Association between pazopanib exposure and safety in Japanese patients with renal cell carcinoma or soft tissue sarcoma.

The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1-67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.

Optimal Timing of Intravenous Acetaminophen Administration for Postoperative Analgesia.

OBJECTIVE: Acetaminophen (APAP) is widely used as an analgesic for postoperative pain relief. However, the pharmacokinetic-pharmacodynamic (PK-PD) properties of intravenous APAP administration remain unclear. We developed a PK-PD model in adult volunteers. METHODS: APAP (1 g) was intravenously administered to 15 healthy volunteers. The pain equivalent current (PEC) was then measured using the pulse current, corresponding to the quantitative value of pain perception. The PK model was developed using a 2-compartment model, and the PD model was developed using a linear model and an effect compartment model. RESULTS: APAP plasma concentration peaked just administration, whereas PEC significantly increased at 90 minutes and lasted through the experimental period (300 minutes). APAP plasma concentrations and PEC were processed for use in the PK-PD model. The developed PK-PD model delineates the analgesic effect profile, which peaked at 188 minutes and lasted until 327 minutes. CONCLUSION: We developed the PK/PD model for APAP administered intravenously. The analgesic effect can be expected ∼90 minutes after administration and to last >5 hours. It is suggested that APAP be administered ∼90 minutes prior to the onset of anticipated postoperative pain.

Evaluation of in vitro transdermal permeation, mass spectrometric imaging, and in vivo analgesic effects of pregabalin using a pluronic lecithin organogel formulation in mice.

In clinical practice, pregabalin is orally administered for neuropathic pain, but causes severe central nervous system side effects, such as dizziness, which results in dose limitation or discontinuation. To reduce the central side effects of pregabalin, we developed four pregabalin preparations for transdermal application: 0.4% aqueous solution, pluronic lecithin organogel (PLO gel), hydrophilic cream, and lipophilic cream. Transdermal permeabilities of pregabalin among the four formulations were compared in vitro using hairless mouse skin. The longitudinal distribution of pregabalin within the skin was analyzed using mass spectrometric (MS) imaging. Furthermore, the in vivo analgesic effects of the formulations were evaluated using the von Frey filament test in a mouse model of diabetic neuropathy (DN). The PLO gel showed the highest permeability of pregabalin, followed by the aqueous solution, and no permeation was observed in the two cream formulations. The MS imaging analysis showed that pregabalin was distributed up to the dermis in the PLO gel 1 h after application, while the aqueous solution was distributed near the epidermis. A significant analgesic effect (p < .05) was observed 1.5 h after PLO gel application in the DN model mice, but the aqueous solution had no effect. This study indicated for the first time that pregabalin penetrated beyond the skin epidermis up to the dermis, from the PLO gel formulation, and that the application of this formulation exhibited an in vivo analgesic effect in the mouse model of DN.

The selective cytotoxicity of silver thiosulfate, a silver complex, on MCF-7 breast cancer cells through ROS-induced cell death.

BACKGROUND: Silver is a transition metal that is known to be less toxic than platinum. However, only few studies have reported the anticancer effects of some silver complexes and their possibility as an alternative to platinum complex. This study investigated the anticancer effects of the silver thiosulfate complex (STS), [Ag(S2O3)2]3-, consisting of silver and sodium thiosulfate. METHODS: In vitro cytotoxic activity of STS was investigated comparatively in human cancer cell lines (K562 and MCF-7) and normal human cells (mesenchymal stem cells and mammary epithelial cells). For its anticancer effects, cell cycle, mode of cell death, morphological changes, and accumulation of intracellular ROS and GSH were evaluated in MCF-7 to provide mechanistic insights. RESULTS: STS showed a concentration-dependent cytotoxicity in MCF-7 cell, which was abolished by pretreatment with N-acetylcysteine, suggesting ROS accumulation by STS. Moreover, STS caused cell cycle arrest at the G1 phase, decrease in the GSH levels, and morphological changes in MCF-7. Direct measurement of ROS demonstrated the elevation of intracellular ROS accumulation in cancer cells treated with STS; however, neither cytotoxicity nor ROS accumulation was observed in normal human cells. CONCLUSION: The results obtained here are the first evidence to show that STS exhibited an anticancer activity through ROS-induced mechanisms, and that its cytotoxicity is highly selective to cancer cells. The results of the present study warrant further investigation on the detailed mechanism of STS actions, as well as its in vivo effectiveness and safety for clinical application.

Effects of dosing frequency on the clinical efficacy of ampicillin/sulbactam in Japanese elderly patients with pneumonia: A single-center retrospective observational study.

This study sought to investigate whether dosing frequency (the number of doses per day) affects the antimicrobial efficacy and safety of ampicillin/sulbactam (ABPC/SBT) in Japanese elderly pneumonia patients treated with ABPC/SBT at 6 g/day. This was a retrospective observational study that included hospitalized elderly patients (aged ≥75 years, 10 ml/min ≤CLcr <50 ml/min) who received 3 g every 12 h (BID; n = 61) or 1.5 g every 6 h (QID; n = 45) for the treatment of pneumonia. The primary endpoint was clinical response, assessed by measuring body temperature, white blood cell count, and C-reactive protein levels. Pharmacokinetic and pharmacodynamic simulations were conducted in silico to rationalize the clinical findings. The clinical response rates (extremely effective and effective) in the BID and QID groups were 36.1% and 55.6%, respectively (p = .0459). QID tended to be more effective in patients with gram-negative rods detected (p = .0563). According to the simulated minimum plasma ABPC concentrations at steady state for BID and QID were 2.5 and 7.3 µg/ml, respectively (p < .0001). Based on the simulated time above minimum inhibitory concentration (MIC), pharmacological (not clinical) efficacy was predicted to be higher with QID. Both groups had similar safety profiles. The main adverse event in both groups was liver damage. The present retrospective survey demonstrated that ABPC/SBT treatment for elderly patients with pneumonia and renal dysfunction was more effective with QID than with BID. Therefore, the QID regimen is worthy of consideration to improve the clinical outcomes of ABPC/SBT therapy in the present patient population.

Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers.

PURPOSE: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. METHODS: The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. RESULTS: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035). CONCLUSION: This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.

Nonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats.

Introduction: Cannabidiol (CBD) is known to affect the pharmacokinetics of other drugs through metabolic inhibition of CYP2C19 and CYP3A4. However, there is a lack of in vivo evidence for such drug interactions. Therefore, we investigated the saturability of CBD metabolism and CBD-drug interactions through inhibition of CYP3A in vivo. Materials and Methods: A nanoemulsion formulation of CBD (CBD-NE) was orally administered to rats at doses of 5, 10, 25, and 50 mg/kg, and plasma concentrations of CBD were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to examine the dose-dependency of CBD exposure (area under the curve [AUC]). To examine the effect of a CYP3A inhibitor on CBD pharmacokinetics, rats were orally pretreated with 50 mg/kg ketoconazole (KCZ), a strong CYP3A inhibitor, before oral administration of CBD-NE at doses of 10 and 50 mg/kg, and plasma concentrations of CBD were measured using LC-MS/MS. Moreover, 13C-erythromycin was orally administered following administration of either NE (without CBD), as a control, or CBD-NE at 1, 10, and 50 mg/kg, and 13C-breath response was measured by using an infrared analyzer. Results: After administration of various doses of the nanoemulsified CBD formulation to rats, the exposure of CBD (i.e., the AUC calculated from the plasma concentration-time profile) increased in a greater than dose-proportional manner, especially at doses above 10 mg/kg. The AUC and maximum plasma concentration (Cmax) of CBD after oral administration of CBD-NE (10 mg/kg) increased approximately three times by the coadministration of KCZ. Moreover, according to the CBD-induced changes of 13C-breath response, the metabolism of 13C-erythromycin was shown to be inhibited by CBD at doses of 10 and 50 mg/kg, but not at 1 mg/kg. Conclusions: Nonlinear disposition and CYP-mediated drug interactions of CBD at doses exceeding 10 mg/kg were demonstrated for the first time in vivo in rats. Given the present results, it is proposed that caution for dose-dependent drug interactions should be considered for CBD.

[Rubric Assessment for Pharmacotherapy in Spiral Curriculum: Development and Usefulness Evaluation].

A requirement, which students must satisfy, for a diploma at the Showa University School of Pharmacy is the ability to "plan, practice, and assess pharmacotherapy". To continuously assess the ability of students to meet this requirement and to provide patients with proper pharmacotherapy during student clinical rotations, we formulated the "Rubric assessment for pharmacotherapy" and evaluated its usefulness in tutorial learning classes. Clinical pharmacy faculty members created the rubric based on the Subjective, Objective, Assessment, and Plan (SOAP) note guidelines of the university. Third- (2016) and fourth-year students (2017) were required to self-assess their SOAP notes to analyze six clinical cases using the rubric. The rubric consists of three domains: (1) Evaluation of patient condition, (2) Proposal of pharmacotherapy, and (3) Plan for an assessment of pharmacotherapy. The rubric comprises 31 subdomains and is evaluated according to four levels of performance. In this study, 978 rubric sheets that were used by students to evaluate their own SOAP notes were analyzed. We found that the students were able to continuously self-assess their performance using the rubric while continuously improving their achievement level (p<0.05). The results of this study suggest that rubric assessments may be used as a tool for supporting students to plan, practice, and assess pharmacotherapy.

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: Immune-related adverse events (irAEs) are associated with the efficacy of immune-checkpoint inhibitors in patients with melanoma and non-small cell lung cancer. We therefore evaluated the relationship between irAEs and nivolumab efficacy against metastatic renal cell carcinoma. PATIENTS AND METHODS: The medical records of 53 consecutive patients were reviewed and analyzed. RESULTS: Median overall survival was significantly better in patients who showed irAEs at any time compared to patients without irAEs (p=0.013). We identified irAEs in 24 of 53 patients (45.3%), including four patients (7.5%) with grade 3 events. Multivariate analysis also revealed that risk factors for the onset of irAEs were positively associated with a platelet-to-lymphocyte ratio <156 before nivolumab treatment (p=0.006). CONCLUSION: Development of irAEs was associated with survival outcomes of nivolumab treated patients with metastatic renal cell carcinoma.

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma.

PURPOSE: Immune-related adverse events (irAEs) have been associated with the efficacy of programmed cell death protein 1 (PD-1) inhibitors in patients with urothelial cancer. We therefore evaluated the relationship between irAEs and pembrolizumab efficacy in urothelial cancer patients. METHODS: Patients with urothelial cancer who were treated with pembrolizumab in a second-line setting or later between January 2018 and December 2018 were identified by reviewing their medical records from the Cancer Institute Hospital, Japanese Foundation for Cancer Research. Data were updated as of December 31, 2018. Kaplan-Meier curves for overall survival (OS) and time to treatment failure (TTF) according to irAE grade were evaluated using the log-rank test. Risk factors for exacerbation of irAEs were also evaluated with multivariate analysis. RESULTS: In this retrospective study, 43 patients received pembrolizumab. We identified irAEs in 22 of the 43 patients (51.2%), including 11 patients (25.6%) with grade 2 or 3 events. In patients with irAE grade 0 or 1, median TTF was 127 days, and median OS was 160 days according to the Kaplan-Meier method. On the other hand, in patients with irAE grade ≥2, median TTF and OS were not reached. Multivariate analysis also revealed that risk factors for exacerbation of irAEs (to grade ≥2) were positively associated with lymphocyte count at baseline (>2,000/µL) before pembrolizumab treatment (p = 0.021). CONCLUSIONS: Development of irAEs was associated with survival outcome of pembrolizumab treatment in patients with advanced urothelial cancer.

Association of Hand-Foot Skin Reaction with Regorafenib Efficacy in the Treatment of Metastatic Colorectal Cancer.

PURPOSE: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC). METHODS: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method. RESULTS: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2). CONCLUSIONS: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC.

Development of a Novel Nano-emulsion Formulation to Improve Intestinal Absorption of Cannabidiol.

BACKGROUND: Cannabidiol (CBD) is highly lipophilic, and its oral bioavailability is known to be very low in humans. In this study, we developed a novel nanoemulsion preparation of CBD (CBD-NE) to improve the poor solubility and absorption of CBD. The pharmacokinetic profiles of CBD in rats were evaluated after oral administrations of CBD oil and CBD-NE, and the effect of bile secretion on CBD absorption was also evaluated. METHODS: The CBD-NE formulation developed in this study consisted of vitamin E acetate, ethanol, Tween-20, and distilled water (1.7/3.8/70/24.5, w/w%). A CBD oil formulation (CBD oil, control) 100 mg/kg or CBD-NE 50 mg/kg was orally administered to rats, and the blood samples were collected over time. Moreover, the CBD oil or CBD-NE was orally administered to bile-fistulated rats, and the pharmacokinetic profiles of CBD were also evaluated. CBD concentrations in plasma were measured using LC-MS/MS. RESULTS: The particle size of CBD-NE was 35.3 ± 11.8 nm. Mean Tmax of CBD-NE was shortened significantly by the factor of 3 (from 8.00 to 2.40 h, p < 0.001) and AUC0-∞/dose increased by 65% (from 0.272 ± 0.045 to 0.448 ± 0.087 h L/kg) compared with CBD oil. AUC0-∞/dose and Cmax/dose after oral administration of CBD oil were significantly reduced by the factor of 27 and 23 (p < 0.05 and p < 0.01), respectively, in bile-fistulated rats compared with the untreated rats. In contrast, all pharmacokinetic parameters after oral administration of CBD-NE were not significantly different between the untreated and bile-fistulated rats. Therefore, these results demonstrated that conventional CBD oil formulation but not CBD-NE requires bile-mediated micelle formation. CONCLUSIONS: The novel NE formulation developed in this study successfully improved the absorption of CBD regardless of bile secretion. The newly developed oral CBD-NE preparation could be useful to achieve a more stable and quicker onset of action by CBD.

Comparison of adverse events following injection of original or generic docetaxel for the treatment of breast cancer.

PURPOSE: The approval of injectable generic drugs does not require bioequivalence testing. However, although generic products contain the same level of the active compound, the levels and types of additives present can differ from those used in the original product. Since docetaxel is highly lipophilic, polysorbate 80 (PS80), polyethylene glycol (PEG), and ethyl alcohol are employed to solubilize this anticancer agent. This retrospective study compared the safety of five docetaxel products (Taxotere®, Docetaxel Hospira, Docetaxel Sandoz, Docetaxel Sawai, and Docetaxel EE). METHODS: The incidence and severity of adverse events were analyzed using the medical records of operable breast cancer patients (n = 363) treated with docetaxel (75 mg/m2) in Showa University Hospital, Japan, from Jan 2013 to Mar 2016. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Significant product-related differences were observed in the following non-hematological adverse events: injection site reaction (P = 0.0012), hand-foot syndrome (≥grade 3) (P = 0.0003), and oral mucositis (≥grade 3) (P = 0.0080). Multivariate logistic regression analyses of the associations between these adverse events and the total additive administered (g/m2) identified significant negative effects of PS80 and ethyl alcohol. CONCLUSIONS: Injectable docetaxel products had different adverse event profiles, which showed negative associations with the amounts of PS80 and ethyl alcohol present. This finding indicated that there might be additive-related pharmacokinetic and physiochemical differences among these products, suggesting a need for further pre- or post-approval testing of injectable generic products containing noticeable different levels of additives.

Hypoglycemic and Antioxidant Activities of the Water Extract of Aquilaria crassna Leaves in Streptozotocin-Nicotinamide-Induced Type-2 Diabetic Mice.

Antidiabetic effect of the water extract of Aquilaria crassna (A. crassna) leaves was recently claimed by some diabetic patients in Thailand, whereas its experimental evidence has not been published yet. The present study was therefore conducted to investigate pharmacological activities of the water extract of A. crassna leaves, focusing on its antioxidative and hypoglycemic effects in vitro and in vivo using streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic (DM) mice. An antioxidant activity of the herb extract was confirmed using a 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) radical scavenging assay, and its IC50 on DPPH inhibition was determined to be 34.6 µg/mL. The extract also inhibited α-glucosidase in a concentration-dependent manner with the IC50 of 36.3 µg/mL. An enzyme-kinetic analysis using a Lineweaver-Burk plot indicated that the inhibition of α-glucosidase by the herb extract is an uncompetitive type with the inhibition constant (K(i)) of 39.8 µg/mL. An intragastric pretreatment of 1,000 mg/kg A. crassna in STZ-NA-induced type-2 DM significantly lowered the blood glucose at 30 and 60 min after an oral loading of 2 g/kg glucose (p < 0.05 and p < 0.01, respectively), as compared with the untreated-diabetic control. After 4 weeks-daily administration of 500 and 1,000 mg/kg A. crassna extract, the blood glucose levels were significantly reduced by about 66% and 86%, respectively, as compared with the untreated-diabetic control (p < 0.01). However, the expression of GLUT4 in skeletal muscle, detected by ELISA, was not significantly changed with the herb extract. In conclusion, our findings are the first to clearly demonstrate the hypoglycemic effects of A. crassna and to propose the α-glucosidase inhibition as an antidiabetic mechanism of the herb activity.

Simultaneous optimization of limited sampling points for pharmacokinetic analysis of amrubicin and amrubicinol in cancer patients.

AIM: Limited sampling points for both amrubicin (AMR) and its active metabolite amrubicinol (AMR-OH) were simultaneously optimized using Akaike's information criterion (AIC) calculated by pharmacokinetic modeling. METHODS: In this pharmacokinetic study, 40 mg/m(2) of AMR was administered as a 5-min infusion on three consecutive days to 21 Japanese lung cancer patients. Blood samples were taken at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h after drug infusion, and AMR and AMR-OH concentrations in plasma were quantitated using a high-performance liquid chromatography. The pharmacokinetic profile of AMR was characterized using a three-compartment model and that of AMR-OH using a one-compartment model following a first-order absorption process. These pharmacokinetic profiles were then integrated into one pharmacokinetic model for simultaneous fitting of AMR and AMR-OH. After fitting to the pharmacokinetic model, 65 combinations of four sampling points from the concentration profiles were evaluated for their AICs. Stepwise regression analysis was applied to select the sampling points for AMR and AMR-OH to predict the area under the concentration-time curves (AUCs) at best. RESULTS: Of the three combinations that yielded favorable AIC values, 0.25, 2, 4 and 8 h yielded the best AUC prediction for both AMR (R(2) = 0.977) and AMR-OH (R(2) = 0.886). The prediction error for AUC was less than 15%. CONCLUSION: The optimal limited sampling points of AMR and AMR-OH after AMR infusion were found to be 0.25, 2, 4 and 8 h, enabling less frequent blood sampling in further expanded pharmacokinetic studies for both AMR and AMR-OH.

Synthesis of ¹³C-lidocaine as a probe of breath test for the evaluation of cytochrome P450 activity.

(13)C-Labeled lidocaine, 2-di[1-(13)C]ethylamino-N-(2,6-dimethylphenyl)acetamide (1), was synthesized from [1-(13)C]acetic acid in six steps, as a probe for a breath test to evaluate in vivo cytochrome P450 activity. The measurement of (13)CO2 in breath was successfully performed following oral administration of (13)C-lidocaine 1 to mice.

Pharmacokinetic and pharmacodynamic study on amrubicin and amrubicinol in Japanese patients with lung cancer.

PURPOSE: The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity-PK relationships in Japanese patients. METHODS: Amrubicin (35-40 mg/m(2)) was administered to 21 lung cancer patients on days 1-3 every 3-4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated. RESULTS: The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC. CONCLUSION: The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK-PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.

The use of 13C-erythromycin as an in vivo probe to evaluate CYP3A-mediated drug interactions in rats.

(14)C-erythromycin breath test has been utilized to evaluate the extent of CYP3A activity in vivo. However, its radioactivity sometimes impedes its clinical application. In this study, we employed erythromycin labeled with (13)C ((13)C-EM), a nonradioactive stable isotope, as an in vivo probe of breath test to evaluate CYP3A-mediated drug interactions in rats. A physiologically based pharmacokinetic (PBPK) model to describe (13)CO(2) exhalation altered by drug interactions was newly constructed. Rats received an intravenous or oral administration of (13)C-EM with or without a CYP3A inhibitor or inducer, that is, ketoconazole (KCZ) or dexamethasone (DEX), respectively. Breath samples were taken at designated times, measured with an infrared spectrophotometer, and the Δ(13) CO(2) value (‰) in each sample was obtained. The C(max) and AUC(0-t) of Δ(13) CO(2) were significantly decreased with KCZ and increased with DEX. The PBPK model in this study successfully described the (13)CO(2) exhalation after (13)C-EM administration in the absence and presence of drug interactions. In conclusion, this study proposed a simple and rapid in vivo methodology to utilize (13)C-EM for the quantitative analysis of CYP3A inhibition and induction. This method using small animals may be useful in early drug development processes.

Estimating pediatric doses of drugs metabolized by cytochrome P450 (CYP) isozymes, based on physiological liver development and serum protein levels.

We established a method for estimating pediatric doses of drugs metabolized by cytochrome P450 (CYP) isozymes, using the free fraction of drug in plasma (fu), serum protein level (P), liver volume (LV), and CYP activity (Vmax/Km) as indices of physiological and biochemical development in children up to 15 years old. This method allows the child/adult dose ratio (D(C)/D(A))=child/adult oral clearance ratio (CL((PO)(C))/CL((PO)(A))) of drugs mainly metabolized in the liver to be estimated by the following equation: [formula: see text]. Major metabolism of drugs was ascribed to CYP1A2 for theophylline and caffeine, and CYP1A2 and CYP2D6 for propranolol and mexiletine. For theophylline and caffeine, CL((PO)(C))/CL((PO)(A)) calculated from the child/adult body surface area ratio (BSA ratio) and the value calculated by our method were compared, using CL((PO)(C))/CL((PO)(A)) calculated from the clearance ratio based on population pharmacokinetics (PPK ratio) as a reference. For all drugs, pediatric doses calculated from the Crawford equation and our equation were compared, with predetermined doses as the reference. For theophylline and caffeine, the relative accuracy of our method was significantly higher than that of BSA-based estimation when the PPK ratio was used for reference. For theophylline, caffeine, and propranolol, the relative accuracy of our method was significantly higher than that of BSA-based estimation when predetermined doses were used for reference. These findings indicate the validity of our method which considers the physiological and biochemical development (i.e., fu, P, LV, and CYP activity) for pediatric dose estimation.

Comparison of physicians' compliance, clinical efficacy, and drug cost before and after introduction of Asthma Prevention and Management Guidelines in Japan (JGL2003).

BACKGROUND: This study investigated the variations in the clinical efficacy and drug cost following the introduction of the Asthma Prevention and Management Guidelines in Japan (JGL2003). METHODS: The medical charts of fifty outpatients treated continuously for asthma, aged 16-50 years, from October 2002 to October 2004 at Showa University Hospital were analyzed for physicians' compliance with asthma guidelines, symptom severity, episodes in various occasions, prescriptions and drug costs. RESULTS: Physicians' compliance with the guidelines, which were defined as the number of patient visits treated in conformity with the JGL over the total number of patient visits, was found to be high before (89.4%) and after (90.3%) the introduction of JGL2003, without a statistical difference. On the other hand, the distribution of asthma symptom severity varied significantly (P<0.0001). Fewer patients were recognized as having more severe asthma symptoms after the introduction of JGL2003. Significantly more patients with severe asthma symptoms were detected in the physicians' noncompliant group than in the compliant group (P<0.0001). The number of patients prescribed with oral corticosteroids, long-acting beta2-agonists containing patches, long-acting oral beta2-agonists, short-acting inhaled beta2-agonists, sustained-released theophylline and leukotriene receptor antagonists decreased after the introduction of JGL2003. Furthermore, the total annual drug cost per patient decreased significantly by an average of 16,259 yen (P=0.006). CONCLUSIONS: The JGL2003 was judged to have improved criteria, which thus resulted in the high compliance of physicians with the guidelines, in the remission of asthma symptoms and in the reduction in the total annual drug cost per patient.