Keita Hirai

Simultaneous microdetermination of bosentan, ambrisentan, sildenafil, and tadalafil in plasma using liquid chromatography/tandem mass spectrometry for pediatric patients with pulmonary arterial hypertension

A simultaneous, selective, sensitive, and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of bosentan, ambrisentan, sildenafil, and tadalafil in 50μL of human blood plasma. Diluted plasma samples were extracted using a solid-phase extraction procedure with 2% formic acid and methanol. The four drugs were separated by high-performance liquid chromatography using a C18 column and an isocratic mobile phase running at a flow rate of 0.2mL/min for 5min. The drugs were detected by a tandem mass spectrometer with electrospray ionization using deuterated compounds as internal standards. Calibration curves were generated over the linear concentration range of 2-1000ng/mL in plasma with a lower limit of quantification of 2ng/mL for all compounds. Finally, this validated method was applied to a clinical pharmacokinetic study in pediatric patients with pulmonary arterial hypertension (PAH) following the oral administration of PAH drugs. These results indicate that this method is suitable for assessing the risk/benefit of combination therapy in the pediatric population and useful for therapeutic drug monitoring for PAH treatment.

Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study

Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR.

Augmented Renal Clearance in Pediatric Patients With Febrile Neutropenia Associated With Vancomycin Clearance

Background: Vancomycin (VCM) dosage optimization in the early stages of therapy is required to achieve target trough serum concentrations, particularly in critically ill patients. Augmented renal clearance (ARC), commonly characterized by an enhanced renal clearance, has been associated with subtherapeutic concentrations of antibiotics. The aim of this study was to investigate the risk factors including febrile neutropenia for both ARC and VCM clearance in Japanese pediatric patients. Methods: A total of 109 pediatric patients with normal renal function were included in this observational study. From VCM serum concentrations, individual VCM clearance was estimated by the Bayesian method using a 1-compartment model. Patients were classified on the basis of the presence of febrile neutropenia, cancer, trauma, systemic inflammatory response syndrome, and surgical operation. Risk factors for ARC, as defined by estimated glomerular filtration rate (eGFR) above median value (≥160 mL·min−1·1.73 m−2), were evaluated. Results: Febrile neutropenia was only an independent risk factor for ARC (odds ratio, 5.86; 95% confidence interval, 1.98–21.66, P = 0.0030), which was the result of a stepwise multivariate logistic regression analysis. Although univariate analysis demonstrated a significant association of febrile neutropenia with VCM clearance, the significant independent factors of VCM clearance were age and eGFR but not febrile neutropenia, as estimated by the stepwise multivariate linear regression analysis. Conclusions: This observational study concluded that febrile neutropenia, a significant risk factor for ARC, indirectly influenced VCM clearance towing to an elevated eGFR. Cancer, trauma, systemic inflammatory response syndrome, and surgical operation were not significantly associated with ARC; however, more studies are needed to validate this observation. Adjustment of the initial dosage of VCM is required for achieving optimal therapeutic concentrations in pediatric patients with febrile neutropenia.

Augmented renal clearance in patients with febrile neutropenia is associated with increased risk for subtherapeutic concentrations of vancomycin.

Background: Augmented renal clearance (ARC) has frequently been observed in critically ill patients. The risk factors for ARC in patients, including those in the general ward, and their influences on vancomycin (VCM) treatment remain unclear. The aims of this study were to investigate the risk factors for ARC and to evaluate the influence of ARC on the pharmacokinetic parameters of VCM. Methods: This study included a total of 292 patients with VCM treatment who had normal serum creatinine concentrations. ARC was defined by an estimated creatinine clearance ≥130 mL·min−1·1.73 m−2. The risk factors for ARC were determined with stepwise logistic regression analysis. The pharmacokinetic parameters of VCM were estimated through the Bayesian method using a 2-compartment model. Results: ARC was observed in 48 patients (16.4%). Age ⩽65 years [odds ratio (OR): 5.77; 95% CI: 2.89–11.97; P < 0.0001], brain injury (OR: 5.11; 95% CI: 1.49–17.57; P = 0.0086), febrile neutropenia (OR: 2.76; 95% CI: 1.11–6.67; P = 0.0254), and a mean volume of infusion fluid ≥1500 mL/d (OR: 2.53; 95% CI: 1.27–5.16; P = 0.0091) were independent risk factors for the occurrence of ARC. The patients with ARC exhibited higher VCM clearance values than the non-ARC patients. The median trough serum concentrations of VCM were 7.4 (interquartile range: 5.2–11.6) mcg/mL in the ARC patients and 12.2 (8.9–16.3) mcg/mL in the non-ARC patients (P < 0.0001). Subtherapeutic trough concentrations of VCM (<10.0 mcg/mL) were found in 68.8% of the ARC patients and in 32.8% of the non-ARC patients (P < 0.0001). Conclusions: This observational study investigated the influence of febrile neutropenia on the emergency of ARC for the first time. ARC was strongly associated with VCM pharmacokinetics, and two-thirds of the ARC patients had subtherapeutic VCM concentrations. In patients with ARC, individualized dosing regimens are required to achieve the target trough concentration.

Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy

INTRODUCTION Warfarin is characterized by a large inter-individual variability in dosage requirement. This study aimed to analyze the contribution of the CYP4F2 genetic polymorphism and plasma vitamin K concentration on the warfarin pharmacodynamics in patients and to clarify the plasma vitamin K concentration affecting warfarin sensitivity index in rats. MATERIALS AND METHODS Genetic analyses of selected genes were performed and plasma concentrations of warfarin, vitamin K1 (VK1) and menaquinone-4 (MK-4) were measured in 217 Japanese patients. We also assessed the association of plasma VK1 and MK-4 concentrations with the warfarin sensitivity index (INR/Cp) in rats. RESULTS Patients with the CYP4F2 (rs2108622) TT genotype had significantly higher plasma VK1 and MK-4 concentrations than those with CC and CT genotypes. The multiple linear regression model including VKORC1, CYP4F2, and CYP2C9 genetic variants, age, and weight could explain 42% of the variability in warfarin dosage. The contribution of CYP4F2 polymorphism was estimated to be 2.2%. In contrast, plasma VK1 and MK-4 concentrations were not significantly associated with warfarin dosage in patients. Nevertheless, we were able to demonstrate that the warfarin sensitivity index was attenuated and negatively correlated with plasma VK1 concentration by the oral administration of VK1 in rats, as it resulted in a higher VK1 concentration than that in patients. CONCLUSIONS The plasma VK1 and MK-4 concentrations are significantly influenced by CYP4F2 genetic polymorphism but not associated with warfarin therapy at the observed concentration in Japanese patients. The CYP4F2 polymorphism is poorly associated with inter-individual variability of warfarin dosage requirement.

A clustering approach to identify and characterize the asthma and chronic obstructive pulmonary disease overlap phenotype

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely understood.

Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study

AbstractChemotherapy-induced neutropenia (CIN) is one of the major adverse events that necessitate chemotherapy dose reduction. This study aimed to evaluate the association between grade 4 neutropenia and genetic polymorphisms in breast cancer patients. In this genetic polymorphism association study, peripheral blood samples from 100 consecutive breast cancer outpatients, between August 2012 and September 2014, treated with doxorubicin and cyclophosphamide (AC) combination chemotherapy were genotyped for polymorphisms in adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), cytochrome P450 (CYP) enzyme-coding genes (CYP2B6 and CYP3A5), glutathione S-transferase (GST), and excision repair cross-complementing 1 (ERCC1). Associations between grade 4 neutropenia and genotypes as well as risk factors were examined using multivariate logistic regression. From 100 patients, 32.0% had grade 4 neutropenia. Multivariate logistic regression analysis revealed that ERCC1 118C > T (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.22–9.69; P = 0.020), CYP2B6*6 (OR, 4.51; 95% CI, 1.21–16.95; P = 0.025), body mass index (BMI) (OR, 6.94; 95% CI, 1.15–41.67; P = 0.035), and baseline white blood cell (WBC) count (OR, 2.99; 95% CI, 1.06–8.40; P = 0.038) were significant predictors of grade 4 neutropenia. ERCC1 and CYP2B6 gene polymorphisms were associated with the extent of grade 4 neutropenia in patients receiving AC chemotherapy. In addition to previously known risk factors, BMI and WBC counts, ERCC1 and CYP2B6 gene polymorphisms were also identified as independent strong predictors of grade 4 neutropenia.

Influence of glutamine synthetase gene polymorphisms on the development of hyperammonemia during valproic acid-based therapy

PURPOSE Valproic acid (VPA), which is widely used to treat epilepsy, migraine, and bipolar disorder, can causes severe hyperammonemia. However, the mechanism responsible for this adverse effect is not readily apparent. We previously reported that phenytoin coadministration is a strong risk factor for the development of hyperammonemia during VPA-based therapy. In this study, we focused on glutamine synthetase, which catalyzes the synthesis of glutamine from glutamate and ammonia and examined the association with the development of hyperammonemia during VPA-based therapy. METHODS For this study, we recruited 202 Japanese pediatric patients having epilepsy. We selected three polymorphisms (rs10911070, rs10797771, and rs10911021) in the glutamine synthetase (GLUL) gene. Hyperammonemia was defined as a plasma ammonia level exceeding 200 or 170 μg/dL. We evaluated the association between the development of hyperammonemia during VPA-based therapy and the patient characteristics, including three GLUL polymorphisms. RESULTS The number of patients who developed hyperammonemia during VPA-based therapy was 20 (9.9%) using the 200 μg/dL cutoff value and 30 (14.9%) using the 170 μg/dL cutoff value. Using a multivariate logistic regression analysis, the GLUL rs10797771 polymorphism and phenytoin coadministration in the 200 μg/dL cutoff value, and female in addition to two factors in the 170 μg/dL cutoff value, had significant associations with a plasma ammonia level elevation during VPA-based therapy. CONCLUSION Phenytoin coadministration, GLUL rs10797771 polymorphism in the 200μg/dL cutoff value, and female in addition to two factors in the 170μg/dL cutoff value, are independent risk factors for elevated plasma ammonia levels during VPA-based therapy.

Genetic risk factors for chemotherapy-induced nausea and vomiting in patients with cancer receiving cisplatin-based chemotherapy

PurposeYounger age and female sex have already been well-known risk factors for chemotherapy-induced nausea and vomiting (CINV), and 30–50% of cancer patients still suffer from CINV. Genetic polymorphisms are suggested to influence antiemetic treatment response.MethodsThis study included a subset of patients previously enrolled in a randomised controlled trial; 156 patients were evaluated. This study aimed to evaluate the role of pharmacogenomic polymorphisms relevant to antiemetic response in patients with cancer receiving cisplatin-based chemotherapy. The study’s efficacy endpoint was the proportion of patients with complete response (CR). The study endpoint was evaluated separately in the acute (CR0–24) and delayed (CR24–120) phases. Thirteen polymorphisms were genotyped, and the association of these genotypes with the efficacy of prophylactic antiemetics was then investigated. Confounding variables for the CR were identified using stepwise multivariate logistic regression analysis. Age and sex were included as independent variables by the forced-entry method, and the stepwise method was used to select the pharmacogenomic factors for inclusion as independent variables.ResultsMultivariate logistic regression analysis revealed that the ERCC1 8092AA (odds ratio [OR] = 11.25; 95% confidence interval [CI] 1.74–72.71; p = 0.011) and female sex (OR = 3.63; 95% CI 1.14–11.58; p = 0.029) were significant predictors of CR0–24. No significant association of CR24–120 with pharmacogenomic polymorphisms was found via multivariate logistic regression analysis.ConclusionsERCC1 polymorphism influenced the extent of CINV control in patients receiving cisplatin-based chemotherapy.Trial registrationClinical trial information: UMIN 000009335

Factors that influence the pharmacokinetics of lamotrigine in Japanese patients with epilepsy

PurposeLamotrigine (LTG) is used to treat epilepsy. The variability of LTG pharmacokinetics among individuals may be attributed to polymorphisms in the genes of uridine diphosphate glucuronosyltransferases (UGTs) 1A4 and UGT2B7 and/or combination with other drugs. In this study, we evaluated the association between LTG concentrations and patient characteristics such as genetic polymorphisms and the co-administration of antiepileptic drugs.MethodsWe recruited 122 patients with epilepsy. LTG concentrations were measured in blood samples from each patient under steady-state condition. We assessed the influence of multiple factors on LTG concentrations and derived a formula for predicting LTG concentrations using multiple linear regression analysis.ResultsWe derived a formula to predict LTG concentrations that considers the daily dose of LTG, body weight, valproic acid concentration, phenytoin co-administration, and the co-administration of phenobarbital and/or carbamazepine as well as UGT1A4 142T>G and UGT2B7 -161C>T polymorphisms (adjusted coefficients of determination R2 = 0.734). Furthermore, we used this formula to reveal a strong positive correlation between measured and predicted LTG concentrations (r2 = 0.76, p < 0.001).ConclusionWe derived a formula that will be useful in clinical practice for predicting LTG concentrations in patients with epilepsy.