Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling.

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.

Evaluation of Drug Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors Based on Target Molecular Binding Occupancy.

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A1c (HbA1c) reduction after administration of the GLP-1 receptor agonists was higher than that of DPP-4 inhibitors. We clarified the differences between the therapeutic effects associated with GLP-1 receptor agonists and DPP-4 inhibitors theoretically. Together, the present findings provide a useful methodology for proper usage of GLP-1 receptor agonists and DPP-4 inhibitors.

Method for Prediction of Efficacy of Sugammadex Administered to Recover from Rocuronium-Induced Neuromuscular Blockade in Gynecological Laparoscopic Surgery Cases.

Sugammadex (SDX), a neuromuscular blocking-reversal agent, quickly reverses neuromuscular blockade induced by rocuronium (RCR). SDX dosage is set according to the state of neuromuscular blockade determined with a neuromuscular monitoring device. However, in clinical situations, such a devise is not frequently used. Here, we report construction of a method for theoretically setting SDX dose by which the optimum reverse time (RT) can be obtained for individual patients even when the device is not available. The subjects were 42 adult female patients who underwent laparoscopic surgery from 1 August 2015 to 31 March 2016, during which RCR and SDX were administered. We formulated an equation for theoretically calculating the RCR residual ratio (RR) in blood after SDX administration. Furthermore, we examined the relationship between RR and RT. Based on the results obtained, we developed a method for predicting RT using RR. We excluded 1 subject as the RT value was detected as an outlier in our analysis. Multiple regression analysis was performed using standard body weight, serum creatinine, total bilirubin, and RR as explanatory variables. The number of subjects with a prediction error of RT within ±1 min was 36 (87.8%) of 41 in multiple regression analysis. We could predict RT following SDX administration by using the RT prediction expression with RR obtained for subjects administered RCR during the surgery. Furthermore, our results suggest that the SDX dose able to achieve optimum RT may be set prior to surgery on the basis of the present methodology.

Pharmacokinetic and pharmacodynamic model for analysis of adalimumab administered for Crohn's disease.

Adalimumab (ADA) is used as a therapeutic agent for Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has not been analysed theoretically. The present study analysed of sequential changes in the Crohn's disease activity index (CDAI) after repeated administrations of adalimumab using a pharmacokinetic and pharmacodynamic model. In addition, we analysed the validity of the dosage regimen, and the potential efficacy gained by increasing the dose and reducing the interval of administration. The sequential changes in CDAI values obtained with our model were in good agreement with observed CDAI values, which is considered to show the validity of our analysis. We consider that our results showed the importance of a loading dose of adalimumab to obtain remission in an early stage of active CD. In addition, we showed that patients who have an incomplete response to adalimumab can obtain similar efficacy from increasing the dose and reducing the dose interval. In conclusion, our results showed that the present model may be applied to predict the CDAI values of adalimumab for CD. They indicate the validity of the dosage regimen, as well as the efficacy of increasing the dose and reducing the dose interval.

Impact of holding position during inhalation on drug release from a reservoir-, blister- and capsule-type dry powder inhaler.

OBJECTIVE: To determine whether drug release may be impaired by tilting some dry powder inhalers (DPIs). METHODS: Using an inhalation simulator, we measured drug release from Turbuhaler® (TBH), Diskus® (DKS) and Breezhaler® (BZH) at several peak inhaled flow rates (PIFs) while the DPIs were held at level and tilted (80°). Drug release was then measured from all three DPIs at 0, 30, 60 and 90° of tilt, and capsule rotation was also recorded. RESULTS: Drug release from TBH was flow-dependent while that from DKS and BZH was flow-independent. With TBH, the plot of drug release vs. PIF either at level or at tilted position scattered along approximately the same regression lines. With DKS and BZH, drug release at tilted position was significantly lower than that while at level. With DKS the decrease was almost 20%, while with BZH, drug release frequently failed. With BZH, significant reductions in drug release were observed while the device was tilted by 30-90°. CONCLUSION: The position in which the DPI is held may affect drug delivery, especially when using BZH.

Analysis of Clinical Efficacy and Adverse Effects of ß-Blocking Agents Used Clinically for Chronic Heart Failure.

Clinical efficacy and adverse effects of the ß-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure. Initially, we evaluated occupancy binding to the ß1 and ß2 receptors (Фssß1 and Фssß2) by these drugs. Thereafter, we examined the relationship between Фssß1 values and left ventricular ejection fraction (LVEF) increase rate to determine efficacy. The result showed that the efficacy with carvedilol could be attained with a lower Фssß1 value than the others. Therefore, we constructed a model under the assumption that ß-blocking agents exert both indirect action of LVEF increase through the ß1 receptor and direct action on ryanodine receptor 2. Using the model, it was suggested that these drugs have no differences in regard to the efficacy, while it was clarified theoretically that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses. We also investigated decreases in heart rate and forced expiratory volume in 1 s as adverse effects of ß-blocking agents using a ternary complex model. It was indicated that carvedilol is less likely to induce a heart rate decrease. Meanwhile, it was also suggested that the risk of an asthmatic attack was higher for carvedilol at clinical doses. Our results are considered useful for selection of a proper ß-blocking agent and its administration at a reasonable dose for successful heart failure therapy.

Evaluation of drug efficacy of DPP-4 inhibitors based on theoretical analysis with pharmacokinetics and pharmacodynamics.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically as therapeutic agents for the treatment of diabetes. To determine the rate of DPP-4 inhibition induced by these inhibitors, pharmacokinetic and pharmacodynamic parameters were used to theoretically examine the relationship between the rate of DPP-4 inhibition and clinical efficacy following the administration of four different DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in the level of glucagon-like peptide-1 (GLP-1) induced by their administration. On the basis of the relationship shown, changes in clinical efficacy in association with dose change were examined in order to discuss clinical dosage from the standpoint of proper usage. The results indicate that a high rate of DPP-4 inhibition is necessary for the onset of the effect of an administered the DPP-4 inhibitor and that the average value for the DPP-4 inhibition rate can be utilized as a common parameter of clinical efficacy. Furthermore, the efficacy profiles of the present DPP-4 inhibitors could be demonstrated on the basis of an increase in the GLP-1 level. It is considered that the present findings provide useful information for promoting the proper clinical use of DPP-4 inhibitors. Copyright © 2016 John Wiley & Sons, Ltd.

Prediction of Therapeutic Effect of Rasburicase on Hyperuricemia Associated with Chemotherapy Based on Theoretical Model.

Rasburicase has a strong and fast effect for reducing blood levels of uric acid. However, there have been no reports of theoretical analysis for the rational dose and interval of administration. Thus we constructed a pharmacokinetic and pharmacodynamic model to determine changes in uric acid level after rasburicase administration at various doses and regimens. The time courses of uric acid level predicted using our model were in good agreement with observed data, indicating adequate performance for our model. The therapeutic effects after a single infusion at various rates of generation of uric acid were predicted. The maximum effect was not a large difference, in spite of the generation rate. Then, the therapeutic effects of repeated administrations were predicted. The effect did not change when rasburicase was administered at more than the usual dose. Besides, as the administration interval increased, the difference between minimum and maximum level of uric acid became greater. However, in all doses and regimens, adequate therapeutic effects were obtained. In conclusion, the model was found useful for predicting therapeutic effect of rasburicase and individually determining rational dosage regimen of rasburicase.

Investigation of Appropriate Inhalation Technique for Mometasone Furoate Dry Powder Inhaler.

The aim of this study was to establish an appropriate inhalation method with a mometasone furoate dry powder inhaler (MF-DPI). Utilizing a tone-based inhalation training device, we investigated the maximum peak inspiratory flow rate time (Tmax PIFR) and peak inspiratory flow rate (PIFR) to determine whether either had an influence on lung deposition with use of an MF-DPI. A low tone indicated a PIFR of 28 L/min and a high tone that of 40 L/min, while 60 L/min was considered to be the standard. We established an inhalation profile in consideration of a human inhalation pattern, in which Tmax PIFR was set at 0.5 s (Tmax PIFR 0.5 s) and 2.5 s (Tmax PIFR 2.5 s). The reference cut-off value derived with a cascade impactor test was used for evaluation of the rate of delivered dose in the lung, which was the amount of drug from stage 3 to 7 at all PIFRs. We then investigated the relationship of the fine particle fraction (FPF) with the claimed dose at Tmax PIFR of 0.5 s and PIFR. There were no differences among the Tmax PIFR values for the doses emitted from the device or for the rate of delivered doses in stages 3-7. However, FPF for the claimed dose at 40 L/min was significantly lower than that at 60 L/min, which was dependent on PIFR. Our results showed that PIFR but not Tmax PIFR has an effect on lung deposition after inhalation with an MF-DPI.

Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin.

5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5-HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin.

Theoretical analysis of headache recurrence in patients administered triptans for migraine based on receptor occupancy.

BACKGROUND: In this study, we retrospectively analyzed the relationship between headache recurrence and serotonin 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Triptans marketed in Japan (sumatriptan, zolmitriptan, eletriptan, rizatriptan, naratriptan) were investigated. METHODS: Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. We examined the relationships between recurrence rate and elimination half-lives, and Ф1B and Ф1D, as calculated from the time-course of plasma drug concentration obtained from other studies. The time until Ф1B and Ф1D became 50% or less, 40% or less, and 30% or less was calculated as duration time to examine the relationship with recurrence rate. RESULTS: For Ф1B, eletriptan remained at a low level. For Ф1D, it was indicated that all triptans obtained an occupancy of 80% or higher at maximum. For all items, though recurrence tended to be lower along with longer half-life, no significant statistical correlation was found. For both Ф1B and Ф1D, the recurrence rate tended to be lower as the duration became longer. In addition, a significant correlation was observed for Ф1D (p < 0.05). For clarifying the Ф value and time period most closely correlated with recurrence rate, recurrence and Ф1B and Ф1D at 6, 12, and 18 h after administration were calculated. The most significant correlation was observed between recurrence rate and Ф1D at 12 h after administration (p < 0.01). CONCLUSIONS: As an index for evaluating headache recurrence following triptan administration, recurrence rate and Ф1D value at 12 h after administration were found to be most closely correlated and useful for analysis. Our results indicate that headache recurrence inhibition can be evaluated using these values.

The evaluation method for antiplatelet effect of acetylsalicylic acid.

Reduced platelet aggregation by acetylsalicylic acid administration has been associated with adverse outcomes in patients with thrombotic diseases, thus it is important to determine aspirin resistance in those cases. The antiplatelet effect of acetylsalicylic acid is rarely measured, but it has many problems. The aim of this study was to find the evaluation method for antiplatelet effect after administration of acetylsalicylic acid. We developed a particle counting method based upon laser light scattering, and utilized the platelet aggregation agonists, collagen, at 0.25, 0.5 and 1.0 µg/mL, and adenosine diphosphate (ADP), at 0.5, 1.0 and 2.0 µM, to determine their effective concentrations. Seventeen healthy volunteers were administered acetylsalicylic acid at 162 mg/day, with platelet aggregation determined before and 20 min after administration. In all subjects, the rate of platelet aggregation induced by 1.0 µg/mL of collagen before taking acetylsalicylic acid was the highest value obtained, while 20 min after acetylsalicylic acid administration, aggregation induced by collagen at 1.0 µg/mL was significantly decreased as compared to before administration. As for the other concentrations of collagen and all those of ADP tested, platelet aggregation was either not significantly induced before taking acetylsalicylic acid or the rate of aggregation was not significantly decreased after taking acetylsalicylic acid. Our results indicate that collagen at 1.0 µg/mL is appropriate as a platelet aggregation agonist for evaluating the antiplatelet effect of acetylsalicylic acid. Thus, it is useful that the measurement is performed only once.

Theory-based analysis of clinical efficacy of triptans using receptor occupancy.

BACKGROUND: Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. METHODS: To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated. RESULTS: Our calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration. CONCLUSIONS: These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Method for individualized evaluation of antiemetic effect induced by 5-HT3 receptor antagonist.

5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 ± 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.

Theoretical analysis of efficacy of biological agent for rheumatoid arthritis based on target molecular binding occupancy.

Recently, biological agents have been used for treatment of rheumatoid arthritis (RA), though the standard therapeutic doses vary among the agents utilized. To investigate the mechanisms related to those differences, we theoretically analyzed the target molecular binding occupancies of 4 biological agents: tocilizumab, infliximab, adalimumab, and etanercept. The average binding occupancy to the target molecule (Φss) was estimated to be 99.50 ± 0.44 % in a steady state after administration of the standard therapeutic dose of each agent. Furthermore, achieved American College of Rheumatology (ACR) 20, used as an index of clinical efficacy, increased in correlation with the value for Φss. These results suggest that clinical effects are achieved with a high value of target molecular binding occupancy. Thus, we considered that all of the agents examined in this study are antagonists and elicit clinical efficacy by inhibiting the signaling of biologically active substances that are not necessary for life maintenance and are secreted or released specifically in pathological conditions. In addition, target molecular binding occupancy can be used as an appropriate index for evaluating the standard therapeutic dose of biological agent for RA.

Interactions between new quinolone antibacterials and diagnostic drug containing manganese.

A diagnostic drug containing manganese chloride tetrahydrate as a major ingredient is available since 2006. It is used in magnetic resonance imaging as a negative contrast medium for magnetic resonance cholangiopancreatography of the gastrointestinal tract. However, there is no report regarding interaction between manganese and new quinolone antibacterials. We investigated the interactions between new quinolone antibacterials and a diagnostic drug containing manganese in vitro. We evaluated the rate of formation of chelate complex by reacting new quinolone antibacterials (levofloxacin, ofloxacin, ciprofloxacin) with a diagnostic drug containing manganese. The EC50 values of the formation of chelate complex for levofloxacin, ofloxacin, and ciprofloxacin were 5.14 ± 0.14, 5.29 ± 0.14, and 0.96 ± 0.04 mM, respectively. The rates of formation of chelate complex by levofloxacin, ofloxacin, and ciprofloxacin in a reaction with the diagnostic drug were 17.0, 18.9, and 55.5 % in clinical condition, respectively. Our results suggest that a complex of each antibacterial and manganese was formed, with ciprofloxacin causing the strongest interaction. In addition, our findings indicate that the degree of interaction may be an important problem in clinical settings with concomitant administration of a new quinolone antibacterial and diagnostic drug containing manganese.

OPTIMAL PLASMA CONCENTRATION OF THROMBOMODULIN ALFA TO TREAT SEPSIS-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION.

ABSTRACT: Thrombomodulin alfa (TM alfa) has been shown effective for treatment of disseminated intravascular coagulation (DIC) associated with sepsis, although the optimal therapeutic plasma concentration has not been clarified. In the present study, the plasma trough concentration of TM alfa in septic patients with DIC was determined, then the cutoff value for that concentration showing influence on treatment outcome was calculated using a receiver operating characteristic curve. With a cutoff value of 1,010, the area under the curve of the receiver operating characteristic was 0.669 (95% confidence interval, 0.530-0.808), with sensitivity of 0.458 and specificity of 0.882. To evaluate its accuracy, patients were divided into those above or below the cutoff value, and 90-day survival rates were compared. The above-cutoff group showed a significantly higher 90-day survival rate (91.7%) as compared with the below-cutoff group (63.4%) ( P = 0.017), with a hazard ratio of 0.199 (95% confidence interval, 0.045-0.871). Interestingly, the incidence of hemorrhagic adverse effects was not significantly different between the groups. Based on these results, the recommended plasma trough concentration of TM alfa for treatment of septic DIC is 1,010 ng/mL, which should minimize the risk of severe bleeding while maximizing the therapeutic effect.

Theoretical investigation of aspirin dosage regimen to exhibit optimal antiplatelet effects and decrease risk of upper gastrointestinal lesions.

We investigated dosage regimens for aspirin therapy in regard to antiplatelet effects in patients without gastrointestinal lesions. Findings for inhibition of biosynthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)) were simulated based on pharmacokinetic and pharmacodynamic models using an irreversible process of inhibition of cyclooxygenase-1 (COX-1) by aspirin. We found that the inhibition of biosynthesis of TXB(2) at a steady state was greater than 90% when the dose of aspirin administered exceeded 81 mg, which was considered to exhibit a sufficient antiplatelet effect. Furthermore, it was confirmed that a dose of 162 mg or more is needed to exert an immediate antiplatelet effect on the initial day of administration. On the other hand, the inhibition of biosynthesis of PGE(2) ranged from 40-90% when aspirin was administered at a dose of 10.125-324 mg. Thus, the risk of gastrointestinal lesions differed in a dosage-dependent manner. The biosynthesis inhibition of PGE(2) was calculated to be 37.9%, with that value set as the target level for prevention of gastrointestinal disorders. We also noted a difference between platelets and gastric mucosa cells in regard to the turnover rate of COX-1, and attempted to simulate the inhibition of biosynthesis of TXB(2) and PGE(2) following administration of aspirin. However, it was not possible, as the inhibition of biosynthesis of TXB(2) was greater than 90% and that of PGE(2) was less than 37.9%, even with various dosage regimens. Our findings suggest that it is difficult to determine a rational dosage regimen of aspirin to exert an antiplatelet effect without inducing gastrointestinal lesions.

Prediction of distribution volume of vancomycin in critically ill patients using extravascular lung water and pulmonary vascular permeability indices.

OBJECTIVE: Alterations in distribution volume affect the concentrations of hydrophilic drugs in plasma and tissues at the time of initial therapy. When the distribution volume of hydrophilic antimicrobials is increased in critically ill patients with a serious infection, antimicrobial concentrations are reduced, which may adversely affect the efficacy of antimicrobial therapy. A transpulmonary thermodilution technique system (PiCCO) enables measurements of pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI), which are related to pulmonary edema and pulmonary vascular permeability, respectively. In addition, those indices may also be related to the distribution volume of hydrophilic antimicrobials. The aim of this study was to investigate the relationships of PVPI and EVLWI with the distribution volume of vancomycin (Vss), as well as to establish a method for estimating Vss for planning an appropriate initial dose for individual patients. METHODS: Seven patients were administered vancomycin intravenously and underwent extended hemodynamic monitoring with the PiCCO system in the intensive care unit (ICU) from April 2009 to March 2011. Vss was calculated using the Bayesian method, and the relationships of PVPI and EVLWI with Vss were investigated. RESULTS: The relationship between Vss/actual body weight (ABW) and median EVLWI on days when blood levels were measured was significant (r = 0.900, p = 0.0057), whereas the relationship between Vss/ABW and PVPI was not significant (r = 0.649, p = 0.1112). CONCLUSION: EVLWI determined by the PiCCO system is useful to predict Vss and should lead to more effective vancomycin therapy for critically ill patients at the initial stage.

Theory-based analysis of anti-inflammatory effect of infliximab on Crohn's disease and rheumatoid arthritis.

In Japan, the recommended dosage regimens of infliximab (IFX) for treatment of rheumatoid arthritis (RA) and Crohn's disease (CD) are different. However, the differences have not been analyzed theoretically. In a previous study, we constructed a pharmacokinetic-pharmacodynamic model to investigate the effects of IFX for CD and found it useful to establish a rational dosage regimen of IFX for individual patients with CD. In the present study, we investigated whether the theory-based model could be used for cases of RA and also used it to evaluate the validity of the dosage regimen. The results obtained with our model were in good agreement with observed tender joint count (TJC) ratio data, which was considered to show the validity of our analysis. Thus, we concluded that the model could be used for patients with RA. Furthermore, a second administration of IFX given 2 weeks after the first infusion was important to achieve remission in the early stage of RA. We also compared the estimated pharmacodynamic parameters of RA with those of CD. The elimination rate constant of inflammation in RA was greater than that in CD, suggesting that the recovery from inflammation in RA is faster than that in CD, and indicating a reason for the difference in dosage between RA and CD. In conclusion, use of our model in light of the individual quantitative factor of tumor necrosis factor (TNF)-α allows establishment of IFX dosage regimens for individual patients.