Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

BACKGROUND: In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. METHODS: We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. RESULTS: The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181-300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3-7.44), 2.61 (95% CI, 1.39-4.91), and 2.38 (95% CI, 1.04-5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62-351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35-14.77) and 6.99 (95% CI, 3.22-15.18). The ß value of EB was 2.07 (95% CI, 1.48-2.76), which was classified as a wear-out failure type. CONCLUSIONS: For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection.

INTRODUCTION: Clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy. METHODS: CAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated. RESULTS: Median area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4-1.8) µg·h/mL vs. 21.5 (IQR, 17.7-32.3) µg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9-10.9) µg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3-9.3) µg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy. CONCLUSIONS: When RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.

Age-Associated Theophylline Metabolic Activity Corresponds to the Ratio of 1,3-Dimethyluric Acid to Theophylline in Mice.

Age is known as one of influencing factor for theophylline (TP)-metabolizing capacity. In a previous our study, the ratio of TP and its major metabolite 1,3-dimethyluric acid (DMU) in serum (DMU/TP) is a useful index to estimate TP-metabolizing capacity, and this value markedly increased by influencing factor, such as the history of smoking. However, it is unknown whether DMU/TP values in serum reflect age-associated changes of TP-metabolizing capacity. In this study, the effect of age on the DMU/TP values in serum were investigated using mice of different age due to the limited blood sampling in human. The concentrations of TP and its metabolites in mouse serum were simultaneously measured using HPLC. As observed in human serum, serum TP concentrations were closely correlated with DMU concentration in mice, which indicates that the DMU/TP ratio is a good indicator of TP metabolic ability in mice. When TP was administered subcutaneously in 2-28-week-old mice, age-associated changes in the DMU/TP ratio in mice were observed. In conclusion, age-associated changes in TP-metabolizing capacity can be estimated by the DMU/TP ratio in serum.

Evaluation of the Expression Time of Ganciclovir-Induced Adverse Events Using JADER and FAERS.

Investigation of the occurrence time of adverse drug reactions helps to prevent the development and aggravation of adverse reactions, but the expression time of ganciclovir-induced adverse events has not been elucidated. In this study, using databases of spontaneous adverse event reports, the Japanese Adverse Drug Event Report database (JADER) and the U.S. Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), the incidence of adverse reactions due to ganciclovir and their expression time were analyzed. As a result of calculation of the reporting odds ratio (ROR) and 95% confidence interval for individual main adverse reactions of ganciclovir (cytopenia, leukopenia, thrombocytopenia, liver damage, and acute renal failure), a signal was detected for all adverse reactions in both databases, except for liver damage in JADER. Furthermore, the Weibull distribution was performed for the analysis of onset time of each ganciclovir-induced adverse event. The results of Weibull parameter α and ß values of each adverse event in both JADER and FAERS suggested that most adverse events occurred within 30 d and classified into the early failure type, except that thrombocytopenia and acute renal failure in JADER classified into the random failure type. Based on these findings, it concluded that the paying attention to signs of each ganciclovir-induced adverse event is required from the early phase after ganciclovir administration. However, in FAERS, development after a long-term course also accounted for 11%, suggesting that long-term periodic monitoring of adverse reactions would be also required.

Dosing optimization of meropenem based on a pharmacokinetic analysis in patients receiving hemodiafiltration and an in vitro model.

The purpose of this study was to estimate the in vivo pharmacokinetics of meropenem during intermittent-infusion hemodiafiltration (I-HDF) and clarify its optimal dosage and dosing interval in patients receiving I-HDF. The clearance of meropenem by online hemodiafiltration (OL-HDF) and I-HDF was predicted using an in vitro system and assessed to establish whether the results obtained are applicable to clinical cases. In the in vivo study, the mean volume of distribution (Vd), non-I-HDF clearance (CLnon-I-HDF), and I-HDF clearance (CLI-HDF) were 15.80 ± 3.59 l, 1.05 ± 0.27 l/h, and 5.78 ± 1.03 l/h. Dosing regimens of 0.25 g once daily for a MIC of 8 µg/ml and of 0.5 g once daily for a MIC of 16 µg/ml achieved 40% T > MIC. In the in vitro and in vivo studies, observed CLHDF was similar to predictive CLHDF (= Cf/Cp × (QD + QSUB)). In conclusion, adjustments to the dose and interval of meropenem were developed based on the presumed susceptibility of pathogens to meropenem in patients receiving I-HDF. We suggest 0.5 g once daily as an appropriate regimen for empirical treatment.

Development of HPLC with fluorescent detection using NBD-F for the quantification of colistin sulfate in rat plasma and its pharmacokinetic applications.

Colistin sulfate, composed of a mixture of colistin A sulfate (CLA) and colistin B sulfate (CLB), is available for treating life-threatening infections caused by multidrug-resistant Gram-negative bacteria. In this study, the CLA and CLB were quantified separately. Colistin sulfate was extracted from rat plasma with a solid-phase extraction C18 cartridge and reacted with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), and the fluorescent derivatives were subjected to reversed-phase high-performance liquid chromatography analysis and used to investigate the pharmacokinetics of CLA and CLB in rat plasma. The recovery rates of CLA and CLB were 41.2 ± 4.4 and 45.5 ± 3.1%, respectively. The recovery rate calculated from the total area of CLA and CLB was 43.9 ± 3.6%. When 2 mm NBD-F and 10 mm boric acid buffer (pH 9.5) were added to colistin sulfate, the highest recovery rate was obtained. The best heating time was 5 min at 60°C. The lower limits of quantification for CLA, CLB and the total area of CLA and CLB were 0.05, 0.05 and 0.1 µg/mL; the coefficients of variations were 13.5, 14.5 and 14.1%, respectively. This method was found to have acceptable linearity, precision and accuracy, and has been successfully applied to a pharmacokinetic study in rat plasma.

Factorial Analysis of Hepatitis B Virus Reactivation-Induced Hepatitis B Using JADER.

Hepatitis B caused by chemotherapy- and immunosuppression-associated hepatitis B virus reactivation is likely to become fulminant, and a high mortality rate has been reported. In this study, using the Japanese adverse drug event report database (JADER), factorial analysis of patients who developed hepatitis B as an adverse event was performed. The number of reported cases of hepatitis B during the survey period was 781 and 185 of them (24%) died. Rituximab and prednisolone were administered to many cases (233, 216 cases, respectively), and the reporting odds ratios were high (65.35, 13.40, respectively), suggesting their strong association with the development of hepatitis B. Regarding the onset time, rituximab-induced hepatitis B developed within one year after administration in 83%, being a high frequency. Prednisolone-induced hepatitis B developed even after one year in 36%. Since prednisolone is used to treat rheumatoid arthritis at a dose ≤10 mg/d, the patients were divided based on the prednisolone dose into the groups treated at >10 and ≤10 mg/d, and the onset time was investigated in each group. The median onset time was 113 and 330 d, respectively, showing a significant difference. On time-to-event analysis using the Weibull distribution, rituximab was classified as the early failure type, and prednisolone and methotrexate for rheumatoid arthritis were classified as the wear out failure type. These findings are important information which may lead to early discovery of and taking actions against hepatitis B being helpful for providing appropriate medical care.

Synthesis of Linezolid Metabolites PNU-142300 and PNU-142586 toward the Exploration of Metabolite-Related Events.

Linezolid (1) is an oxazolidinone antibiotic that is partially metabolized in vivo via ring cleavage of its morpholine moiety to mainly form two metabolites, PNU-142300 (2) and PNU-142586 (3). It is supposed that accumulation of 2 and 3 in patients with renal insufficiency may cause thrombocytopenia, one of the adverse effects of linezolid. However, the poor availability of 2 and 3 has hindered further investigation of the clinical significance of the accumulation of these metabolites. In this paper, we synthesized metabolites 2 and 3 via a common synthetic intermediate, 4; this will encourage further exploration of events related to these metabolites and lead to improved clinical use of linezolid.

Pharmacokinetics and brain penetration of carbapenems in mice.

An adverse effect associated with the administration of carbapenems is central nervous system (CNS) toxicity, with higher brain concentrations of carbapenems being linked to an increased risk of seizures. However, the pharmacokinetics and brain penetration of carbapenems have not yet been examined. Thus, the aim of this in vivo investigation was to determine the pharmacokinetics and brain penetration of carbapenems in mice. Blood samples and brain tissue samples were obtained 10, 20, 30, 60, and 120 min after the subcutaneous administration of carbapenems (91 mg/kg). We obtained the following values for the pharmacokinetic parameters of carbapenems in mice: 1.20-1.71 L/h/kg for CLtotal/F, 1.41-2.03 h(-1) for Ke, 0.34-0.51 h for T1/2, 0.66-0.95 L/kg for Vss/F, 0.49-0.73 h for MRT, 83.46-110.58 µg/mL for Cmax, plasma, and 0.28-0.83 µg/g for Cmax, brain tissue. The AUC0-∞ of the carbapenems tested in plasma were in the following order: doripenem > meropenem > biapenem > imipenem, and in brain tissue were: imipenem > doripenem > meropenem > biapenem. The degrees of brain tissue penetration, defined as the AUC0-∞, brain tissue/fAUC0-∞, plasma ratio, were 0.016 for imipenem, 0.004 for meropenem, 0.002 for biapenem, and 0.008 for doripenem. The results of the present study demonstrated that, of the carbapenems examined, imipenem penetrated brain tissue to the greatest extent.

Anti-inflammatory effects of linezolid on carrageenan-induced paw edema in rats.

The immunomodulatory activity of linezolid has recently been reported using in vitro experimental models. However, the anti-inflammatory activity of linezolid has not yet been demonstrated using in vivo experimental models. Therefore, the aim of the present study was to demonstrate the anti-inflammatory activity of linezolid and other anti-MRSA agents using the carrageenan-induced rat paw edema model. The pretreatment with 50 mg/kg linezolid significantly suppressed edema rates, compared with control (5% glucose), with edema rates at 0.5 and 3 h after the administration of carrageenan being 17.3 ± 3.5 and 30.8 ± 3.0%, respectively. On the other hand, edema rates were not suppressed by the pretreatments with 50 mg/kg vancomycin, teicoplanin, arbekacin, and daptomycin. Furthermore, we demonstrated that linezolid exhibited anti-inflammatory activity in a concentration-dependent manner. These effects were observed at linezolid concentrations that are achievable in human serum with conventional dosing. In conclusion, the results of the present study suggest that the anti-inflammatory activities of linezolid, in addition to its antimicrobial effects, have a protective effect against destructive inflammatory responses in areas of inflammation.

Pharmacokinetics and dosing estimation of meropenem in Japanese patients receiving continuous venovenous hemodialysis.

The pharmacokinetics of meropenem have not yet been examined in Japanese patients receiving Continuous venovenous hemodialysis (CVVHD). The aim of this clinical investigation was to determine the pharmacokinetic parameters of meropenem in critically ill patients receiving CVVHD in order to estimate dosing regimens for the patient population in Japan. The values of pharmacokinetic parameters were 17.5 ± 5.6 l for V1, 1.27 ± 0.38 h(-1) for K12, 0.71 ± 0.40 h(-1) for K21 and 0.17 ± 0.02 h(-1) for K10. Based on these mean parameters (V1, K12, K21 and K10), time above MIC (T > MIC) values were estimated at different MICs using various meropenem regimens. For bacteria with a meropenem MIC of ≤ 2 µg/ml, a dosing regimen of 0.25 g every 24 h achieved more than 40% T > MIC. For a MIC of 4 µg/ml, all the regimens tested, except for 0.25 g every 24 h, achieved more than 40% T > MIC. For a MIC of 16 µg/ml, dosing regimens of 0.5 g every 8 h, 1 g every 12 h, and 1 g every 8 h achieved 40% T > MIC, reaching the pharmacokinetic-pharmacodynamic target range. This is the first study to examine the pharmacokinetics of meropenem under a CVVHD setting in Japan. The pharmacokinetic-pharmacodynamic profile of dosing regimens tested in this study will assist in selecting the appropriate meropenem regimens for patients receiving CVVHD.

The efficacy, safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly.

Biapenem has been widely used to treat bacterial pneumonia; however, there is little information concerning its efficacy and safety in elderly patients. Based on pharmacokinetic-pharmacodynamic theory, administration of biapenem thrice rather than twice daily would be expected to be more effective because of longer time above the minimum inhibitory concentration. In this study, we aimed to evaluate the efficacy, safety, and pharmacokinetics of biapenem (300 mg) administered thrice daily in pneumonic patients aged 65 years or older. Biapenem was effective in 22 of 25 patients, as assessed by the improvement in clinical symptoms and/or the eradication of the causative organisms, and caused no serious adverse events. The pharmacokinetic profile was established based on simulations using a modeling program. Among 17 patients whose causative organisms were detected, time above the minimum inhibitory concentration was estimated to be 100% in 16 patients, all of whom showed clinical improvement. The results of this study confirmed the efficacy and safety of 300 mg of biapenem administered thrice daily for the treatment of pneumonia in elderly patients.

Investigating the hypothermic effects of fluoroquinolone antimicrobials on non-bacterial fever model mice.

BACKGROUND: Fluoroquinolone (FQ) antimicrobials have antipyretic effects during the treatment of bacterial infections; however, it is not clear whether these are due to their antimicrobial activities or their hypothermic effects. In this study, we investigated the hypothermic effects of FQ antimicrobials (ciprofloxacin [CPFX], gatifloxacin [GFLX], and levofloxacin [LVFX]) on fever by evaluating rectal body temperature changes in a mouse model of non-bacterial fever. METHODS: CPFX, GFLX, and LVFX were administered intraperitoneally to non-bacterial fever model mice induced by yeast. Rectal body temperature was measured up to 180 min after administration. RESULTS: A decrease in rectal body temperature of up to 1.2 °C for CPFX, 3.4 °C for GFLX, and 1.0 °C for LVFX was observed. The decrease in temperature was induced by an increase in the plasma concentration of FQ antimicrobials, suggesting that they are responsible for the temperature reduction. Focusing on glucocorticoids, one thermoregulation mechanism, we investigated the substances responsible for the reduction in rectal body temperature induced by FQ antimicrobials. Aminoglutethimide (an inhibitor of glucocorticoid production) were premedicated, followed by intraperitoneal administration of GFLX in the yeast-induced fever mouse model, resulting in attenuated GFLX-induced hypothermic effects. CONCLUSIONS: These results suggest that certain antipyretic effects of CPFX, GFPX, and LVFX during fever may contribute to their hypothermic effects; certain mechanisms are glucocorticoid-mediated.

Dissolution profile of 24 levofloxacin (100 mg) tablets.

Although there are 23 generic levofloxacin (100 mg) tablets (LVFX tablets) and 1 brand name LVFX tablet (supply now discontinued) in Japan, there have been no reports that have evaluated and compared the dissolution profiles of LVFX tablets using the same dissolution method. We studied the dissolution profile of LVFX tablets by the Paddle method, a standard dissolution test method. Among 23 generic LVFX tablets, 2 LVFX tablets had lower dissolution rates and 14 had higher dissolution rates than the brand name LVFX tablet. It is suggested that LVFX tablets have different dissolution profiles, which could cause different pharmacokinetic profiles.

Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer.

No established supportive therapy to prevent and treat chemotherapy-induced peripheral neuropathy (PN) is available. Minimizing the severity of PN is therefore critical in clinical use. We aimed to determine when and how often PN occurs in association with paclitaxel plus carboplatin (PC therapy), a regimen used to treat non-small cell lung cancer, and factors that exacerbate this condition. Patients who received PC therapy for non-small cell lung cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between May 20, 2009, and November 30, 2010, were included. PN was evaluated by the study pharmacist using specific questions based on the Common Terminology Criteria for Adverse Events Version 3.0. Univariate analysis was used to compare a group with no, Grade 1, or Grade 2 PN (non-serious) and a group with Grade 3 PN (serious). Analyses were conducted using the Cox proportional hazard model with patient characteristics having p < or = 0.20 when assessed as independent variables. Of 50 patients, 38 (76.0%) developed PN by day 6 of the first course of anticancer treatment. Grade 3 PN had an incidence of 25.0% in the fourth course. In multivariate analysis with the Cox proportional hazard model, pack-year [hazard ratio = 1.029; 95% confidence interval (CI): 1.009-1.050, p = 0.005] and creatinine clearance (hazard ratio = 0.957; 95% CI: 0.920-0.996, p = 0.031) were significant factors. A high pack-year and a low creatinine clearance exacerbated PN in patients treated with PC. PN must be carefully evaluated in patients with exacerbating factors.

Usefulness of the simultaneous determination of serum levels of theophylline and its metabolites in patients medicated with theophylline preparation.

OBJECTIVE: Measurement of the serum level of theophylline is essential for its proper use; however, it is difficult to infer the metabolic ability of individual patients by only the serum theophylline level and to decide the appropriate medication. In this study, we simultaneously measured serum theophylline and metabolite levels in patients treated with theophylline, and investigated their usefulness. EXPERIMENTAL: The subjects were asthma patients who visited the outpatient clinic of Respiratory Medicine, St Luke's International Hospital, between April and October 2003, and were medicated with sustained-release theophylline tablets (Theodur®). The serum level of theophylline and its metabolites was measured by HPLC in patients who gave written consent. RESULTS: A strong correlation was noted between the serum theophylline (TP) and 1,3-dimethyluric acid (DMU) levels of 52 patients (r = 0.670), and DMU/TP was about 0.04. In a patient whose the DMU/TP was 0.216, it was recognized that metabolic ability was promoted due to a history of smoking. DISCUSSION: In this study, it was shown that simultaneous measurement by HPLC of the serum level of theophylline and its metabolites and DMU/TP was useful to assess the metabolic ability of individual patients.

Intellectual development after treatment in children with acute leukemia and brain tumor.

BACKGROUND: The influence of central nervous system (CNS)-directed chemotherapy on intelligence remains controversial. In this study, we investigated the influence of treatment on intellectual development in acute lymphoblastic leukemia (ALL) and brain tumor patients undergoing CNS-directed treatments. METHODS: Among patients treated in the Department of Pediatrics, St Luke's International Hospital between April 2000 and March 2009, the subjects were 38 patients with ALL or brain tumors who underwent regular Wechsler intelligence tests. RESULTS: The subjects consisted of 26 patients with ALL and 12 with brain tumors. Prophylactic cranial irradiation was not performed in patients with ALL, whereas it was done for all those with brain tumor. In patients with ALL, the IQ 1 year later was not changed from the start of treatment. In those with brain tumors, the verbal IQ 1 year later was significantly lower than that at the start of treatment. In patients with ALL, intelligence tests were performed 3 years after the start of treatment and there were no marked changes between the two time-points (n = 11). In those with a brain tumor, intellectual functions further decreased after the completion of treatment to as late as 5 years after the initiation of treatment (n = 7). CONCLUSIONS: There is no intellectual impairment in any patient with ALL at post-treatment follow-up 3 years after the start of treatment, while intelligence is serially reduced in brain tumor patients. An innovative intervention may be needed for this group of patients.

Multivalent cation and polycation polymer preparations influence pharmacokinetics of dolutegravir via chelation-type drug interactions.

Dolutegravir (DTG) is an integrase inhibitor, whose gastrointestinal absorption is impaired by the formation of chelates with multivalent metal cation preparations. However, little is known regarding the interactions of DTG with preparations containing other multivalent metal cations or with polycation polymer preparations. This study examined how the pharmacokinetics of DTG are affected by co-administration with Al(OH)3, LaCO3, and the polycation polymers bixalomer (Bxl) and sevelamer (Svl). Prior to oral administration of DTG (5 mg/kg), rats were orally administered Al(OH)3 (150 or 300 mg/kg), LaCO3 (50 or 75 mg/kg), Bxl (250 or 500 mg/kg), or Svl (300 or 600 mg/kg). Serum concentrations of DTG were then measured over the next 24 h. Compared to the administration of DTG alone, its co-administration with Al(OH)3, LaCO3, Bxl, and Svl led to reduced serum concentration of DTG, and consequently, a significantly reduced area under the curve. These comparisons also revealed a considerable reduction in the maximum concentration, suggesting that the interactions of these agents with DTG in the intestinal tract inhibit absorption of DTG. The above results demonstrate that Al(OH)3, LaCO3, Bxl, and Svl affect the pharmacokinetics of DTG and indicate the need for caution when combining any of the above preparations with DTG.

Concurrent administration with multivalent metal cation preparations or polycationic polymer preparations inhibits the absorption of raltegravir via its chelation.

OBJECTIVES: Raltegravir (RAL) that can form chelates with multivalent metal cations shows lateral interactions with multivalent metal cation and polycationic polymer. We investigated the interactions of RAL with multivalent metal cation preparations, Al(OH)3 and LaCO3 , and polycationic polymer preparations, bixalomer (Bxl) and sevelamer (Svl). METHODS: Immediately before the oral administration of 40 mg/kg RAL, the rats were administered orally with the vehicle, Al(OH)3 , LaCO3 , Bxl, or Svl, and the time course of RAL serum concentration was followed. The in vitro binding affinity of RAL with multivalent metal cation and polycationic polymer was also evaluated using isothermal titration calorimetry (ITC). RESULTS: When Al(OH)3 , LaCO3 , Bxl, or Svl was concomitantly administered with RAL, the maximum concentration and area under the curve were significantly lower than those when RAL was administered alone. ITC showed the interaction of RAL with Al(OH)3 as an enthalpy-driven reaction and its interactions with LaCO3 and Bxl as entropy-enthalpy mixed reactions. CONCLUSIONS: The interaction of RAL with Al(OH)3 , LaCO3, Bxl, or Svl can inhibit RAL absorption into the gastrointestinal tract, and thus, the multivalent metal cation and polycationic polymer are the modifying factors that can affect RAL pharmacokinetics.

Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research.

OBJECTIVES: As commercially available pregabalin preparations are limited to oral administration, it is impossible to use it as an adjuvant analgesic for neuropathic cancer-related pain in terminally ill cancer patients with oral feeding difficulties. The objective of this study was to develop a pregabalin suppository to be available at hospitals. METHODS: Pregabalin suppositories were prepared using bases comprising six different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test and stability test were performed in vitro. The pharmacokinetics and pharmacodynamics of the suppositories were assessed in rats. KEY FINDINGS: In the in vitro releasing test, the pregabalin suppositories with H-15, H-15 : S-55 = 1 : 1, H-15 : S-55 = 2 : 1, H-15 : S-55 = 1 : 2 released approximately 100% of the pregabalin within 180 min. Among these pregabalin suppositories, only the suppository with H-15 : S-55 = 2 : 1 demonstrated an equivalent AUC0-∞ with the oral administration group. Consistent with the results of the pharmacokinetic study, the pregabalin suppository with H-15 : S-55 = 2 : 1 exhibited antinociceptive effects. In addition, the pregabalin suppository with H-15 : S-55 = 2 : 1 was stable for 12 weeks when refrigerated with light shielding. CONCLUSIONS: The pregabalin suppositories prepared in this study may be applicable for pain control for terminally cancer ill patients with oral feeding difficulties.