Pharmacokinetic evaluation of oxaliplatin combined with S-1 (SOX) chemotherapy in a rat model of colorectal cancer with acute kidney injury: predictive renal biomarkers for dose optimisation.

Dose adjustment based on renal function is essential in S-1, which contains the 5­fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats.AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (sCr) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours.No alterations in the area under the plasma concentration-time curve (AUC0-24h) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The AUC0-24h for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified sCr as a covariate in platinum distribution after SOX chemotherapy.To optimise dose adjustment of SOX chemotherapy in patients with AKI, sCr may be a key factor in determining the appropriate dose.

Comparing the pharmacokinetics and organ/tissue distribution of anti-methicillin-resistant Staphylococcus aureus agents using a rat model of sepsis.

Sepsis is a major cause of death, and sepsis-derived physiological changes complicate the understanding of drug distribution in organs/tissues, which determines the efficacy and toxicity of antimicrobial agents. In this study, we evaluated and compared the pharmacokinetics of methicillin-resistant Staphylococcus aureus treatment agents in sepsis with that of vancomycin, arbekacin, linezolid, and daptomycin.Rat models of sepsis were prepared using caecal ligation puncture. The pharmacokinetics of vancomycin, arbekacin, linezolid, and daptomycin were evaluated using their drug concentration profiles in plasma, kidneys, liver, lungs, skin, and muscles after intravenous administration in normal and septic rats.The kidney/plasma concentration ratio was higher in septic rats than in normal rats for vancomycin, arbekacin, and daptomycin but not for linezolid. The increase in the kidney/plasma concentration ratio for vancomycin was time-dependent, indicating an association between sepsis and stasis of vancomycin in the kidneys. In contrast, the distribution of linezolid from the blood to the organs/tissues in septic rats was comparable to that in normal rats.Sepsis-induced nephrotoxicity results in the stasis of vancomycin in the kidney, suggesting that this exacerbates proximal tubular epithelial cell injury. No dose modification of linezolid may be required for patients with sepsis.

Pharmacokinetics and lung distribution of macrolide antibiotics in sepsis model rats.

Recent studies have shown azithromycin-specific clinical efficacy against macrolide-resistant strains of Streptococcus pneumoniae, despite the low susceptibility of the bacteria in vitro. This discrepancy complicates dosing and selection for treatment of macrolide-resistant strains. Although phagocyte delivery of azithromycin to inflamed tissues is considered a possible factor for clinical efficacy, there is a lack of sufficient evidence, and other pharmacokinetic factors under systemic inflammation may contribute.The concentrations of azithromycin, clarithromycin and erythromycin in the plasma and buffy coat were determined in normal and sepsis model rats. Furthermore, we compared the transport of the drug into the lung.The levels of all three macrolides in the buffy coat were higher than the levels in the plasma, and lower leukocyte counts in plasma were observed in septic rats, suggesting accumulation of the drugs per leukocyte was increased. The concentrations in the lung tissue of septic rats at each sampling time were the same as those in normal rats, and azithromycin-specific long-term stasis in the lung was evident.These results suggest that both the phagocyte delivery and the stasis of azithromycin in the lung could contribute to its clinical efficacy in treating infections caused by macrolide-resistant strains.

Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity.

Capecitabine is a 5-fluorouracil (5-FU) derivative that is used widely in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH2 ) to uracil (Ura) is expected to gain relevance as an indirect-response biomarker to estimate the activity of dihydropyrimidine dehydrogenase (DPD). The latter is a rate-limiting enzyme in the catabolism of 5-FU in the capecitabine-based regimen. However, the relationship between the pharmacokinetics of capecitabine and the plasma UH2 /Ura ratio is still unknown. This study evaluated the time-course alterations of the plasma UH2 /Ura ratio in rats treated with 180 mg/kg capecitabine. The molar ratio tended to increase within 1.5 h (1.85 ± 0.76 at 1.5 h after administration of capecitabine) and gradually recovered to its initial level (1.00 ± 0.46). The results of the current study suggest that the plasma UH2 /Ura ratio temporarily increases following administration of capecitabine, possibly related to the DPD activity levels. The plasma UH2 /Ura ratio might assist in monitoring the alteration of DPD activity levels in capecitabine treatments.

Co-precipitation molecules hemopexin and transferrin may be key molecules for fibrillogenesis in TTR V30M amyloidogenesis.

The disease model of familial amyloidotic polyneuropathy-7.2-hMet30 mice-manifests amyloid deposition that consists of a human amyloidogenic mutant transthyretin (TTR) (TTR V30M). Our previous study found amyloid deposits in 14 of 27 7.2-hMet30 mice at 21-24 months of age. In addition, non-fibrillar TTR deposits were found in amyloid-negative 7.2hMet30 mice. These results suggested that TTR amyloidogenesis required not only mutant TTR but also an additional factor (or factors) as an etiologic molecule. To determine the differences in serum proteome in amyloid-positive and amyloid-negative mice in the 7.2-hMet30 model, we used proteomic analyses and studied serum samples obtained from these mice. Hemopexin (HPX) and transferrin (Tf) were detected in the serum samples from amyloid-positive mice and were also found in amyloid deposits via immunohistochemistry, but serum samples from amyloid-negative mice did not contain HPX and Tf. These two proteins were also not detected in non-fibrillar TTR deposits. In addition, in silico analyses suggested that HPX and Tf facilitate destabilization of TTR secondary structures and misfolding of TTR. These results suggest that HPX and Tf may be associated with TTR amyloidogenesis after fibrillogenesis in vivo.

Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors.

Objectives: In Japan, sodium-glucose co-transporter type 2 (SGLT2) inhibitors have been reported to be associated with serious skin and subcutaneous tissue disorders. A post-marketing surveillance (PMS) study suggested that the association was specific for ipragliflozin and, to a lesser extent for dapagliflozin. These studies were performed to confirm the association of 6 SGLT2 inhibitors with serious skin disorders in a clinical setting, to elucidate the role of melanin in serious skin disorders and to understand the underlying mechanisms. Methods: The latest PMS records were retrieved from the Japanese Adverse Drug Event Report (JADER) database, and the associations were analyzed by data mining techniques. In silico 3-D docking simulation of SGLT2 inhibitors with melanin was performed using the MOE software. The skin tissue distribution of SGLT2 inhibitors was evaluated using albino rats after oral administration at clinical doses. Results: The adjusted reporting odds ratio (95% confidential limit) was 1.667 (1.415, 1.963) for ipragliflozin, 0.514 (0.317, 0.835) for dapagliflozin, 0.149 (0.048, 0.465) for tofogliflozin, 0.624 (0.331, 1.177) for luseogliflozin, 0.590 (0.277, 1.257) for canagliflozin and 0.293 (0.073, 1.187) for empagliflozin, when drugs other than the SGLT2 inhibitors were referred, and the association was detected only for ipragliflozin in clinical use. In silico 3-D docking simulation suggested the influence of melanin in ipragliflozin-specific serious skin disorders. The skin tissue-to-plasma concentration ratio of ipragliflozin was 0.45 ± 0.20 (±SD) at 1 hr after administration and increased in a time-dependent manner to 5.82 ± 3.66 at 24 hr (p<0.05), but not in case of other SGLT2 inhibitors. Conclusions: Serious skin disorders were suggested to be specific for ipragliflozin. Interaction with melanin might be implicated in ipragliflozin-specific serious skin disorders. Ipragliflozin was retained in the skin tissue, which suggested its interaction with the skin tissue in serious skin disorders.

Dissolving Microneedles as Skin Allergy Test Device.

The possibility of using dissolving microneedles (DMs) as a skin allergy test device was studied in rats. Poly-L-arginine was used as a model allergen. Dextran was used to prepare three kinds of DM array chips containing different doses of poly-L-arginine: 17.1±0.5 µg (low-dose DM), 42.2±0.8 µg (medium-dose DM), and 87.4±1.1 µg (high-dose DM); each 1.0 cm2 chip contained 300 DMs. The mean lengths of the low-, medium-, and high-dose DM were 489±3, 485±3, and 492±1 µm and mean diameters of the base were 301±2, 299±1, and 299±2 µm, respectively. Furthermore, for the low-, medium-, and high-dose DM, the administered doses of poly-L-arginine were estimated to be 9.3±1.9, 31.1±1.3, and 61.9±4.7 µg and the scratching behavior per 30 min was 9.8±3.4, 60.4±8.3, and 95.7±10.6 times, respectively. These results demonstrate the dose dependence of the immunoreactivity of the poly-L-arginine DMs, suggesting that DMs can be used an alternative skin allergy device.

Transport of Azithromycin into Extravascular Space in Rats.

Recent clinical trials showed a prolonged retention of subinhibitory concentrations of unbound azithromycin in the interstitial fluid of soft tissues despite the fact that azithromycin is extensively distributed in tissues. In these clinical trials, interstitial fluid samples were obtained by using the microdialysis method, and it was established that drug concentrations represent protein-unbound drug concentrations. The present study was designed to measure total azithromycin concentrations in the interstitial fluid of the skin of rats by directly collecting interstitial fluid samples from a pore formed on the skin by a dissolving microneedle array. The total azithromycin concentrations in interstitial fluid of the skin were about 4 to 5 times higher than those in plasma throughout the experimental period, and stasis of the azithromycin concentration in interstitial fluid was observed when the concentration of azithromycin in plasma was at the lower limit of quantification. In addition, the skin/plasma concentration ratio transiently increased after dosing (from 4.3 to 83.1). Our results suggest that azithromycin was trapped inside white blood cells and/or phagocytic cells in not only blood but also interstitial fluid, resulting in a high total azithromycin concentration and the retention of its antimicrobial activity at the primary infection site. The stasis of azithromycin in interstitial fluid and skin would lead to long-lasting pharmacological effects (including those against skin infection) at concentrations exceeding the MIC.

Therapeutic Drug Monitoring of Vancomycin in Dermal Interstitial Fluid Using Dissolving Microneedles.

OBJECTIVE: To design an alternative painless method for vancomycin (VCM) monitoring by withdrawing interstitial fluid (ISF) the skin using dissolving microneedles (DMNs) and possibly replace the conventional clinical blood sampling method. METHODS: Male Wistar rats were anesthetized with 50 mg/kg sodium pentobarbital. Vancomycin at 5 mg/mL in saline was intravenously administered via the jugular vein. ISF was collected from a formed pore at 15, 30, 45, 60, 75, 90, and 120 min after the DMNs was removed from the skin. In addition, 0.3 mL blood samples were collected from the left femoral vein. RESULTS: The correlation between the plasma and ISF VCM concentrations was significantly strong (r = 0.676, p < 0.05). Microscopic observation of the skin after application of the DMNs demonstrated their safety as a device for sampling ISF. CONCLUSION: A novel monitoring method for VCM was developed to painlessly determine concentrations in the ISF as opposed to blood sampling.

Lower Body Mass Index is a Risk Factor for In-Hospital Mortality of Elderly Japanese Patients Treated with Ampicillin/sulbactam.

Objectives: A retrospective examination was conducted to identify risk factors for in-hospital mortality of elderly patients (65 years or older) treated with the beta-lactam/beta-lactamase inhibitor combination antibiotic, ampicillin/sulbactam (ABPC/SBT). Methods: Clinical data from 96 patients who were hospitalized with infectious diseases and treated with ABPC/SBT (9 g/day or 12 g/day) were analyzed. Risk factors examined included demographic and clinical laboratory parameters. Parameter values prior to treatment and changes after treatment were compared between survivors and non-survivors. Results: The study patients had an average age of 81.9±8.4 years (±SD) and body mass index (BMI) of 19.9±4.2 kg/m2. They were characterized by anemia (low hemoglobin and hematocrit levels), inflammation (high leukocyte count, neutrophil count, C-reactive protein level, and body temperature), and hepatic and renal dysfunction (high aspartate aminotransferase, alanine aminotransferase and blood urea nitrogen levels). The BMI of non-survivors, 16.2±2.9 kg/m2, was lower than that of survivors, 20.4±4.1 kg/m2. In addition, the hematological parameters deteriorated more remarkably, inflammation markers were not altered (or the decrease was marginal), and hepatic function was not improved, in non-survivors. Conclusions: A lower BMI value is a risk factor for in-hospital mortality of elderly patients treated with ABPC/SBT.

Population pharmacokinetic modelling and simulation of 5-fluorouracil incorporating a circadian rhythm in rats.

1. The aim of this study was to develop a population pharmacokinetic (PK) model for 5-fluorouracil (5-FU) and perform simulations to identify the circadian rhythm of the PK of 5-FU and the degree of circadian effects on the 5-FU plasma concentrations. 2. 5-FU plasma concentrations in rats following administration of 5-FU at varying time points throughout the day were obtained and used to develop the population PK model incorporating a circadian rhythm. The Cosinor method was used to describe the circadian variation of 5-FU clearance. 3. Our population PK model could successfully characterize the 5-FU disposition and provide reliable PK parameter estimates. The mesor, amplitude and acrophase of Cosinor model were estimated as 1.93 L/h/kg, 0.10 L/h/kg and 2.02 h, respectively. The peak clearance levels were estimated at ∼2 Hours After Light Onset (HALO) and the trough levels at ∼14 HALO. The plasma concentration-time profile of 5-FU after continuous infusion of 5-FU in rats successfully simulated the circadian variation of steady-state plasma concentrations. 4. The population PK model with individual 5-FU plasma concentrations, dose levels and sampling time points could be valuable for estimating area under the curve (AUC) levels and determining individual 5-FU dose management.

A validated LC-MS/MS method for the determination of canagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, in a lower volume of rat plasma: application to pharmacokinetic studies in rats.

Canagliflozin is a novel, orally selective inhibitor of sodium-dependent glucose co-transporter-2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus. In this study, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative analysis of canagliflozin in a lower volume of rat plasma (0.1 mL) was established and applied to a pharmacokinetic study in rats. Following liquid-liquid extraction by tert-butyl methyl ether, chromatographic separation of canagliflozin was performed on a Quicksorb ODS (2.1 mm i.d. × 150 mm, 5 µm size) using acetonitrile-0.1% formic acid (90:10, v/v) as the mobile phase at a flow rate of 0.2 mL/min. The detection was carried out using an API 3200 triple-quadrupole mass spectrometer operating in the positive electrospray ionization mode. Selected ion monitoring transitions of m/z = 462.0 [M + NH4 ](+) → 191.0 for canagliflozin and m/z = 451.2 [M + H](+) → 71.0 for empagliflozin (internal standard) were obtained. The validation of the method was investigated, and it was found to be of sufficient specificity, accuracy and precision. Canagliflozin in rat plasma was stable under the analytical conditions used. This validated method was successfully applied to assess the pharmacokinetics of canagliflozin in rats using 0.1 mL rat plasma. Copyright © 2016 John Wiley & Sons, Ltd.

Antipsychotics-associated serious adverse events in children: an analysis of the FAERS database.

OBJECTIVE: The reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 1997 to 2011 were reviewed to assess serious adverse events induced by the administration of antipsychotics to children. METHODS: Following pre-processing of FAERS data by elimination of duplicated records as well as adjustments to standardize drug names, reports involving haloperidol, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, and aripiprazole were analyzed in children (age 0-12). Signals in the data that signified a drug-associated adverse event were detected via quantitative data mining algorithms. The algorithms applied to this study include the empirical Bayes geometric mean, the reporting odds ratio, the proportional reporting ratio, and the information component of a Bayesian confidence propagation neural network. Neuroleptic malignant syndrome (NMS), QT prolongation, leukopenia, and suicide attempt were focused on as serious adverse events. RESULTS: In regard to NMS, the signal scores for haloperidol and aripiprazole were greater than for other antipsychotics. Significant signals of the QT prolongation adverse event were detected only for ziprasidone and risperidone. With respect to leukopenia, the association with clozapine was noteworthy. In the case of suicide attempt, signals for haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole were detected. CONCLUSIONS: It was suggested that there is a level of diversity in the strength of the association between various first- and second-generation antipsychotics with associated serious adverse events, which possibly lead to fatal outcomes. We recommend that research be continued in order to gather a large variety and quantity of related information, and that both available and newly reported data be placed in the context of multiple medical viewpoints in order to lead to improved levels of care.

Semi-physiological pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats.

1. The aim of this study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model that could characterize the complete time-course of alterations in platelet counts to predict the onset and degree of thrombocytopenia, which severely limits the use of the anticancer agent 5-fluorouracil (5-FU), in rats. 2. Platelet counts were measured in rats following the intravenous administration of various doses of 5-FU for 4 days to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with three compartments for the PD model and 10 structural PK-PD model parameters. 3. After the 5-FU treatment, platelet counts transiently decreased to a nadir level, showed a rebound to above the baseline level before recovering to baseline levels. Nadir platelet counts and rebounds varied with the AUC0-∞ level. The final PK-PD model effectively characterized platelet count data and final PD parameters were estimated with high certainty. 4. This PK-PD model and simulation may represent a valuable tool for quantifying and predicting the complete time-course of alterations in blood cell counts, and could contribute to the development of therapeutic strategies with 5-FU and assessments of various novel anticancer agents that are difficult to examine in humans.

Application of dissolving microneedles to glucose monitoring through dermal interstitial fluid.

Dissolving microneedles (DMs) were applied to glucose monitoring in the dermal interstitial fluid (ISF) of rats and their potential as an alternative blood glucose monitoring device was evaluated. Sodium chondroitin sulfate was used to prepare DM array chips, which consisted of 300 DMs/cm(2). The mean length of the DMs was 475±18 µm and the mean diameter of the basement was 278±8 µm. After DMs were inserted into the skin of the hair-removed rat abdomen, a wet unwoven cloth containing 10-30 µL of water was placed on the skin and ISF was extracted. By increasing the absorbed amount of water on the unwoven cloth from 10 to 30 µL, the extracted amount of glucose increased from 1.66±0.35 µg to 2.75±0.61 µg. Increasing the adhesion time of the wet unwoven cloth to the skin from 0.1 to 5.0 min, increased the amount of ISF glucose from 1.99±0.13 µg to 5.04±0.38 µg. The relation between the amount of glucose in ISF and blood glucose concentrations was examined. With increase in the adhesion time, the coefficient of determination, r(2), increased from 0.501 to 0.750. The number of DMs also affected the relationship and values of the coefficient of determinations, r(2) were: 0.340 (25 DMs), 0.758 (50 DMs), 0.763 (100 DMs), 0.774 (200 DMs), and 0.762 (300 DMs). These results indicate the usefulness of DMs as an alternative blood glucose monitoring device.

Commonality of drug-associated adverse events detected by 4 commonly used data mining algorithms.

OBJECTIVES: Data mining algorithms have been developed for the quantitative detection of drug-associated adverse events (signals) from a large database on spontaneously reported adverse events. In the present study, the commonality of signals detected by 4 commonly used data mining algorithms was examined. METHODS: A total of 2,231,029 reports were retrieved from the public release of the US Food and Drug Administration Adverse Event Reporting System database between 2004 and 2009. The deletion of duplicated submissions and revision of arbitrary drug names resulted in a reduction in the number of reports to 1,644,220. Associations with adverse events were analyzed for 16 unrelated drugs, using the proportional reporting ratio (PRR), reporting odds ratio (ROR), information component (IC), and empirical Bayes geometric mean (EBGM). RESULTS: All EBGM-based signals were included in the PRR-based signals as well as IC- or ROR-based ones, and PRR- and IC-based signals were included in ROR-based ones. The PRR scores of PRR-based signals were significantly larger for 15 of 16 drugs when adverse events were also detected as signals by the EBGM method, as were the IC scores of IC-based signals for all drugs; however, no such effect was observed in the ROR scores of ROR-based signals. CONCLUSIONS: The EBGM method was the most conservative among the 4 methods examined, which suggested its better suitability for pharmacoepidemiological studies. Further examinations should be performed on the reproducibility of clinical observations, especially for EBGM-based signals.

Genetic polymorphisms in SLC23A2 as predictive biomarkers of severe acute toxicities after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma.

OBJECTIVE: Definitive chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is one of the standard therapies for esophageal squamous cell carcinoma (ESCC); however, inter-individual variations in clinical outcomes have yet to be investigated. In the present study, single nucleotide polymorphisms (SNPs) in SLC23A2 gene were retrospectively evaluated in 49 Japanese patients with ESCC who were treated with a definitive 5-FU/CDDP-based CRT, and the predictive values for the clinical response, severe acute toxicities, and long-term survival were assessed. METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course being repeated after a 2-week interval. The SLC23A2 SNPs rs2681116, rs13037458, rs1715364, rs4987219, and rs1110277 were evaluated. RESULTS: The rs2681116 and rs13037458 had a tendency to predict the clinical response (p=0.144 and 0.085, respectively) and long-term survival (p=0.142 and 0.056, respectively). The rs4987219 and rs1110277 correlated with severe acute leukopenia (p=0.025) and stomatitis (p=0.019), respectively. CONCLUSIONS: Further investigations with a larger number of patients or an in vitro study are needed to confirm the predictive values of genetic polymorphisms in SLC23A2.

Serum lactate dehydrogenase levels as a predictive marker of oxaliplatin-induced hypersensitivity reactions in Japanese patients with advanced colorectal cancer.

OBJECTIVE: Clinical laboratory test data obtained prior to treatments were previously analyzed from the standpoint of susceptibility to hypersensitivity reactions in patients treated with the platimun anticancer agent, oxaliplatin (L-OHP). In the present study, the time course from the first to last cycle of the treatment was additionally analyzed to determine a better predictor of these reactions. METHODS: A total of 20 laboratory test data were obtained from 108 Japanese patients with advanced colorectal cancer who were treated with the L-OHP-containing regimens, FOLFOX4 and/or mFOLFOX6. The averages and variation coefficients (CV%) of the data until the last cycle of the treatment were compared between patients with hypersensitivity reactions and those without. RESULTS: The average serum lactate dehydrogenase (LDH) level was lower in patients with grade 1/2 reactions (P=0.016), whereas its CV% value was higher in patients with grade 3/4 reactions (P=0.005) than in those without reactions. An increase in serum LDH levels was observed in some patients with grade 3/4 reactions as the cycle number increased, and thereafter hypersensitivity reactions occurred. This phenomenon was not always observed, but was never detected in patients with grade 1/2 reactions. CONCLUSIONS: Serum LDH levels may be a predictive marker of hypersensitivity reactions in patients treated with L-OHP. Further extensive examinations with a larger number of patients are needed to establish a patient management strategy.

Pharmacokinetic-toxicodynamic Modeling to Elucidate the Involvement of Dorsal Root Ganglion Neuron in Oxaliplatin-induced Peripheral Neuropathy.

BACKGROUND/AIM: Oxaliplatin (L-OHP)-induced peripheral neuropathy (OIPN) limits L-OHP dosage due to nerve cell damage in the dorsal root ganglion (DRG) caused by platinum (Pt). Despite various recommended approaches for OIPN management, no effective approach has been established. The aim of this study was to evaluate Pt distribution into DRG after repeat administrations of L-OHP in rats and to develop a pharmacokinetic-toxicodynamic (PK-TD) model using Pt concentrations in DRG to predict neuropathy severity. MATERIALS AND METHODS: Male Wistar rats were administered L-OHP (3, 5, or 8 mg/kg i.v.) once weekly. Blood and DRG samples were collected following L-OHP administration. For toxicodynamic (TD) study, OIPN was evaluated using the von Frey test. Plasma and DRG Pt concentrations and thresholds values in von Frey test were used for PK-TD modeling using Phoenix WinNonlin® version 8.3 software. RESULTS: Pt concentration in the DRG increased with repeated administration of L-OHP in a dose-dependent manner, indicating Pt accumulation in DRG following multiple administrations. The PK-TD model, consisting of an indirect response model and a transit compartment model with the DRG compartment, adequately described the temporal changes in OIPN with reliable TD parameters (≤36.4% with coefficient of variation). The maximum drug inhibition model could be employed to establish a quantitative correlation between the Pt content present in the DRG and the toxic potency resulting in OIPN. CONCLUSION: The utility of the PK-TD model for predicting neuropathy outcomes was established, suggesting that models composed of the DRG compartment contribute to determining an optimal dosing strategy for reducing OIPN.

Molecular pathology of Sandhoff disease with p.Arg505Gln in HEXB: application of simulation analysis.

Sandhoff disease is a GM2 gangliosidosis caused by mutations in HEXB encoding the ß-subunit of ß-hexosaminidase A. ß-Hexosaminidase A exists as a heterodimer consisting of α- and ß-subunits, and requires a GM2 activator protein to hydrolyze GM2. To investigate the molecular pathology in an adult Sandhoff disease patient with an early disease onset, we performed mutation detection, western blot analysis and molecular simulation analysis. The patient had compound heterozygous mutations p.Arg505Gln and p.Ser341ValfsX30. Western blot analysis showed that the amount of mature form of the α- and ß-subunits was markedly decreased in the patient. We then performed docking simulation analysis of the α- and ß-subunits with p.Arg505Gln, the GM2AP/GM2 complex and ß-hexosaminidase A, and GM2 and ß-hexosaminidase A. Simulation analysis showed that p.Arg505Gln impaired each step of molecular conformation of the α- and ß-subunits heterodimer, the activator protein and GM2. The results indicated that p.Ser341ValfsX30 reduced the amount of ß-subunit, and that p.Arg505Gln hampered the maturation of α- and ß-subunits, and hindered the catalytic ability of ß-hexosaminidase A. In conclusion, various methods including simulation analysis were useful to understand the molecular pathology in Sandhoff disease.