Daiki Hira

Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment

The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m2, including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment.

BCRP/ABCG2 and high-alert medications: Biochemical, pharmacokinetic, pharmacogenetic, and clinical implications

ABSTRACT The human breast cancer resistance protein (BCRP/ABCG2) is an ATP‐binding cassette efflux transporter that uses ATP hydrolysis to expel xenobiotics from cells, including anti‐cancer medications. It is expressed in the gastrointestinal tract, liver, kidney, and brain endothelium. Thus, ABCG2 functions as a tissue barrier to drug transport that strongly influences the pharmacokinetics of substrate medications. Genetic polymorphisms of ABCG2 are closely related to inter‐individual variations in therapeutic performance. The common single nucleotide polymorphism c.421C>A, p.Q141K reduces cell surface expression of ABCG2 protein, resulting in lower efflux of substrates. Consequently, a higher plasma concentration of substrate is observed in patients carrying an ABCG2 c.421C>A allele. Detailed pharmacokinetic analyses have revealed that altered intestinal absorption is responsible for the distinct pharmacokinetics of ABCG2 substrates in genetic carriers of the ABCG2 c.421C>A polymorphism. Recent studies have focused on the high‐alert medications among ABCG2 substrates (defined as those with high risk of adverse events), such as tyrosine kinase inhibitors (TKIs) and direct oral anti‐coagulants (DOACs). For these high‐alert medications, inter‐individual variation may be closely related to the severity of side effects. In addition, ethnic differences in the frequency of ABCG2 c.421C>A have been reported, with markedly higher frequency in East Asian (˜30–60%) than Caucasian and African‐American populations (˜5–10%). Therefore, ABCG2 polymorphisms must be considered not only in the drug development phase, but also in clinical practice. In the present review, we provide an update of basic and clinical knowledge on genetic polymorphisms of ABCG2.

Impact of abcb1 , abcg2 , and cyp3a5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation

Objectives During anticoagulant therapy, major bleeding is one of the most severe adverse effects. This study aimed to evaluate the relationships between ABCB1, ABCG2, and CYP3A5 polymorphisms and plasma trough concentrations of apixaban, a direct inhibitor of coagulation factor X. Patients and methods A total of 70 plasma concentrations of apixaban from 44 Japanese patients with atrial fibrillation were analyzed. In these analyses, the plasma trough concentration/dose (C/D) ratio of apixaban was used as a pharmacokinetic index and all data were stratified according to the presence of ABCB1 (ABCB1 1236C>T, 2677G>T/A, and 3435C>T), ABCG2 (ABCG2 421C>A), and CYP3A5 (CYP3A5*3) polymorphisms. Influences of various clinical laboratory parameters (age, serum creatinine, estimated glomerular filtration rate, aspartate amino transferase, and alanine amino transferase) on the plasma trough C/D ratio of apixaban were included in analyses. Results Although no ABCB1 polymorphisms affected the plasma trough C/D ratio of apixaban, the plasma trough C/D ratio of apixaban was significantly higher in patients with the ABCG2 421A/A genotype than in patients with the ABCG2 421C/C genotype (P<0.01). The plasma trough C/D ratio of apixaban in patients with CYP3A5*1/*3 or *3/*3 genotypes was also significantly higher than that in patients with the CYP3A5*1/*1 genotype (P<0.05). Furthermore, the plasma trough C/D ratio of apixaban decreased with increased estimated glomerular filtration rate. Conclusion These results indicate that ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered potential factors affecting trough concentrations of apixaban.

Opioid analgesics increase incidence of somnolence and dizziness as adverse effects of pregabalin: a retrospective study

BackgroundPregabalin, a gabapentinoid, is an adjuvant analgesic for treatment of neuropathic pain, but it has serious adverse effects such as somnolence and dizziness, particularly in elderly patients. Although decreased renal function is considered to the contributing factor for high frequency of these adverse effects in elder patients, only a few systematic clinical investigations, especially for hospitalized patients, have been performed on factors that might affect the incidence of its adverse effects. In this study, we performed a retrospective study on the effect of concomitant drugs on induction of somnolence and dizziness as adverse effects of pregabalin in hospitalized patients.MethodsThe subjects were all pregabalin-administered patients in Shiga University of Medical Science Hospital from September 2010 to September 2012, and the subject number was 195. Multivariate logistic regression analysis was performed to determine predictors of the adverse effects, creatinine clearance, duration of pregabalin therapy, initial and maintenance doses of pregabalin, and concomitant drugs, including hypoglycemic drugs, anti-hypertensive ones, non-steroidal anti-inflammatory ones, opioids and central nervous system depressants, being used as independent variables.ResultsThe median initial doses of pregabalin in each renal function group were the same with the case of the defined dose. Although renal function is a well-known factor for prediction of development of adverse effects of pregabalin, we did not detect significant contribution of it. Alternatively, it was demonstrated that concomitant administration of opioids was the significant factor of the incidence of somnolence and dizziness. The first onset date of the adverse effects was frequently detected in the early days of the pregabalin therapy.ConclusionsThe fine tuning of pregabalin dosage schedule based on the renal function appeared to be critical for prevention of development of its adverse effects. Adverse effects tended to develop in the initial phase of pregabalin therapy. Concomitant administration of opioids with pregabalin has the potential to increase the incidence of adverse effects, and thus much more careful attention has to be paid especially in those situations.

In Vitro Evaluation of Optimal Inhalation Flow Patterns for Commercial Dry Powder Inhalers and Pressurized Metered Dose Inhalers With Human Inhalation Flow Pattern Simulator

This study aimed at developing a novel analytical method to identify optimal inhalation flow patterns for commercial dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs). As typical commercial DPI and pMDI, Pulmicort® Turbuhaler®, and Sultanol® Inhaler were evaluated by an in vitro inhalation performance testing system with a flow pattern simulator. An 8-stage Andersen cascade impactor (ACI) or twin stage liquid impinger (TSLI) was applied to determine the inhalation performance. The peak flow rate (PFR) of the inhalation flow pattern was set from 15 to 80 L/min in reference to our previous study. From TSLI test results, a higher PFR improved the inhalation performance of the DPI, while the performance of the pMDI was less affected by the PFR. Conversely, from ACI test results, the pMDI performance decreased with a higher PFR, while the DPI followed a similar pattern as in the TSLI test results, because ACI is a finer aerodynamic classification apparatus than TSLI. These results suggested that our in vitro system using a human inhalation flow pattern simulator successfully detected different optimal inhalation patterns between DPI and pMDI. That is, the higher PFR is better for Pulmicort® Turbuhaler® (DPI). Conversely, lower PFR is desirable for Sultanol® Inhaler (pMDI).

A Systematic Review Of Salivary Versus Blood Concentrations Of Anti-Tuberculosis Drugs And Their Potential For Salivary Therapeutic Drug Monitoring

Background: Therapeutic drug monitoring is useful in the treatment of tuberculosis to assure adequate exposure, minimize antibiotic resistance, and reduce toxicity. Salivary therapeutic drug monitoring could reduce the risks, burden, and costs of blood-based therapeutic drug monitoring. This systematic review compared human pharmacokinetics of antituberculosis drugs in saliva and blood to determine if salivary therapeutic drug monitoring could be a promising alternative. Methods: On December 2, 2016, PubMed and the Institute for Scientific Information Web of Knowledge were searched for pharmacokinetic studies reporting human salivary and blood concentrations of antituberculosis drugs. Data on study population, study design, analytical method, salivary Cmax, salivary area under the time–concentration curve, plasma/serum Cmax, plasma/serum area under the time–concentration curve, and saliva–plasma or saliva–serum ratio were extracted. All included articles were assessed for risk of bias. Results: In total, 42 studies were included in this systematic review. For the majority of antituberculosis drugs, including the first-line drugs ethambutol and pyrazinamide, no pharmacokinetic studies in saliva were found. For amikacin, pharmacokinetic studies without saliva–plasma or saliva–serum ratios were found. Conclusions: For gatifloxacin and linezolid, salivary therapeutic drug monitoring is likely possible due to a narrow range of saliva–plasma and saliva–serum ratios. For isoniazid, rifampicin, moxifloxacin, ofloxacin, and clarithromycin, salivary therapeutic drug monitoring might be possible; however, a large variability in saliva–plasma and saliva–serum ratios was observed. Unfortunately, salivary therapeutic drug monitoring is probably not possible for doripenem and amoxicillin/clavulanate, as a result of very low salivary drug concentrations.

Pharmacokinetic Analysis of a Hemodialyzed Patient Treated With Pazopanib

Pazopanib, an oral multitargeted tyrosine inhibitor, is approved for the treatment of advanced and/or metastatic renal cell carcinoma (RCC) as the first-line treatment. However, no information is available regarding the dosage adjustment of pazopanib for patients undergoing hemodialysis. Therefore, evaluation of the influence of dialysis treatment on pazopanib pharmacokinetics is needed. We examined the effects of hemodialysis on the pharmacokinetics of pazopanib in a patient with RCC. The patient was a 70-year-old man diagnosed with RCC and undergoing hemodialysis. The patient was treated with pazopanib 400 mg daily. On day 3, pazopanib was discontinued due to hepatic dysfunction. Ten days after the cessation of pazopanib (day 13), he was re-challenged with pazopanib using a 200 mg alternate-day regimen. On day 7 after the re-challenge (day 20), the serum trough concentration of pazopanib was 2915 ng/mL (target concentration: > 15,000-20,500 ng/mL), and the patient did not show any severe toxicity. Consequently, the pazopanib dosage was increased to 200 mg daily. There was little difference in the area under the concentration-time curve of pazopanib at 200 mg daily between day 34 (off-hemodialysis) and day 35 (on-hemodialysis). The patient developed grade 1 aspartate aminotransferase elevation on day 60, and the pazopanib treatment was discontinued. We show, for the first time, that the pharmacokinetics of pazopanib are rarely affected by hemodialysis, and that dose adjustment is not necessary. However, this case report refers to only 1 patient undergoing hemodialysis, so further studies are needed.

Dry mouth as a novel indicator of hoarseness caused by inhalation therapy

Abstract Objective: To investigate the influence of dry mouth on the incidence and severity of inhalation therapy-induced hoarseness. Methods: The volume of saliva secreted without stimulation was measured in patients with asthma or chronic obstructive pulmonary disease (COPD) who also answered a questionnaire on subjective ratings for hoarseness. The relationship between salivary secretion and hoarseness was analyzed by the Pearson correlation and multiple linear regression. The prediction accuracy of salivary secretion for the grade of hoarseness was evaluated using a receiver-operating characteristic (ROC) analysis. Results: A total of 232 patients participated in this study. The subjective rating score of hoarseness was negatively correlated with the volume of saliva secreted (r = −0.273, p < 0.001). A stepwise multiple linear regression analysis revealed that salivary secretion (p < 0.001) and the dose of fluticasone administered (p < 0.05) were significant variables for predicting hoarseness. The ROC analysis for predicting severe hoarseness by salivary secretion showed significant prediction accuracy (AUC = 0.690, 95% CI: 0.614–0.766, p < 0.001) and was higher in patients administered fluticasone (AUC = 0.732, 95% CI: 0.644–0.821, p < 0.001). Conclusions: Hyposalivation is a significant prediction factor of hoarseness induced by inhaled corticosteroids (ICS). The prediction accuracy was higher in patients administered fluticasone than in those administered another inhalation drug. Although the pharmaceutical efficacy of fluticasone is high, patients with hyposalivation should be prescribed other inhalation drugs.

Quantification of Sorafenib in Human Serum by Competitive Enzyme-Linked Immunosorbent Assay

The multikinase inhibitor sorafenib has been used in the treatment of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. Here we have demonstrated the production of the first specific antibody against sorafenib. Anti-sorafenib serum was obtained by immunizing mice with an antigen conjugated with bovine serum albumin and carboxylic modified 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (AMPC) using the N-succinimidyl ester method. Enzyme labeling of sorafenib with horseradish peroxidase was similarly performed using carboxylic modified AMPC. A simple competitive enzyme-linked immunosorbent assay (ELISA) for sorafenib was developed using the principle of direct competition between sorafenib and the enzyme marker for anti-sorafenib antibody, which had been adsorbed by the plastic surface of a microtiter plate. Serum sorafenib concentrations lower than 0.04 µg/mL were reproducibly measurable using the ELISA. This ELISA was specific to sorafenib and showed very slight cross-reactivity (2.5%) with a major metabolite, sorafenib N-oxide. The values of serum sorafenib levels from 32 patients measured by this ELISA were comparable with those measured by HPLC, and there was a strong correlation between the values determined by the two methods (Y=1.016X-0.137, r=0.979). The specificity and sensitivity of the ELISA for sorafenib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of sorafenib.

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation

This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban.