Alvimopan Is Associated With a Reduction in Length of Stay and Hospital Costs for Patients Undergoing Radical Cystectomy.

OBJECTIVE: To evaluate the impact of alvimopan in patient undergoing radical cystectomy (RC) for bladder cancer. We hypothesize that alvimopan can decrease cost for RC by reducing length of stay (LOS). METHODS: We identified patients who underwent elective RC for bladder cancer from 2009 to 2015 in the Premier Healthcare Database, a nationwide, all-payer hospital-based database, and compared patients who received and did not receive alvimopan in the perioperative period. Hospitals that had no record of administering alvimopan for patients undergoing RC were excluded. The primary outcomes were LOS and the direct hospital costs. The secondary outcomes were 90-day readmission for ileus and major complications. RESULTS: After applying the inclusion criteria, the study cohort consisted of 1087 patients with 511 patients receiving perioperative alvimopan. Alvimopan was associated with a reduction in hospital costs by -$2709 (95% confidence interval: -$4507 to -$912, P = .003), decreased median LOS (7 vs 8 days, P < .001), and lower likelihood of readmission for ileus (adjusted odds ratio: 0.63, P = .041). While alvimopan use led to higher pharmacy costs, this was outweighed by lower room and board costs due to the reduced LOS. There was no significant difference between 2 groups regarding major complications. These results were robust across multiple adjusted regression models. CONCLUSION: Our data show that alvimopan is associated with a substantial cost-saving in patients undergoing RC, and suggest that routine use of alvimopan may be a potential cost-effective strategy to reduce the overall financial burden of bladder cancer.

Prediction of treatment failure during infliximab induction therapy in inflammatory bowel disease patients based on pharmacokinetic and pharmacodynamic modeling.

BACKGROUND: In infliximab (IFX) treatment for Crohn's disease (CD) and ulcerative colitis (UC), it is difficult to predict treatment failure during the induction phase. In the present study for optimal IFX treatment, we attempted to estimate serum IFX concentration and clinical response in individual patients during the induction phase to predict the indication of therapeutic effect and the possibility of treatment failure in the maintenance phase. METHODS: We estimated pharmacokinetic and pharmacodynamic (PK/PD) parameters and predicted the serum IFX concentration and clinical response using a PK/PD model and Markov chain Monte Carlo Bayesian analysis method during the induction phase. Then, we determined whether the indication of therapeutic effect between predicted and observed clinical response were matched during the maintenance phase. RESULTS: Data obtained from 15 patients were analyzed. The correlation between predicted and observed values of serum IFX concentration (Pearson product-moment correlation coefficient, 0.700; P < 0.0001, n = 68) and clinical response of CD patients (0.790; P < 0.0001, n = 25) and UC patients (0.702; P = 0.0004, n = 21) were significantly high. The indication of therapeutic effect at the final time point of each patient (from day 115 to day 203) were successfully predicted in 14 of 15 patients (93.3%). CONCLUSIONS: This study presents prediction of serum IFX concentration and clinical response in individual patients during induction therapy, with presumption of the indication of therapeutic effect and the treatment failure in the maintenance phase. Our results show the possibility of optimizing IFX therapy during the induction phase.

Implementation of infliximab standardized doses after pharmacokinetic modelization in a cohort of patients with Crohn's disease.

BACKGROUND: According to infliximab (IFX) license in Crohn's disease (CD), infusion doses are based on patient's body-weight. Dose banding providing standardized doses (SD) has been implemented in parenteral chemotherapy in order to optimize aseptic unit capacity and reduce drug expenditure, duration of hospital stay and costs without decreasing efficacy. MATERIAL AND METHOD: The first part was a single-center retrospective analysis of consecutive CD patients receiving IFX maintenance therapy to determine standardized doses covering more than 50% of infusions. The second part was a prospective cohort study assessing the impact of SD compared to body-weight doses (BWD) on admission duration and costs. RESULTS: Six IFX SD covering more than 90% of infusion doses were implemented for dose banding. According to the Monte-Carlo simulation, there was no significant difference between IFX SD and BWD maintenance regimens. When assessed prospectively in 116 patients (75 patients treated with SD and 41 with BWD) corresponding to 128 infusions, hospitalization duration was shortened by 70 min per patient (p < 0.001). CONCLUSION: According to a pharmacokinetic model, IFX SD has a pharmacokinetic profile close to BWD and is associated with reduced length of hospitalization in a cohort of patients with CD. IFX SD implementation could optimize infusion units functioning and, save time and costs without decreasing efficacy.

Infliximab Maintenance Dosing in Inflammatory Bowel Disease: an Example for In Silico Assessment of Adaptive Dosing Strategies.

Infliximab is an anti-tumour necrosis factor alpha monoclonal antibody used to treat inflammatory diseases. Many patients fail during induction and others respond initially but relapse during maintenance therapy. Although anti-drug antibodies (ADA) are associated with some clinical failures, there is evidence that some failures may be due to subtherapeutic exposure. Adapting doses based on clinical outcomes and trough concentrations can improve response and reduce the proportion that develop ADA, but identification of appropriate doses in the presence of time-varying patient factors is complicated. Several adaptive dosing strategies (label recommendations versus therapeutic drug monitoring with an established stepwise algorithm or proportional dose adjustments or Bayesian population pharmacokinetic model-based dosing) were simulated on a virtual population (constructed with time-varying covariates and random effects on individual pharmacokinetic parameters) using R to assess their relative performance. Strategies were evaluated on their ability to maintain trough infliximab concentrations above an established target, 3 mg/L, during maintenance phase. Model-based dosing was superior in maintaining target trough concentrations, showing individuals in maintenance achieving concentrations above the target faster and a lower proportion of individuals who developed ADA. Model-based dosing results were consistent across a range of baseline covariate groups. This in silico assessment of adaptive dosing strategies demonstrated that, when challenged with dynamic covariate and random effect changes occurring in individual pharmacokinetic parameters, model-based approaches were superior to other strategies. Model-based dosing has not been tested clinically; however, the potential benefits of model-based dosing for infliximab suggest that it should be investigated to reduce subtherapeutic exposure.

Biosimilar monoclonal antibodies: preclinical and clinical development aspects.

Biological drugs and their originated biosimilars are large, highly complex molecules derived from living cells or organisms. Traditional medicines, by contrast, are usually simple molecules of low molecular weight, synthesised by chemical means. The distinct complexities and methods of manufacture create an important difference between biosimilars and conventional generic drugs: while chemical generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biological therapies are inherently variable, creating unavoidable differences between even subsequent batches of the same product. An expiring patent does not necessarily mean that the manufacturing process of the originator product becomes available to the biosimilar developers (for instance, the relevant cell line clone and growth medium). Therefore, it cannot be guaranteed that biosimilar products are identical to their reference product on a molecular level. This difference has important implications for the regulation and licensing of biosimilars. While conventional generic drugs require only a limited comparison and demonstration of identical chemical structure to the reference product, biosimilars require far more rigorous testing. In general, there must be a thorough comparison of structural and functional characteristics between biosimilar and originator drug. Stepwise nonclinical in vitro and in vivo approaches are recommended to evaluate the similarity of both drugs and any identified micro-heterogeneities must then be assessed for their impact on safety and clinical performance. Subsequently, clinical pharmacokinetic (PK) studies need to be performed in order to demonstrate a similar PK profile, prior to conducting clinical efficacy trials.

Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease.

OBJECTIVES: Standard infliximab maintenance dosing of 5 mg/kg every 8 weeks may be inadequate to consistently achieve sufficient drug exposure to minimize loss of response or treatment failure in pediatric Crohn disease (CD). We aimed to determine the predicted infliximab trough concentrations in children with CD during maintenance therapy and the percentage of patients achieving target trough concentration >3 µg/mL. METHODS: A Monte Carlo simulation analysis was constructed using a published population pharmacokinetic model based on data from 112 children in the REACH trial. We assessed maintenance dosing strategies of 5, 7.5, and 10 mg/kg at dosing intervals of every 4, 6, and 8 weeks for children that differed by age, weight, albumin level, and concomitant immunomodulator therapy. RESULTS: Based on the index case of a 10-year-old with CD receiving standard infliximab dosing with concomitant immunomodulator therapy, the median (interquartile range) simulated infliximab trough concentration at week 14 was 1.3 (0.5-2.7) µg/mL and 2.4 (1.0-4.8) µg/mL for albumin levels of 3 and 4 g/dL, respectively. Among 1000 simulated children in the model, trough concentration >3 µg/mL at week 14 was achieved 21% and 41% of the time for albumin levels of 3 and 4 g/dL, respectively. CONCLUSIONS: Standard infliximab maintenance dosing in children with CD is predicted to frequently result in inadequate exposure, especially when albumin levels are low. Optimized dosing strategies for individual patients are needed to achieve sufficient drug exposure during infliximab maintenance therapy.

Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice.

BACKGROUND: Infliximab (IFX) is effective in the treatment of inflammatory bowel diseases (IBD). Currently, IFX is administered at fixed doses and intervals; however, costs are high and optimisation is necessary. Several publications indicate that IFX should be dosed on trough levels ≥3.0 mg/L. For optimising IFX dosing, the use of a pharmacokinetic model is important. Population pharmacokinetics of IFX have been described earlier; however, these models were not used for dose optimising. AIMS: To develop a pharmacokinetic model for IFX in IBD patients that can be used for dose-optimisation of IFX and to predict serum trough levels in this population. METHODS: An observational retrospective study was performed in 42 IFX-treated IBD patients. Serum samples were drawn before infusion at T = 0, 2, 6, 14, 22 and 54 weeks and analysed for IFX and antibodies against IFX (ATI). Relevant covariates were recorded and a population pharmacokinetic model was developed. RESULTS: Individual plots created using the final model showed good correspondence between observed and model predicted values. Serum levels were influenced by ATI, disease activity, sex and albumin. Our results show that in patients without ATI target trough levels ≥3.0 mg/L can be achieved by increasing dosing intervals from 8 to 12 weeks combined with a dose increase. This results in a reduction of 33% in concomitant costs. CONCLUSIONS: In IBD patients without ATI, trough level dosing based on longer intervals can reduce IFX therapy-related visits to the hospital with one-third. Trough level based dose intensification should always be justified by disease activity parameters.

A pharmacokinetic approach to model-guided design of infliximab schedules in ulcerative colitis patients.

BACKGROUND: Infliximab, an anti-tumour necrosis factor approved for treatment of Crohn´s disease and ulcerative colitis, is administered at predefined interdose intervals. On insufficient response or loss of response, treatment can be intensified. The lack or loss of response is likely related to complex pharmacokinetics of infliximab. AIMS: To explore optimal dosing strategies of infliximab in treatment-naïve patients with ulcerative colitis through predictive Monte Carlo simulations based on a validated population PK model. METHODS: A population of 2,000 treatment-naïve patients was generated by Montecarlo simulation. Six dosing strategies for maintenance therapy were simulated on this population. Strategies 1 and 2 consisted on 5 mg/kg and 6 mg/kg doses, respectively, and 8 weeks inter-dose interval. Strategies 3 and 4 used Individualized doses, adjusted to albumin level, sex and body weight, and a fix interdose interval of 8 weeks to achieve a target trough concentration of 5 mg/L or 6 mg/L, respectively. Strategies 5 and 6 used a fix dose of 5 mg/kg and individualized inter-dose intervals, adjusted to the same covariates, to achieve a target concentration, of 5 mg/L or 6 mg/L, respectively. RESULTS: Strategies 2-6 reached trough levels statistically higher than strategy 1 (p < 0.05). Strategy 5 proved to be the best dosing strategy. It was associated with a higher proportion of responder patients than strategy 1 (62 % vs. 40 %) without reaching higher peak concentrations. CONCLUSIONS: Optimization of maintenance treatment of colitis with infliximab by a pharmacokinetic approach could benefit infliximab-naive patients with ulcerative colitis.

Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. METHODS: We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 µg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. RESULTS: At screening, 115 of 263 patients had a TC of infliximab of 3-7 µg/mL (43.7%). Of 76 patients with TCs <3 µg/mL, 69 patients (91%) achieved TCs of 3-7 µg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 µg/mL, 67 patients (93%) achieved TCs of 3-7 µg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018). CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 µg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.

Experimental assessment of chemotherapy-induced early intestinal damage in colon cancer the lactulose-mannitol permeability test.

AIMS AND BACKGROUND: Although chemotherapy plays an important role in the management and cure of cancer, it has undesiderable side effects mostly affecting the bone marrow and gastrointestinal tract, which greatly limit patient compliance and treatment efficacy. METHODS: The lactulose-mannitol test was used to assess intestinal mucosa damage 48 hours after the end of the first adjuvant chemotherapy cycle with 5-fluorouracil (5-FU) and levamisole in 12 patients with colon cancer. Fifteen age- and sex-matched subjects were studied as controls. The excreted amount of lactulose and mannitol was expressed as the percentage of the administered doses recovered in the urine as well as their ratio. RESULTS: The percent urinary recovery of lactulose was significantly (P < 0.001) higher in colon cancer patients (1.1 +/- 0.5%) than in the control group (0.3 +/- 0.03%), whereas the mannitol recovery was only slightly reduced in the former. As a result, the lactulose/mannitol excretion ratio was significantly (P < 0.001) higher in colon cancer patients (0.07 +/- 0.03) than in the control group (0.01 +/- 0.01). CONCLUSIONS: As assessed by the lactulose-mannitol test, the combined chemotherapy regimen with 5-FU and levamisole affects mainly the barrier function of the intestinal mucosa rather than its absorption capacity. The toxic effect seems to be attributable to the 5-FU molecule rather than to levamisole. The lactulose-mannitol test is a simple, safe and reliable tool to evaluate chemotherapy-induced early damage to the intestinal epithelium, in particular when new kinds of substances are being administered. Its use in clinical practice seems appropriate to establish the correct timing of drug administration, thereby enhancing treatment efficacy and improving patient compliance.

Pharmacokinetic/pharmacodynamic assessment of the effects of E4031, cisapride, terfenadine and terodiline on monophasic action potential duration in dog.

1. Torsades de pointes (TDP) is a potentially fatal ventricular tachycardia associated with increases in QT interval and monophasic action potential duration (MAPD). TDP is a side-effect that has led to withdrawal of several drugs from the market (e.g. terfenadine and terodiline). 2. The potential of compounds to cause TDP was evaluated by monitoring their effects on MAPD in dog. Four compounds known to increase QT interval and cause TDP were investigated: terfenadine, terodiline, cisapride and E4031. On the basis that only free drug in the systemic circulation will elicit a pharmacological response target, free concentrations in plasma were selected to mimic the free drug exposures in man. Infusion regimens were designed that rapidly achieved and maintained target-free concentrations of these drugs in plasma and data on the relationship between free concentration and changes in MAPD were obtained for these compounds. 3. These data indicate that the free ED50 in plasma for terfenadine (1.9 nM), terodiline (76 nM), cisapride (11 nM) and E4031 (1.9 nM) closely correlate with the free concentration in man causing QT effects. For compounds that have shown TDP in the clinic (terfenadine, terodiline, cisapride) there is little differentiation between the dog ED50 and the efficacious free plasma concentrations in man (< 10-fold) reflecting their limited safety margins. These data underline the need to maximize the therapeutic ratio with respect to TDP in potential development candidates and the importance of using free drug concentrations in pharmacokinetic/pharmacodynamic studies.