Factors Influencing Serum Posaconazole Concentrations in Patients with Hematologic Malignancies Receiving Delayed-Release Tablets.

BACKGROUND: Posaconazole (PCZ) plays a crucial role in the prophylaxis and treatment of invasive fungal infections in hematologic malignancies. PCZ concentrations reportedly vary among patients receiving delayed-release tablets (DRT). However, the factors influencing these concentrations remain insufficiently elucidated. Therefore, this study aimed to evaluate the factors influencing PCZ concentrations and their effect on the probability of target attainment (PTA) using a population pharmacokinetic (PPK) approach. We also explored the relationship between PCZ exposure and hepatotoxicity. METHODS: This retrospective study included adult patients with hematologic malignancies who received PCZ DRT. A PPK model was developed based on observational data for 130 concentrations in 28 patients. Simulation analyses were performed to assess the PTA at standard doses of 0.7 and 1.0 mg/L for prophylaxis and treatment, respectively. Estimated concentrations were used to evaluate the correlation between PCZ exposure and hepatotoxicity. RESULTS: Significant factors influencing PCZ concentrations included body weight, serum total protein levels, and diarrhea. Diarrhea correlated with decreased PCZ concentrations resulting in up to 26% lower PTA compared with that without diarrhea. Moreover, PTA declined markedly as the total protein levels decreased from 6.6 g/dL to 4.4 g/dL. The incidence of hepatotoxicity was 17.4% (4/23); no significant relationship could be established between the PCZ concentrations and hepatotoxicity (P = 0.188). CONCLUSIONS: We identified the factors affecting PCZ exposure, which could not be detected by PPK analysis using data from clinical trials. Our results suggest that the generally recommended dose of PCZ causes underexposure in patients with hematologic malignancies characterized by high body weight, hypoproteinemia, or concurrent diarrhea. Therapeutic drug monitoring for DRT may be recommended, especially in patients with these risk factors.

Risk Factors of Cetuximab-Induced Hypomagnesemia and the Effect of Magnesium Prophylaxis in Patients with Head and Neck Cancer: A Retrospective Study.

Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78-20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52-19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.

Isoniazid level and flu-like symptoms during rifapentine-based tuberculosis preventive therapy: A population pharmacokinetic analysis.

AIM: A population pharmacokinetic (PPK) study of the correlation of adverse drug reactions (ADRs) with the 3HP regimen (weekly high-dose rifapentine plus isoniazid for 12 doses) for latent tuberculosis infection (LTBI) remains lacking. The purpose of this study is to determine the association of rifapentine or isoniazid concentration and ADRs. METHODS: This prospective, multicentre, observational study enrolled LTBI contacts receiving 3HP treatment between January 2017 and August 2020. The concentrations of rifapentine, isoniazid and their metabolites (25-desacetyl-rifapentine and acetyl-isoniazid) in plasma samples collected monthly after 3HP treatment were determined. A PPK model was constructed to predict the maximum concentration (Cmax ) and area under the concentration-time curve from 0 to 24 h (AUC). Their association with ADRs was evaluated by applying three multivariate logistic regression models with adjustment for various covariates. RESULTS: A total of 415 LTBI cases were ultimately enrolled; 355 (85.5%) completed the 3HP treatment. Among them, 47 (11.3%) experienced systemic drug reactions and 291 (70.0%) experienced one or more flu-like symptom. The plasma concentration-time profiles of isoniazid, rifapentine and their metabolites were adequately described by the developed models. A higher Cmax of isoniazid was significantly correlated with a higher risk of any ADR (adjusted odds ratio and 95% confidence interval: 3.04 [1.07-8.65]) and any or at least two flu-like symptoms (all severity grades) (2.76 [1.06-7.17]). CONCLUSIONS: Isoniazid may be responsible for ADRs, especially flu-like symptoms, during 3HP treatment.

Population Pharmacokinetic Analysis of Drug-Drug Interactions Between Perampanel and Carbamazepine Using Enzyme Induction Model in Epileptic Patients.

BACKGROUND: Perampanel (PER) is an oral antiepileptic drug and its concomitant use with carbamazepine (CBZ) leads to decreased PER concentrations. However, the magnitude of its influence may vary, depending on the dynamics of the enzyme induction properties of CBZ. This study aimed to develop a population pharmacokinetic (PPK) model considering the dynamics of enzyme induction and evaluate the effect of CBZ on PER pharmacokinetics. METHODS: We retrospectively collected data on patient background, laboratory tests, and prescribed drugs from electronic medical records. We developed 2 PPK models incorporating the effect of CBZ-mediated enzyme induction to describe time-concentration profiles of PER using the following different approaches: (1) treating the concomitant use of CBZ as a categorical covariate (empirical PPK model) and (2) incorporating the time-course of changes in the amount of enzyme by CBZ-mediated induction (semimechanistic PPK model). The bias and precision of the predictions were investigated by calculating the mean error, mean absolute error, and root mean squared error. RESULTS: A total of 133 PER concentrations from 64 patients were available for PPK modelling. PPK analyses showed that the co-administration of CBZ increased the clearance of PER. Goodness-of-fit plots indicated a favorable description of the observed data and low bias. The mean error, mean absolute error, and root mean square error values based on the semimechanistic model were smaller than those obtained using the empirical PPK model for predicting PER concentrations in patients with CBZ. CONCLUSIONS: We developed 2 PPK models to describe PER pharmacokinetics based on different approaches, using electronic medical record data. Our PPK models support the use of PER in clinical practice.

Population pharmacokinetic model and dosing optimization of vancomycin in hematologic malignancies with neutropenia and augmented renal clearance.

AIM: Data on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies. METHODS: A retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC0-24 of 400-600 mg h/L at the steady-state. RESULTS: The VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients. CONCLUSION: AML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended.

Systematic surveillance of immune-related adverse events in clinical practice and impact of subsequent steroid medication on survival outcomes.

BACKGROUND: Recent advances in immune-checkpoint inhibitors (ICIs) have highlighted the need for effective management of immune-related adverse events (irAEs). This study aimed to conduct a systematic surveillance of real-world development of irAEs for understanding their characteristics and examine the prognostic impact of steroid use for these events. METHODS: We retrospectively investigated cancer patients treated with ICIs between 2014 and 2021 and collected information about irAEs throughout their development, management, and clinical outcomes. RESULTS: Overall, 458 patients (45.4%) developed 670 irAEs. The prevalence of irAEs varied by cancer type, but it was increased in regimens with longer treatment durations. Severe irAEs were more common in the nivolumab + ipilimumab and pembrolizumab + axitinib regimens. Patients who received steroids for irAEs at a dosage of < 2 mg/kg had comparable prognosis to those who did not receive steroids; however, patients who received methylprednisolone pulse therapy, primarily for severe pneumonitis and hepatitis, had shorter overall survival than those who did not receive steroids (7.8 versus 23.4 months, p = 0.016). Furthermore, methylprednisolone pulse therapy for irAEs was a poor prognostic factor in multivariate analysis (hazard ratio: 2.19, 95% confidence interval: 1.34-2.86, p < 0.001). CONCLUSION: Steroid treatment for irAE does not affect prognosis and should thus be used promptly to control inflammation. However, pulse therapy for severe cases is a poor prognostic factor, and early detection remains the key to managing such irAEs. The irAE characteristics in each regimen should be clarified to establish and provide more sophisticated irAE management, and the current findings will be beneficial to this goal.

Neuroprotective effects of ibudilast against tacrolimus induced neurotoxicity.

Neurotoxicity is one of the major side effects caused by calcineurin inhibitors such as tacrolimus in clinical practice. The underlying mechanisms remain unclear, and no potential protective agents have been identified yet. Here, we aimed to investigate tacrolimus-induced neurotoxicity and assess the protective effects of ibudilast, a nonselective phosphodiesterase inhibitor with neuroprotective effects, against tacrolimus-induced neurotoxicity. An in vitro assay of human neuroblastoma SH-SY5Y cells showed that ibudilast reduced tacrolimus-induced cell death. Subsequently, using in vivo studies, we assessed the pathological mechanism of neurotoxicity and evaluated the protective effect of ibudilast. Wistar rats were subcutaneously administered tacrolimus (2.5 or 5.0 mg/kg/day) for 14 d, and ibudilast (7.5 mg/kg/day) was intraperitoneally administered once a day beginning 2 d prior to tacrolimus (5 mg/kg/day) administration. We observed that ibudilast significantly reduced the tacrolimus-induced neurotoxic events. From the assessment of excised brains, we found that tacrolimus was penetrated to brain and the brain concentration was correlated with the neurotoxicity-score, although ibudilast had no effect on this pharmacokinetics. Tacrolimus-induced neuronal damage was histopathologically evaluated using Nissl and TUNEL staining, where only the cerebral cortex and CA1 region in hippocampus exhibited neuronal death, but not the CA3 region, dendrite gyrus, and cerebellum. Co-administration of ibudilast significantly attenuated these histopathological changes. In conclusion, these results suggest that tacrolimus translocation into the brain and neuronal damage in the cerebral cortex and CA1 are the underlying mechanisms of tacrolimus-induced neurotoxicity and that ibudilast could be a protective agent against this adverse event.

Effect of liver cirrhosis on theophylline trough concentrations: A comparative analysis of organ impairment using Child-Pugh and MELD scores.

AIMS: Theophylline clearance is known to be reduced in patients with chronic liver diseases (CLDs) such as chronic hepatitis (CH) and liver cirrhosis (LC). The Child-Pugh (CP) score is generally used for pharmacokinetic evaluation, whilst a model for end-stage liver disease (MELD) has not yet been fully evaluated. This study aimed to predict theophylline clearance in patients with LC classified based on CP and MELD scores by population pharmacokinetic (PPK) analysis. METHODS: PPK analysis included 433 steady-state trough concentrations from 192 Japanese bronchial asthma patients with and without CLDs and was performed using NONMEM. The severity of LC was assessed by CP and MELD scores. RESULTS: The final CP and MELD models which described apparent theophylline clearance (CL/F) were obtained. The CP model showed that the mean CL/F in patients without CLDs, CH patients and LC patients with CP class A, B and C was 0.0473, 0.0413, 0.0330, 0.0280 and 0.0209 L/h kg-1 , respectively. The MELD model predicted that CL/F in patients without CLDs, CH patients and LC patients with MELD scores of <10, 10-14, 15-19, 20-24 and ≥25 was 0.0472, 0.0413, 0.0324, 0.0268, 0.0230, 0.0197 and 0.0155 L/h kg-1 , respectively. CONCLUSIONS: CL/F in various stages of LC was evaluated, and a change in CL/F was highly dependent on the severity of CLDs in both models. The MELD model provided a more accurate and precise description of theophylline clearance in LC than the CP model, which may be due to the wider dynamic range of the MELD score.

Optimal Teicoplanin Dosing Regimen in Neonates and Children Developed by Leveraging Real-World Clinical Information.

BACKGROUND: Teicoplanin is a glycopeptide antibiotic used for the treatment of methicillin-resistant Staphylococcus aureus infections. To ensure successful target attainment, therapeutic drug monitoring-informed dosage adjustment is recommended. However, it relies on the experience of the clinician and the frequency of drug measurements. This study aimed to design a new optimal dosing regimen of teicoplanin with a maintenance dosing strategy for neonates and children based on their physiological characteristics. METHODS: Data from teicoplanin-treated patients (n = 214) were collected from electronic medical records. Covariate analyses were performed using population pharmacokinetic (PK) modeling with 399 serum teicoplanin concentrations from 48 neonates and 166 children. Multiple PK simulations were conducted to explore optimal dosing regimens that would allow control of the trough concentration to the target of 15-30 mg/L quicker than the current standard regimen. RESULTS: Allometrically scaled body weight, postmenstrual age (PMA), renal function, and serum albumin were implemented as substantial covariates for teicoplanin clearance in a two-compartment PK model. Covariate analyses and comprehensive simulation assessments recommended the following modifications to the current regimen: (1) decreased dose for premature babies (PMA ≤28 weeks), (2) decreased dose for children with renal dysfunction, and (3) increased dose for children (0.5-11 years) with an estimated glomerular filtration rate of ≥90 mL/min/1.73 m2. CONCLUSIONS: This study leverages real-world clinical information and proposes new optimal dosing regimens for teicoplanin in neonates and children through PK modeling and simulation analyses, taking into account the age, including PMA, and renal function of patients.

Development and Validation of A Liquid Chromatography-Tandem Mass Spectrometry Method to Simultaneously Measure Tacrolimus and Everolimus Concentrations in Kidney Allograft Biopsies After Kidney Transplantation.

BACKGROUND: Therapeutic drug monitoring is necessary for immunosuppressive therapy with tacrolimus and everolimus after kidney transplantation. Several studies have suggested that the concentrations of immunosuppressive agents in allografts may better reflect clinical outcomes than whole blood concentrations. This study aimed to develop a method for the simultaneous quantification of tacrolimus and everolimus concentrations in clinical biopsy samples and investigate their correlation with histopathological findings in kidney transplant recipients. METHODS: Fourteen biopsy samples were obtained from kidney transplant recipients at 3 months after transplantation. Kidney allograft concentrations (Ctissue) of tacrolimus and everolimus were measured by liquid chromatography-tandem mass spectrometry, and the corresponding whole blood trough concentrations (C0) were obtained from clinical records. RESULTS: The developed method was validated over a concentration range of 0.02-2.0 ng/mL for tacrolimus and 0.04-4.0 ng/mL for everolimus in kidney tissue homogenate. The Ctissue of tacrolimus and everolimus in kidney biopsies ranged from 21.0 to 86.7 pg/mg tissue and 33.5-105.0 pg/mg tissue, respectively. Dose-adjusted Ctissue of tacrolimus and everolimus was significantly correlated with the dose-adjusted C0 (P < 0.0001 and P = 0.0479, respectively). No significant association was observed between the Ctissue of tacrolimus and everolimus and the histopathologic outcomes at 3 months after transplantation. CONCLUSIONS: This method could support further investigation of the clinical relevance of tacrolimus and everolimus allograft concentrations after kidney transplantation.

Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients With FLT3 Mutation-Positive Acute Myelogenous Leukemia.

BACKGROUND: Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography-tandem mass spectrometry. METHODS: Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 µm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode. RESULTS: The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10-1000 ng/mL, r 2 > 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias -4.2% to 1.9%), precision (intraday CV ≤ 7.9%; interday CV ≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML. CONCLUSIONS: The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.

Risk Factors for Gemcitabine-Induced Vascular Pain in Patients With Pancreatic Cancer.

BACKGROUND: Peripheral intravenous injection of gemcitabine often causes vascular pain; however, preventive measures have not yet been established. OBJECTIVES: This study focused on identifying predictive factors for gemcitabine-induced vascular pain. METHODS: We retrospectively analyzed risk factors for developing vascular pain in patients with pancreatic cancer receiving gemcitabine infusions at our institution. Infusions were divided into groups according to presence or absence of vascular pain symptoms, and variables were compared. Odds ratios for risk factors were calculated using logistic regression analyses. RESULTS: Overall, 272 patients with pancreatic cancer were subjected to 725 gemcitabine infusions, and of these, 18.4% (n = 50) experienced vascular pain. There were significant differences in the gemcitabine dose (P = 0.025), dose of gemcitabine/body surface area (BSA; P = 0.004), concentration of gemcitabine (P = 0.025), and hot pack use (P = 0.011) between the vascular pain and no vascular pain groups. Multivariable analyses indicated that gemcitabine dose/BSA and lack of hot pack use were risk factors for developing vascular pain. Moreover, on administration of a higher dosage (>930 mg/m2), the incidence of vascular pain in patients using a hot pack (6.7%) was significantly lower than that in patients not provided a hot pack (16.2%). CONCLUSIONS AND RELEVANCE: High gemcitabine dosages and lack of hot pack use were predictive factors for gemcitabine-induced vascular pain in patients with pancreatic cancer. Patients receiving gemcitabine treatment should apply a hot pack to the injection site. Scrupulous clinical attention is required for patients presenting with these risk factors to improve pain management.

Development and Full Validation of a Bioanalytical Method for Quantifying Letermovir in Human Plasma Using Ultra-Performance Liquid Chromatography Coupled with Mass Spectrometry.

With the aim of studying the pharmacokinetics of letermovir, which is a newly developed antiviral agent for human cytomegalovirus, a rapid and simple ultra-performance liquid chromatography coupled with mass spectrometry (UPLC/MS) method was developed and validated for the quantification of letermovir in human plasma. Separation was performed in reverse phase mode using an ACQUITY UPLC BEH C18 column (130 Å, 1.7 µm, 2.1 × 50 mm) at a flow rate of 0.3 mL/min, 10 mM ammonium acetate-0.1% formic acid solution as mobile phase A, and acetonitrile as mobile phase B with a gradient elution. The method was validated over a linear range of 10-1000 ng/mL with a coefficient of determination (R2) >0.99 using weighted linear regression analysis. The intra- and inter-assay accuracy (nominal%) and precision (relative standard deviation%) were within ±15 and ≤15%, respectively. The specificity, recovery, matrix effect, stability, and dilution integrity of this method were also within acceptable limits. This method could be useful in studying the pharmacokinetics and pharmacodynamics, as well as performing the therapeutic drug monitoring of letermovir.

Regulation of Organic Anion Transporting Polypeptide 2B1 Expression by MicroRNA in the Human Liver.

Organic anion transporting polypeptide 2B1 (OATP2B1, SLCO2B1) is an uptake transporter expressed in several tissues, including the liver, intestine, brain, kidney, and skeletal muscle. Hepatocyte nuclear factor 4 alpha (HNF4α) is known as an important transcriptional factor of OATP2B1 in the liver. It has been reported that there are large interindividual differences in OATP2B1 mRNA and protein expressions in human livers. The mechanism causing the interindividual differences in OATP2B1 expression is still unclear. MicroRNAs (miRNAs) control gene expression by leading translational repression and/or degradation of the target mRNA. There is no significant correlation between OATP2B1 mRNA and protein expression, suggesting that post-transcriptional regulating mechanisms, such as miRNAs, play an important role in the interindividual differences in OATP2B1 expression. In this study, we hypothesized that certain miRNAs cause the interindividual differences in OATP2B1 expression in the human liver. In silico analysis showed that miR-24 was a candidate miRNA regulating OATP2B1 expression. It has been reported that miR-24 degrades HNF4α mRNA expression. We revealed that the miR-24 expression level was negatively correlated with OATP2B1 mRNA, protein, and HNF4α mRNA expression levels in human livers. Transfection by the miR-24 precursor decreased the luciferase activity in the transfected cells with the vector containing the OATP2B1 3' untranslated region (3'UTR) or SLCO2B1 promoter region. In HepaRG cells, miR-24 decreased the OATP2B1 and HNF4α expression levels. These results suggest that miR-24 represses not only the translation of OATP2B1 but also the transcription of OATP2B1 by HNF4α mRNA degradation.

Differences in Theophylline Clearance Between Patients With Chronic Hepatitis and Those With Liver Cirrhosis.

BACKGROUND: Theophylline, a xanthine derivative drug, is used for the treatment of respiratory diseases, such as asthma, and is primarily eliminated by hepatic metabolism. There is marked interindividual variability in theophylline clearance. Therefore, the aim of this study was to evaluate the influence of chronic hepatitis (CH), liver cirrhosis (LC), and other covariates on theophylline clearance by population pharmacokinetic (PPK) analysis. METHODS: The authors retrospectively obtained 496 trough concentrations of theophylline at steady state from 226 adult patients with bronchial asthma. The liver functions of the patients were classified into 3 categories: normal hepatic function, CH, and LC. The PPK analysis was performed using the NONMEM program. CH, LC, age, smoking status, coadministration of clarithromycin (CAM), and sex were considered as covariates that affected theophylline clearance. RESULTS: Theophylline clearance (CL/F per kg) was significantly influenced by CH, LC, smoking, and CAM. The final model of theophylline clearance was as follows: CL/F (L/h·kg) = 0.0484 × 1.40 × 0.861 × 0.889 × 0.557. Smoking is a well-known factor that markedly enhances CL/F through the induction of CYP1A enzymes, whereas CAM has been reported to inhibit CYP3A4. The final model for hepatic function showed that CL/F in CH and LC patients was 0.043 and 0.027 L/h/kg, respectively, and it was lower than that in patients with normal hepatic function. As theophylline clearance depends on intrinsic hepatic clearance, lower CL/F in patients with LC than in those with CH may be due to a decrease in the metabolic enzymatic capability of LC patients. CONCLUSIONS: Differences exist in theophylline clearance between CH and LC patients as per the PPK analysis.

Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy.

Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy.

Elucidation of N 1-methyladenosine as a Potential Surrogate Biomarker for Drug Interaction Studies Involving Renal Organic Cation Transporters.

Endogenous substrates are emerging biomarkers for drug transporters, which serve as surrogate probes in drug-drug interaction (DDI) studies. In this study, the results of metabolome analysis using wild-type and Oct1/2 double knockout mice suggested that N 1-methyladenosine (m1A) was a novel organic cation transporter (OCT) 2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2, and multidrug and toxin exclusion protein (MATE) 2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 ± 4.9 ml/min per kilogram) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 ± 2.6 and 24.3 ± 0.6 ml/min per kilogram, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of 7-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid in cynomolgus monkeys resulted in the elevation of the area under the curve of m1A (1.72-fold) as well as metformin (2.18-fold). The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. The renal clearance of m1A in younger (21-45 year old) and older (65-79 year old) volunteers (244 ± 58 and 169 ± 22 ml/min per kilogram, respectively) was about 2-fold higher than the creatinine clearance. The renal clearances of m1A and creatinine were 31% and 17% smaller in older than in younger volunteers. Thus, m1A could be a surrogate probe for the evaluation of DDIs involving OCT2/MATE2-K. SIGNIFICANCE STATEMENT: Endogenous substrates can serve as surrogate probes for clinical drug-drug interaction studies involving drug transporters or enzymes. In this study, m1A was found to be a novel substrate of renal cationic drug transporters OCT2 and MATE2-K. N 1-methyladenosine was revealed to have some advantages compared to other OCT2/MATE substrates (creatinine and N 1-methylnicotinamide). The genetic or chemical impairment of OCT2 or MATE2-K caused a significant increase in the plasma m1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. Thus, m1A could be a better biomarker of variations in OCT2/MATE2-K activity caused by inhibitory drugs.

Efficacy of DPP-4 inhibitors, GLP-1 analogues, and SGLT2 inhibitors as add-ons to metformin monotherapy in T2DM patients: a model-based meta-analysis.

AIMS: The aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add-on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model-based meta-analysis (MBMA). METHODS: A systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)- and haemoglobin A1c (HbA1c)-lowering effects of three antidiabetic classes using NONMEM 7.3.0. RESULTS: Seventy-six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add-on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (-22.5 and -16.6%), liraglutide (-22.1 and -16.3%), and dulaglutide (-19.3 and -14.3%). The hypoglycaemic effects of DPP-4i and SGLT2i were similar. CONCLUSIONS: Once weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long-acting GLP-1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy.

Population Pharmacokinetic Analysis of Phenytoin After Intravenous Administration of Fosphenytoin in Adult and Elderly Epileptic Patients.

BACKGROUND: Fosphenytoin, the diphosphate ester salt of phenytoin, is widely used to treat status epilepticus. The aim of this study was to develop a population pharmacokinetic (PPK) model to describe serum phenytoin concentrations after the intravenous administration of fosphenytoin in adult and elderly epileptic patients. METHODS: Patient backgrounds, laboratory tests, and prescribed drugs were retrospectively collected from electronic medical records. Patients who received fosphenytoin were enrolled. The PPK analysis was performed using NONMEM 7.3.0 with the first-order conditional estimation method with interaction. Age, sex, laboratory tests, and coadministered drugs were selected as candidates for covariates. Significance levels for forward inclusion and backward elimination were set at 0.05 and 0.01, respectively. The study protocol was approved by the Fukuoka Tokushukai Ethics Committee. RESULTS: A total of 340 serum phenytoin concentrations from 200 patients treated with fosphenytoin were available. The median age and body weight of the population were 71 years and 53.4 kg, respectively. A linear 1-compartment model with the conversion rate of fosphenytoin to phenytoin clearly described the pharmacokinetics of phenytoin after the intravenous administration of fosphenytoin. Age was detected as a covariate of clearance (CL): CL (L/h) = 1.99 × (body weight/53.4) × (age/71). Goodness-of-fit plots revealed the high-predictive performance of the final PPK model, and systematic deviations were not observed. The final model was validated by a prediction-corrected visual predictive check and bootstrap analysis. CONCLUSIONS: We herein developed a PPK model to describe phenytoin concentrations after the intravenous administration of fosphenytoin. Age was identified as a significant covariate for CL.

Effects of magnesium oxide on pharmacokinetics of L-dopa/carbidopa and assessment of pharmacodynamic changes by a model-based simulation.

BACKGROUND: Magnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson's disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA). METHODS: The effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa. RESULTS: In vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC0-12 of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa. CONCLUSIONS: This is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required.