab in cancer patients.Thirty-eight non-small-cell lung cancer or renal cell cancer patients receiving biweekly intravenous nivolumab were enrolled. Blood samples were collected just before dosing at the 7th administration of nivolumab or later. Serum nivolumab together with serum proteins, inflammatory markers, and peripheral blood leukocytes were determined. Cancer cachexia was classified using the Glasgow Prognostic Score (GPS). Immune-related adverse events (irAEs) were monitored during the study period.Cancer patients had a large variation in serum nivolumab concentrations (interquartile range, 12-21 µg/mL per mg/kg). The serum nivolumab concentration was positively correlated with serum albumin, while negatively associated with serum globulin and immunoglobulin G (IgG). A negative correlation was observed between serum nivolumab and blood lymphocytes. Regarding cachexia progression, the patients with GPS 2 had a higher serum interleukin-6 concentration and a lower serum nivolumab concentration than those with GPS 0 or 1. The GPS, serum IgG, and blood lymphocytes were identified as independent variables for serum nivolumab. The incidence of irAEs was not associated with the nivolumab dose or serum nivolumab.Cachexia progression had a negative impact on serum nivolumab in cancer patients. The interindividual variation in serum nivolumab was characterized by cachexia progression in addition to blood components.

BACKGROUND Aprepitant, an antiemetic selective neurokinin-1 receptor antagonist, is primarily metabolized to the active N-dealkylated form (ND-AP) and then converted to its carbonyl form (ND-CAP) in humans. This study developed a simple liquid chromatography-tandem mass spectrometry method using electrospray ionization for the quantitation of plasma total and free aprepitant and its N-dealkylated metabolites and used them to analyze patient plasma. METHODS Free aprepitant and ND-AP in plasma were fractionated using centrifugal ultrafiltration. The analytes in plasma or their ultrafiltered specimens treated with triethylamine/acetonitrile were isocratically separated using a 3-μm octadecylsilyl column with a total run time of 10 minutes and scanned using positive ion electrospray ionization. RESULTS The calibration curves of total aprepitant, ND-AP, and ND-CAP were prepared at concentration ranges of 50-2500, 20-1000, and 5-250 ng/mL, respectively, whereas that of free aprepitant and ND-AP were at a concentration range of 2-150 ng/mL. The intraassay and interassay accuracy and imprecision values were 93.5%-107.7% and 94.6%-103.3%, and 2.1%-7.5% and 1.0%-8.9%, respectively. Aprepitant and its metabolites did not exhibit any matrix effects or instabilities in the plasma specimens. In cancer patients receiving oral aprepitant, the plasma concentration ranges of total aprepitant, ND-AP, and ND-CAP, and free aprepitant and ND-AP were 137-2170, 104-928, 22.4-97.6, 8.11-60.0, and 3.53-56.0 ng/mL, respectively. The median plasma free fraction proportion of aprepitant and ND-AP was 4.14% and 4.90%, respectively. CONCLUSIONS The present developed method showed an acceptable analytical performance and can be used to evaluate total and free aprepitant and its N-dealkylated metabolites in patient plasma.

Purpose: Serum markers of renal function have not been characterized in patients treated with itraconazole (ITZ). This study aimed to evaluate the associations between plasma ITZ and its hydroxylated metabolite (OH-ITZ) concentrations and serum markers of renal function in hematopoietic or immune-related disorder patients.Methods: This study enrolled 40 hematopoietic or immune-related disorder patients receiving oral ITZ solution. Plasma concentrations of ITZ and OH-ITZ at 12 hours after dosing were determined at steady state. Their relationships with serum levels of creatinine and cystatin C, and their estimated glomerular filtration rate (eGFR) were evaluated.Results: The free plasma concentration of ITZ had no correlation with serum creatinine and serum creatinine-based estimated glomerular filtration rate (eGFR-cre). The free plasma concentration of OH-ITZ was positively and negatively correlated with serum creatinine and eGFR-cre, respectively. The free plasma concentrations of ITZ and OH-ITZ had no association with serum cystatin C and serum cystatin C-based eGFR. Serum creatinine was higher by 16% after than before starting ITZ treatment, while eGFR-cre was lower by 9.3%. The serum creatinine ratio after/before ITZ treatment was positively correlated with the free plasma concentration of OH-ITZ. The patients co-treated with trimethoprim-sulfamethoxazole had higher serum creatinine. Concomitant glucocorticoid administration did not significantly alter serum cystatin C.Conclusions: Hematopoietic or immune-related disorder patients treated with oral ITZ had a higher level of serum creatinine. Although serum creatinine potentially increases in conjunction with the free plasma concentration of OH-ITZ, concomitant ITZ administration has a slight impact on the eGFR-cre level in clinical settings.

Background: Proteomics-based LC–MS/MS methods using trypsin solution have some problems including ion suppression and long protein digestion times. Few practical methods to quantify denosumab in human serum have been published. Methodology: Immunoglobulins in serum were extracted using immobilized protein G. Denatured, reduced and alkylated serum samples were digested with immobilized trypsin for 14 min. A denosumab-unique peptide was identified using a Fourier transform mass spectrometer as a signature peptide. The signature peptide was quantitated with a hybrid triple–quadrupole/linear ion-trap mass spectrometer. Conclusion: A rapid and practical proteomics-based LC–MS/MS method using immobilized trypsin for denosumab quantitation in human serum was developed. The present method has an acceptable analytical performance and can be helpful for the determination of serum denosumab in clinical settings.

Clinical responses to oral tramadol show a large variation in cancer patients. This study aimed to evaluate the impacts of cytochrome P450 (CYP) genotype and serum inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients. The predose plasma concentrations of tramadol and its demethylated metabolites were determined at day 4 or later in 70 Japanese cancer patients treated with oral tramadol. The CYP genotypes, serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels, and the duration of tramadol treatment were evaluated. The CYP2D6 genotype did not affect the plasma tramadol concentration. The plasma concentration of O-desmethyltramadol and its ratio to tramadol were lower in the CYP2D6 intermediate and poor metabolizer (IM + PM) group than in the normal metabolizer (NM) group (P = 0.002 and P = 0.023). The plasma concentration of N-desmethyltramadol and its ratio to tramadol were higher in the CYP2D6 IM + PM group than in the NM group (P = 0.001 and P = 0.001). The CYP2B6*6 and CYP3A5*3 alleles had no effect on the plasma concentrations of tramadol and its demethylated metabolites. The serum IL-6 and CRP levels were inversely correlated with the plasma concentration ratios of N-desmethyltramadol to tramadol and of N,O-didesmethyltramadol to O-desmethyltramadol. The serum IL-6 level was associated with the treatment duration of oral tramadol. The CYP2D6 genotype but not the CYP2B6 and CYP3A5 genotypes affected the plasma concentrations of O- and N-desmethyltramadol through alteration of the tramadol metabolic pathway. The serum IL-6 level was associated with N-demethylation activity and tramadol tolerability.

Proteomic approaches using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) without an immunopurification technique have not been applied to the determination of serum cetuximab. This study developed a simple and rapid LC-MS/MS method for the absolute determination of cetuximab in human serum and applied it to clinical settings. Surrogate peptides derived from cetuximab digests were selected using a Fourier transform mass spectrometer. Reduced-alkylated serum cetuximab without immunopurification was digested for 20minutes using immobilized trypsin, and the digestion products were purified by solid-phase extraction. The LC-MS/MS was run in positive ion multiple reaction monitoring mode. This method was applied to the determination of serum samples in head and neck cancer patients treated with cetuximab. The chromatographic run time was 10minutes and no peaks interfering with surrogate peptides in serum digestion products were observed. The calibration curve of absolute cetuximab in serum was linear over the concentration range of 4-200μg/mL. The lower limit of quantification of cetuximab in human serum was 4μg/mL. The intra-assay and inter-assay precision and accuracy were less than 13.2% and 88.0-100.7%, respectively. The serum concentration range of cetuximab was 19-140μg/mL in patients. The serum cetuximab concentrations in LC-MS/MS were correlated with those in ELISA (r=0.899, P

Aripiprazole, a partial agonist of dopamine D2 receptors, is primarily metabolized to active dehydroaripiprazole and then converted to its urinary metabolites 1-(2,3-dichlorophenyl) piperazine (DCPP) and 3,4-dihydro-7-(3′carboxy) propoxy-2(1H) quinolinone (DCPQ). This study aimed to develop a simultaneous determination method for aripiprazole and its three metabolites in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and then to apply it to pharmacokinetic analyses. The pretreatments for human plasma involve protein precipitation using acetonitrile under basic conditions. Aripiprazole and its metabolites were separated on an octadecylsilyl column filled with 3-µm particles using an isocratic mixture of 30% acetonitrile containing 0.1% formic acid with a total run time of 10 min. The mass spectrometer was run in the positive ion multiple reaction monitoring mode. The calibration curves were linear over the plasma concentration ranges 2–2000 ng mL−1 for aripiprazole, and 1–1000 ng mL−1 for dehydroaripiprazole, DCPP, and DCPQ. The lower limits of quantification in human plasma were 2 ng mL−1 for aripiprazole and 1 ng mL−1 for the metabolites. Their pretreatment recoveries were 88.3–102.7%. The intra-assay precision and accuracy were within 1.7–9.6 and 86.9–105.9% and inter-assay precision and accuracy were within 3.1–9.1 and 87.4–102.4%, respectively. The plasma concentrations of aripiprazole, dehydroaripiprazole, DCPP, and DCPQ ranged from 42.8 to 1369, 1.01–548, 1.02–46.1, and 1.69–475 ng mL−1, respectively, in 20 schizophrenia patients. In conclusion, this simultaneous determination method with acceptable analytical performance can be helpful for evaluating the pharmacokinetics of aripiprazole including the determination of its metabolites, in clinical research.

BACKGROUND Pregabalin has been used for the treatment of pain. A clinically accepted method applied to patients with pain has not been published for the determination of pregabalin in human plasma. This study developed a fluorometric ultrahigh-performance liquid chromatography (UHPLC) method to measure pregabalin concentration in patients with pain. METHODS After plasma pretreatment involving protein precipitation, pregabalin and gabapentin as an internal standard were derivatized with 4-fluoro-7-nitrobenzofurazan (NBD-F) under the following reaction conditions: 1 minute, pH 10, and 60°C. The UHPLC separation was performed using a 2.3-μm particle size octadecylsilyl column. The fluorescence detector was set at excitation and emission wavelengths of 470 and 530 nm, respectively. The predose blood samples were collected from 40 patients with pain who have been treated with 75 mg of pregabalin twice daily. RESULTS The chromatographic run time was 1.25 minutes. No interfering peaks were observed in the blank plasma at the retention times of NBD derivatives. The calibration curve of pregabalin was linear at a range of 0.05-10 mcg/mL (r > 0.999). The lower limit of quantification was 0.05 mcg/mL. The intra-assay accuracy and precision were 98.3%-99.8% and within 4.3%, respectively. The inter-assay accuracy and precision were 103.2%-107.1% and within 4.1%, respectively. The predose plasma concentration of pregabalin in patients with pain ranged from 0.14 to 8.5 mcg/mL. CONCLUSIONS This study provides a validated fluorometric UHPLC method with fast analytical performance for the determination of pregabalin in human plasma. The present method could be applied to patients with pain and be used for the clinical research or therapeutic drug monitoring of pregabalin.

Racemic tolvaptan possessing an asymmetric carbon is metabolized to three pairs of monohydroxylate enantiomers of diol form with V2 receptor antagonistic activity via CYP3A. This study aimed to develop a simultaneous quantitative liquid chromatography-tandem mass spectrometry method for 5R- and 5S-tolvaptan and their monohydroxylate enantiomers in human plasma and to apply it to patient samples. Deproteinized plasma specimens were separated using a polysaccharide derivative chiral column in a reversed-phase elution mode. The mass spectrometer was run in positive ion electrospray ionization mode. The chromatographic peaks of tolvaptan monohydroxylate enantiomers were identified by the recombinant CYP3A4/5 digestion of 5R- and 5S-tolvaptan. The calibration curves ranged over the plasma concentrations of 0.25–125 ng/mL for 5R- and 5S-tolvaptan, 0.025–12.5 ng/mL for 4R5R- and 4S5S-diols, and 0.025–38.15 ng/mL for 4S5R-, 4R5S-, 3S5R-, and 3R5S-diols with a large variation. Their pre-treatment recovery rates and matrix factors in human plasma were 85.2–112.9 % and 86.9–113.1 %, respectively. The intra- and inter-day accuracy and imprecision were 92.3–113.8 % and 3.5–14.6 % for all analytes, respectively. The plasma concentration ranges of 5R- and 5S-tolvaptan, 4R5R-, 4S5S-, 4S5R-, 4R5S-, 3S5R-, and 3R5S-diols in heart failure patients with a 5-fold dilution procedure were 0.634–28.4, 2.37–131, 0.525–15.4, 0.0970–4.08, 6.82–108, 0.271–6.49, 0.394–4.18, and 4.81–39.8 ng/mL, respectively. In conclusion, the present method has an acceptable analytical performance level and can be helpful for characterization of the plasma 5R- and 5S-tolvaptan and their monohydroxylate enantiomers in heart failure patients.

There are large inter- and intra-individual variations in CYP3A4 activity. Midazolam, which is predominantly metabolized to 1'-hydroxymidazolam and 4-hydroxymidazolam by CYP3A4, is considered an effective probe for CYP3A4. To determine the area under the curve (AUC) of midazolam or midazolam clearance for CYP3A4 activity, multiple plasma samples of midazolam are required. This study aimed to evaluate whether measurement of a single plasma concentration or urinary excretion of midazolam could be used to predict the AUC of midazolam in healthy volunteers. We conducted a retrospective analysis of two pharmacokinetic studies. Nineteen volunteers received intravenous (5, 15, and 30 µg/kg) and oral (15, 50, and 100 µg/kg) administration of midazolam on sequential days. The midazolam concentration in plasma and urine was determined by LC-MS/MS. Plasma midazolam concentrations showed a good correlation with the AUC at all blood sampling points after the administrations. The coefficient of determination was highest at 1-2 and 2-4 h after intravenous (>0.96) and oral administration (>0.94), respectively, among all the sampling times. The errors for bias and accuracy of prediction were the lowest at 1.5 and 4 h after intravenous and oral administration, respectively. In case of urinary excretion, a significant positive correlation between midazolam and the AUC was observed only after oral administration. Thus, the AUC of midazolam can be evaluated by blood sampling at 1.5 h after intravenous administration and at 4 h after oral administration.

Objective This study aimed to evaluate the relationship between endogenous CYP3A markers and plasma amlodipine (AML) exposure and metabolism parameters in early postpartum and non-peripartum women. Methods Twenty-four AML-treated early postpartum women with hypertensive disorders of pregnancy and 30 non-peripartum women with essential hypertension were enrolled. Blood samples for determination of CYP3A markers including total cholesterol-adjusted 4β-hydroxycholesterol (4β-OHC/TC), 25-hydroxyvitamin D (25-OHD), and AML and its metabolites in plasma were collected at 24 h after the AML treatment. Results The plasma 4β-OHC/TC in postpartum women was higher than that in non-peripartum women, while the plasma 25-OHD was lower. The postpartum women had a lower plasma AML concentration and its metabolic ratio was higher. The plasma 4β-OHC/TC decreased as the number of days post-delivery increased. The plasma AML concentration increased as the number of days post-delivery increased, while the metabolic ratio of AML declined slightly. Tendency toward negative correlations between the plasma 4β-OHC/TC but not 25-OHD, and AML concentration were observed in both postpartum and non-peripartum women. In both groups, the plasma 4β-OHC/TC was correlated with the metabolic ratio of AML. Conclusions The early postpartum women had higher plasma 4β-OHC and AML metabolism. The plasma 4β-OHC had positive relationships with amlodipine metabolism in both women groups. AML metabolism and plasma 4β-OHC may be useful as CYP3A markers in early postpartum and non-peripartum women.

What is known and objective Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). Methods We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. Results and discussion The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. What is new and conclusion There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

Background Tolvaptan is converted to major metabolites including three monohydroxylates (DM-4110, DM-4111 and DM-4119), an oxidate (MOP-21826) and a carboxylate (DM-4103) in humans. This study developed a simultaneous quantitative method for tolvaptan and its five major metabolites in human plasma using liquid chromatography coupled to tandem mass spectrometry. Methods Deproteinized plasma specimens using acetonitrile were separated using a 3- μm particle size octadecylsilyl column with 250 mm length and a simple linear gradient program at a flow rate of 0.3 mL/min with a total run time of 15 min. This method was applied to the determination of plasma samples collected from 20 heart failure patients treated with 3.75–15 mg tolvaptan. Results No interfering peak was found in drug-free plasma specimens. The calibration curves of tolvaptan, DM-4110, DM-4111, DM-4119, MOP-21826 and DM-4103 were linear over the concentration ranges of 3.125–1000, 0.3125–100, 1.25–400, 0.625–200, 0.125–40 and 31.25–10,000 ng/mL, respectively. Their pretreatment recovery rates and matrix factors were 94.1–113.9% and 86.9–108.0%, respectively. The intra- and inter-day accuracies and imprecisions were 91.6–106.5% and 0.9–10.9%, respectively, for all analytes. The plasma concentration ranges of tolvaptan, DM-4110, DM-4111, DM-4119, MOP-21826 and DM-4103 were 9.37–280, 1.91–16.3, 3.43–88.9, 1.43–10.4, 0.160–1.01 and 40.2–1471 ng/mL, respectively, in heart failure patients. Conclusions This validated method with acceptable analytical performance can be utilized for evaluating the pharmacokinetics of oral tolvaptan, including the determination of its major metabolites, in heart failure patients.

OBJECTIVE: Although clinical outcomes after arthroscopic rotator cuff repair are generally favorable, postoperative return to work is also an important issue. This study aimed to assess clinical outcomes and clarify the factors affecting return to work in patients who had undergone arthroscopic rotator cuff repair. METHODS: In total, 63 patients who had undergone arthroscopic rotator cuff repair were included in this study. Clinical assessment was performed using Japanese Orthopaedic Association (JOA) scores, along with measurements of pain, range of motion, muscle strength, cuff integrity, and fatty infiltration. Depending on their return-to-work status at the final follow-up, subjects were assigned to either the complete return group (the patient returned to work) or the incomplete return group (the patient had quit or had changed their occupation at final follow-up). Various clinical parameters affecting the return to work outcome were examined through univariate and multivariate analyses. RESULTS: Of the 63 subjects, 42 belonged to the complete return group and 21 belonged to the incomplete return group. Therefore, the working capability recovery rate following arthroscopic rotator cuff repair was 66.7%. Both groups showed significant improvement from their preoperative status, but there were statistically significant differences in JOA scores between the groups at 9 and 12 months postoperatively (P

Background This study aimed to evaluate the relationships between concomitant biologic disease-modifying anti-rheumatic drugs (DMARDs) and prednisolone administration and blood tacrolimus exposure or serum CYP3A4/5-related markers in rheumatoid arthritis (RA) patients without severe disease activity. Methods Forty-six RA patients treated with oral tacrolimus once daily for maintenance of clinical remission to moderate disease activity were enrolled. The blood concentrations of tacrolimus and its major metabolite were determined at 12 h after the evening dosing. Blood samples for determination of serum markers including 4β-hydroxycholesterol (4β-OHC), 25-hydroxyvitamin D (25-OHD) and interleukin-6 (IL-6), and CYP3A5 genotype were collected. Results Most enrolled patients had RA with clinical remission to mild disease activity. Concomitant tocilizumab or low-dose prednisolone administration did not alter the blood tacrolimus exposure. Serum 4β-OHC level was lower in tocilizumab co-treated patients than in the biologic DMARD non-treated patients. The blood tacrolimus concentration was inversely correlated with the serum level of 25-OHD, but not 4β-OHC and IL-6. The serum level of 4β-OHC was positively associated with that of 25-OHD. No correlations were observed between the serum levels of CYP3A4/5 activity markers and IL-6. The patients with the homozygous CYP3A5*3 had the higher blood tacrolimus concentration, while CYP3A5*3 allele was not associated with the serum levels of 4β-OHC and 25-OHD. Conclusions Concomitant use of tocilizumab or low-dose prednisolone had no effect on the pharmacokinetics of tacrolimus, while tocilizumab lowered serum 4β-OHC. Blood tacrolimus exposure was negatively associated with serum 25-OHD in RA patients with clinical remission to moderate disease activity.

Elevated serum proinflammatory cytokines are associated with the reduction of cytochrome P450 enzyme (CYP) activity. This study aimed to evaluate the oxycodone pharmacokinetics, central symptoms, and serum proinflammatory cytokines based on cachexia stage in cancer patients.Forty-seven cancer patients receiving extended-release oxycodone were enrolled. Predose plasma concentrations of oxycodone and its metabolites were normalized with the daily dose and body weight. The central symptoms and serum level of proinflammatory cytokines were investigated at each cachexia stage.The plasma concentrations of oxycodone in patients with cachexia and refractory cachexia were significantly higher than that in patients with precachexia. The metabolic ratio to noroxycodone in patients with cachexia was significantly lower than that in patients with precachexia. The patients with a higher cachexia stage had a higher serum level of interleukin-6 (IL-6), but not tumor necrosis factor-α and interleukin-1β. The serum IL-6 level was correlated with the plasma concentration of oxycodone and inversely with the metabolic ratio to noroxycodone. The incidence of somnolence was not associated with the plasma oxycodone concentration. In contrast, the cachexia stage and its associated serum IL-6 level were correlated with the incidence of somnolence.Cancer cachexia raised the plasma exposure of oxycodone through the reduction of CYP3A metabolic pathway. The reduction of CYP3A in cachectic cancer patients was associated with an elevation of serum IL-6. Although cachectic cancer patients with higher serum IL-6 levels had the symptom of somnolence, the alterations in oxycodone pharmacokinetics were not related to the incidence of symptom.

Background Mycophenolate mofetil has recently been reported to be effective against systemic lupus erythematosus. The influence of the pharmacokinetics of mycophenolic acid, the active form of mycophenolate mofetil and the major inactive mycophenolic acid phenolic glucuronide on the activity of the target enzyme inosine 5′-monophosphate dehydrogenase, is expected to be revealed. The aim of this study was to identify the factors associated with inosine 5′-monophosphate dehydrogenase activity in systemic lupus erythematosus patients. Methods Fifty systemic lupus erythematosus patients in remission maintenance phase (29 received mycophenolate mofetil [MMF+] and 21 did not [MMF−]) were enrolled. Median and interquartile range of dose of mycophenolate mofetil were 1500 and 1000–1500 mg/day, respectively. Stepwise multiple linear regression analysis was performed to assess the dependence between inosine 5′-monophosphate dehydrogenase activity and 25 predictor values including predose plasma concentrations of free mycophenolic acid and mycophenolic acid phenolic glucuronide. Results Median and interquartile range of predose total plasma concentrations of mycophenolic acid and mycophenolic acid phenolic glucuronide were 2.73 and 1.43–5.73 and 25.5 and 13.1–54.7 µg/mL, respectively. Predose inosine 5′-monophosphate dehydrogenase activity was significantly higher in MMF+ than MMF− patients (median 38.3 and 20.6 nmoL xanthosine 5′-monophosphate/g haemoglobin/h, P2 = 0.52, P Conclusions Predose inosine 5′-monophosphate dehydrogenase activity was higher in systemic lupus erythematosus patients receiving mycophenolate mofetil therapy. Inosine 5′-monophosphate dehydrogenase activity may be determined by mycophenolic acid exposure and complement fraction C3 in systemic lupus erythematosus patients.

This study aimed to evaluate plasma 4β-hydroxycholesterol as an endogenous marker of CYP3A4/5 activity in early postpartum women and its impact on the plasma disposition of amlodipine. Twenty-seven early postpartum women treated with amlodipine for pregnancy-induced hypertension were enrolled. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum and in non-perinatal women were evaluated. The predose plasma concentration of amlodipine was determined at steady state. The medians of the plasma 4β-hydroxycholesterol concentration at day 0-3 and 8-21 after delivery were 146 and 161 ng/mL, respectively. No significant difference was observed in the plasma concentration of 4β-hydroxycholesterol between the postpartum periods. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum women were significantly higher than those in non-perinatal women. A large individual variability was observed in the dose-normalized plasma concentration of amlodipine in early postpartum women. A weak negative correlation was observed between the dose-normalized plasma concentration of amlodipine and the plasma concentration of 4β-hydroxycholesterol. In conclusion, early postpartum women possessed higher CYP3A activity based on plasma 4β-hydroxycholesterol and had a large pharmacokinetic variability in amlodipine. CYP3A activity during the early postpartum period had an effect on the plasma disposition of amlodipine.

Clinical pharmacology and pharmacoepidemiology research may converge in practise. Pharmacoepidemiology is the study of pharmacotherapy and risk management in patient groups. For many drugs, adverse reaction(s) that were not seen and/or clarified during research and development stages have been reported in the real world. Pharmacoepidemiology can detect and verify adverse drug reactions as reverse translational research. Recently, development and effective use of medical information databases (MID) have been conducted in Japan and elsewhere for the purpose of post-marketing safety of drugs. The Ministry of Health, Labour and Welfare, Japan has been promoting the development of 10-million scale database in 10 hospitals and hospital groups as "the infrastructure project of medical information database (MID-NET)". This project enables estimation of the frequency of adverse reactions, the distinction between drug-induced reactions and basal health-condition changes, and usefulness verification of administrative measures of drug safety. However, because the database information is different from detailed medical records, construction of methodologies for the detection and evaluation of adverse reactions is required. We have been performing database research using medical information system in some hospitals to establish and demonstrate useful methods for post-marketing safety. In this symposium, we aim to discuss the possibility of reverse translational research from clinical settings and provide an introduction to our research.