Schedule Of Drug Administration Research Articles

Antisecretory treatment: clear-cut benefit and potential risk

Proton pump inhibitors (PPI) remain a key element in the management of acid-dependent diseases. The antisecretory drug administration schedule should take into account the nature of the disease and the research data reflected in relevant international consensus. The patient’s adherence to the PPI intake has a significant impact on the results of management of acid-dependent diseases. The benefit of PPI intake significantly exceeds the potential harm that is low or very low. To date, there is no conclusive evidence of the adverse effects of the prolonged use of PPI, however, if there is no indication for the PPI intake, it is not recommended to use high doses of the drug. The pharmacodynamic effect of different PPIs doesn’t differ significantly, however, according to experts’ opinion based on meta-analysis, esomeprazole has some advantage over other drugs.

Mathematical modelling of chemotherapy combined with bevacizumab

AbstractAntiangiogenic therapy is aimed at the blocking of angiogenesis, i.e., the process of new blood vessels formation, which should decrease oxygen and nutrients inflow to tumor and thus slow down its growth. This type of therapy is frequently administered together with chemotherapy, which kills rapidly proliferating tumor cells, as well as other dividing cells of the body, thus leading to significant adverse effects. However, action of bevacizumab inevitably influences the inflow of chemotherapeutic drug in tumor, therefore, optimal scheduling of drug administration is an important problem. Using a model based on consideration of the most crucial processes happening during tumor progression and therapy, we compare effectiveness of different schemes of combined chemotherapy with bevacizumab and propose new scheme of drug administration which may lead to enhanced antitumor effect compared to classical clinical scheme of simultaneous drug administration.

Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution.

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. ©2017 AACR.

Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model

Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30–40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.

Impact of CTLA-4 blockade in conjunction with metronomic chemotherapy on preclinical breast cancer growth

Background:Although there are reports that metronomic cyclophosphamide (CTX) can be immune stimulating, the impact of its combination with anti-CTLA-4 immunotherapy for the treatment of cancer remains to be evaluated.Methods:Murine EMT-6/P breast cancer, or its cisplatin or CTX-resistant variants, or CT-26 colon, were implanted into Balb/c mice. Established tumours were monitored for relative growth following treatment with anti-CTLA-4 antibody alone or in combination with; (a) metronomic CTX (ldCTX; 20 mg kg−1 day−1), b) bolus (150 mg kg−1) plus ldCTX, or (c) sequential treatment with gemcitabine (160 mg kg−1 every 3 days).Results:EMT-6/P tumours responded to anti-CTLA-4 therapy, but this response was less effective when combined with bolus plus ldCTX. Anti-CTLA-4 could be effectively combined with either ldCTX (without a bolus), or with regimens of either sequential or concomitant gemcitabine, including in orthotopic EMT-6 tumours, and independently of the schedule of drug administration. Tumour responses were confirmed with CT-26 tumours but were less pronounced in drug-resistant EMT-6/CTX or EMT-6/DDP tumour models than in the parent tumour. A number of tumour bearing mice developed spontaneous metastases under continuous therapy. The majority of cured mice rejected tumour re-challenges.Conclusions:Metronomic CTX can be combined with anti-CTLA-4 therapy, but this therapy is impaired by concomitant bolus CTX. Sequential therapy of anti-CTLA-4 followed by gemcitabine is effective in chemotherapy-naive tumours, although tumour relapses can occur, in some cases accompanied by the development of spontaneous metastases.

1H NMR-Based Metabonomic Study of Functional Dyspepsia in Stressed Rats Treated with Chinese Medicine Weikangning.

1H NMR-based metabolic profiling combined with multivariate data analysis was used to explore the metabolic phenotype of functional dyspepsia (FD) in stressed rats and evaluate the intervention effects of the Chinese medicine Weikangning (WKN). After a 7-day period of model establishment, a 14-day drug administration schedule was conducted in a WKN-treated group of rats, with the model and normal control groups serving as negative controls. Based on 1H NMR spectra of urine and serum from rats, PCA, PLS-DA, and OPLS-DA were performed to identify changing metabolic profiles. According to the key metabolites determined by OPLS-DA, alterations in energy metabolism, stress-related metabolism, and gut microbiota were found in FD model rats after stress stimulation, and these alterations were restored to normal after WKN administration. This study may provide new insights into the relationship between FD and psychological stress and assist in research into the metabolic mechanisms involved in Chinese medicine.

Azacitidine Use in the Real World Does Not Replicate AZA-001 Results in Higher Risk MDS/Low Blast Count AML: An Audit of 1101 Patients in the Cancer Care Ontario Registry

▪Background: In the AZA-001 trial, azacitidine (AZA) altered the natural history of patients with higher-risk MDS (Fenaux et al., Lancet 2009) by significantly improving overall survival compared to conventional care regimens (24.5 months versus 15.0 months). Once approved for drug reimbursement by the provincial health ministry, Cancer Care Ontario (CCO) mandated that all eligible patients be enrolled in a prospective registry to ensure compliance with eligibility criteria and schedules of drug administration. Baseline characteristics were recorded and treatment response were to be submitted every 6 cycles of treatment. Our objectives were to audit this clinical program for results after 6 years and identify the prognostic markers for survival in a homogenous higher-risk MDS/low blast count AML patient population.Methods: Only higher-risk MDS patients (intermediate-2, high) as defined by the International Prognostic Scoring System (IPSS) and low blast count AML (20-30% blasts) treated with AZA in Ontario, Canada from June 1, 2010 to March 2, 2016 were eligible and included. Our primary outcome was overall survival (OS) from date of first AZA treatment. Our secondary outcomes were overall response rates and the predictors of OS including administration schedules, centre size or type (regional cancer versus community). Univariate and multivariable Cox proportional hazard model were used to determine the predictors of OS. Hazard ratios and generalized R2 (higher the R2, stronger association with OS) were also calculated.Results: 825 higher-risk MDS and 276 low blast count AML were included (n = 1101 total). Median age was 74 years (range 19 to 99), 65.2% were male and the IPSS scores were intermediate-2 (64.3%) and high-risk (35.7%). Sixty-six percent of patients were transfusion dependent (TD) at time of AZA initiation and 15.5% had received previous chemotherapy. By dosing schedule, 24.7% received AZA for 7 consecutive days (7d), 12.4% for 6 consecutive days (6d) and 62.9% by the 5-2-2 schedule. Overall, the median number of cycles received was 6 (range 1 to 67) and 8 (range 6 to 14) when restricted to the 692 (63%) patients who received at least 4 cycles of treatment. Dose reductions were seen in 33.3% of patients (mean 11.1 mg/m2 in those with reductions) and were more common over time (negative slope 0.178; p < .0001). Of those with repeat bone marrow (n = 293) best response was complete response (CR) in 16.7% and partial response (PR) in 10.6%. Of those without CR/PR/progressive disease on bone marrow (n = 814), 20.4% experienced hematologic improvement including those with marrow CR and marrow stable disease. The actuarial median survival was 11.6 months (95% CI 10.7- 12.4) with a significantly longer OS for MDS compared with low blast count AML (12.4 months vs. 9.6 months; p = .0002) and 16.7 months (95% CI 15.2-18.1) for those receiving at least 4 cycles. There was no difference in OS between the 3 dosing schedules (11.7 months (7d) vs. 10.2 months (6d) vs. 12.0 months (5-2-2); p = .87; figure 1A), regional cancer centre vs. community (11.3 months vs. 11.7 months; p = .19; figure 1B) or by centre volume (11.4 months < 50 patients vs. 11.6 months > 50 patients; p = .38; figure 1C). On univariate analysis, the following were predictive of OS: blast percentage, number of cytopenias, karyotype, IPSS, WHO classification, TD, greater transfusion burden and secondary MDS. The multivariate model with the highest R2 (13.5%) included blast percentage (p < .0001), karyotype (p < .0001), cytopenias (p = .038), TD (p < .0001) and secondary MDS (p = .0006) as summarized in the table below.Conclusions: In our large real world evaluation of AZA use in higher-risk MDS/low blast count AML, we validated the expected overall response rates to AZA but demonstrated a lower than expected OS compared to the AZA-001 trial. Reassuringly, survival did not differ by dosing schedules, centre volumes or center type (regional cancer vs. community). OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realized. This represents the largest real world evaluation of AZA in higher-risk MDS/low blast count AML and additional analyses are underway. [Display omitted] [Display omitted] DisclosuresMozessohn:Celgene: Honoraria. Buckstein:Celgene: Honoraria, Research Funding; Novartis: Honoraria.

Optimization of an in vitro chemotherapy to avoid resistant tumours

Chemotherapy use against solid tumours often results in the resistance of the cancer cells to the molecule used. In this paper, we will set up and analyse an ODE model for heterogeneous in vitro tumours, consisting of cells that are sensitive or resistant to a certain drug. We will then use this model to develop different protocols, that aim at reducing the tumour volume while preserving its heterogeneity. These drug administration schedules are determined through analysis of the system dynamics, and optimal control theory.

Evaluation of multidrug cancer chronotherapy based on cell cycle model under influences of circadian clock.

The intracellular circadian clock mechanisms are known to affect various substantial cellular machinery such as cell cycle progression, inflammatory response, apoptosis, and DNA repair. Cancer growth in various tissues is still under circadian control, which may be at least partly underlain by the survived connections between the intracellular machinery and the clock. Considering such findings, chronotherapy has been applied to cancer treatments, in which anti-cancer drugs are administered in scheduled circadian times so as to resolve the trade-off between damages against the normal and cancer cells. However, any effective administration strategy has not yet been established especially in a quantitative sense. In this study, we develop an automaton model of cell division cycle interacting with circadian clock and suffering from a probability of cell death. A cancer cell is modeled by shortening/ lengthening the cell division interval and a transition to motility state under starving condition. Population proliferating dynamics in 3D space are simulated under the diffusion of nutrient factor and the anti-cancer drugs from a vessel. The simulation results show that the drug administration schedule could differentiate the damages against proliferation of normal and cancer cells. This implies the existence of optimal timing for the drug administration, which could provide an efficient strategy of chronotherapeutic treatment of cancer.

Novel Bioluminescent Activatable Reporter for Src Tyrosine Kinase Activity in Living Mice.

Aberrant activation of the Src kinase is implicated in the development of a variety of human malignancies. However, it is almost impossible to monitor Src activity in an in vivo setting with current biochemical techniques. To facilitate the noninvasive investigation of the activity of Src kinase both in vitro and in vivo, we developed a genetically engineered, activatable bioluminescent reporter using split-luciferase complementation. The bioluminescence of this reporter can be used as a surrogate for Src activity in real time. This hybrid luciferase reporter was constructed by sandwiching a Src-dependent conformationally responsive unit (SH2 domain-Srcpep) between the split luciferase fragments. The complementation bioluminescence of this reporter was dependent on the Src activity status. In our study, Src kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to clinical small-molecular kinase inhibitors, dasatinib and saracatinib. This system was also applied for high-throughput screening of Src inhibitors against a kinase inhibitor library in living cells. These results provide unique insights into drug development and pharmacokinetics/phoarmocodynamics of therapeutic drugs targeting Src signaling pathway enabling the optimization of drug administration schedules for maximum benefit. Using both Firefly and Renilla luciferase imaging, we have successfully monitored Src tyrosine kinase activity and Akt serine/threonine kinase activity concurrently in one tumor xenograft. This dual luciferase reporter imaging system will be helpful in exploring the complex signaling networks in vivo. The strategies reported here can also be extended to study and image other important kinases and the cross-talks among them.

Long-lasting effect of NMDA receptor antagonist memantine on ethanol-cue association and relapse.

It is well known that the glutamatergic system plays a crucial role in alcohol addiction and especially in relapse-like behaviour. However, results of clinical studies on compounds that influence the activity of the glutamatergic system have been disappointing so far. The aim of our study was to establish treatment conditions under which the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine may produce more reliable treatment effect with respect to alcohol relapse-like behaviour. For this purpose, male Wistar rats were trained to associate several discrete stimuli with ethanol delivery. Thereafter, half of the animals received a brief memory reactivation session followed by two administrations of 20 mg/kg of memantine, while the other half received the same treatment without memory reactivation. Afterwards, a cue-induced ethanol-seeking behaviour test was performed followed by repeated extinction sessions and a reacquisition test. Our data show that administration of memantine reduced responding on the ethanol-associated lever in a cue-induced ethanol-seeking test. This reduction did not depend on whether or not a memory reactivation session was introduced prior to memantine administration. Following extinction, however, reacquisition of ethanol self-administration was only impaired in the group where memantine was given after a short memory reactivation session, showing that this schedule of drug administration produced a long-lasting disruption of the association between the conditioned stimuli and the delivery of ethanol. In conclusion, we show that memantine disrupted the drug-cue association, which consequently interfered with relapse-like behaviour supporting the possibility that memantine is a treatment option for alcoholism. Our data supports the possibility that memantine is a treatment option for alcoholism. However, the effectiveness of this drug seems to lie in its ability to disrupt conditioned behaviours and should be given in conjunction with exposure to conditioned drug stimuli.

Effect of taking L-T4 in bedtime vs morning on changes of serum thyroid hormone concentration in patients with hypothyroidism

Objective To compare the effect of L-T4 taken in the morning vs bedtime on serum thyroid hormone in patients with hypothyroidism. Methods Seventeen patients with primary hypothyroidism were prospectively included. They took L-T4 in the morning for 2 months followed by L-T4 taken during the bedtime for 2 months. Thyroid hormone levels and cholesterol, triglyceride, albumin, creatinine and heart rate were measured. Wilcoxon test and paired t test were used to compare the data. The correlation between the changes of TSH and FT3, FT4 was analyzed respectively by Pearson correlation analysis. Results TSH, FT3, FT4 were: (12.10±7.19) vs (3.90±3.47) mU/L, (4.14±0.86) vs (5.24±1.11) pmol/L, (12.72±4.40) vs (18.48±2.87) pmol/L for L-T4 taken in the morning and during the bedtime respectively (t value: 6.371, -3.166, -5.435, all P 0.05), respectively. The averaged changes were (8.20±5.31) mU/L, (1.09±1.42) pmol/L and (5.76±4.37) pmol/L. Triglyceride, cholesterol, albumin, creatinine levels and heart rate were not significantly different with L-T4 taken in the morning and during bedtime (t=0.240, 0.017; z=0; t=-0.610, 1.588, all P>0.05). Conclusions L-T4 taken during the bedtime by patients with hypothyroidism would reduce TSH and increase FT3, FT4 levels. This method can maintain the stability of TSH level with no need to increase the dose. Key words: Hypothyroidism; Thyroxine; Drug administration schedule

Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors

RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors. In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs. In part 2, schedule optimization (4 schedules of drug administration under fasting condition and 2 cohorts with liquid supplementation) was investigated in parallel, dose escalation designs. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) including MIC-1 elevation and platelet reduction, and safety/tolerability. With a single-dose treatment, a high-fat/high-energy meal and a new formulation under fasting condition, respectively, enhanced overall bioavailability of RG7112 slightly over twofold. Following multiple-dose administrations, all four schedules yielded the comparable per-cycle (28-d) exposure (AUC), as designed; liquid supplements also enhanced bioavailability. High-dose treatments of consecutive daily dosing for 5 and 3 days resulted in higher on-treatment-day exposure to RG7112 than both weekly and low-dose/long-duration (20-day) daily schedules. Serum MIC-1 and blood platelet profiles showed similar patterns to those of PK when the clinical pharmacology conditions were varied, suggesting the relative importance of treatment-day exposure than overall per-cycle AUC. Food (both high-fat and low-fat meals) and new formulation enhanced bioavailability. High-dose consecutive daily treatment for 3-5 days is superior to weekly and low-dose/long-duration (20-day) daily schedules in yielding the sufficiently high drug exposure and PD effects potentially required for cancer treatment efficacy.

Adherence to Anti-Retroviral Therapy in North Central Nigeria.

Nigeria bears nearly 10% of the global burden of HIV/AIDS. Most of the AIDS patients dwell in the part of Nigeria known as the "North Central" geopolitical region. Sustaining HIV patients in this high risk region is critical for the overall success of the ART program in Nigeria. We assessed the level of adherence to ART and adherence determinants among participants who had been on ART for an average of three and half years. Eligible study participants initiated HAART between 2004 and 2010. HAART regimens contained AZT/3TC +NVP or EFV; AZT/3TC/NVP; 3TC/NVP/d4T; TDF/FTC +EFV or NVP and TDF+3TC+LPV/r. A composite adherence measure defined as not missing a dose and taking the correct dose and adhering to the correct frequency and correct schedule of drug administration was used to assess self-reported adherence over a period of three days. Selfreported adherence was validated with viral load test. Base line adherence was fixed at ≥95% adherence level. Significant test was fixed at p<0.05. We included 502 participants in the analysis. Median age for men was 42 years (IQR: 38 - 44 years) and women, 36 years (IQR: 30-40 years). Mean duration of therapy was 43 (16-70) months. Effective self-reported adherence was 97.3%. Only age and virologic suppression were significantly associated with adherence to ART. Forgetfullness (43%) was the major reason for non-adherence, while improvement in health condition (40%) was the main facilitator of adherence to the medications. Most participants achieved optimal adherence (≥95%) with high virologic suppression. Strategies to sustain optimal adherence, e.g., the use of fixed dose combinations (FDCs) and comprehensive adherence counselling should be maintained.

Cronoterapia en hipertensión arterial

The blood pressure profile in most normo- and hypertensive subjects are currently known, as well as the impact their changes induced on the cardio- and cerebrovascular risk. Ambulatory blood pressure monitoring (ABPM) has contributed greatly to the knowledge of this parameter. It to correct the schedule of drug administration (chronotherapy) with changes in any component of the BP profile that have better correlation with risk. These include the nocturnal decrease and the morning BP surge. Investigations in this direction are still scarce, and multicenter studies need to be conducted that can answer the true preventive impact of such modifications.

Commentary on: "A Multi-Institutional Experience in Pediatric High Grade Glioma".

Commentary on: "A Multi-Institutional Experience in Pediatric High Grade Glioma".

A mathematical programming approach to the fractionation problem in chemoradiotherapy

In concurrent chemoradiotherapy, chemotherapeutic agents are administered during the course of radiotherapy to enhance the primary tumor control. However, this treatment often comes at the expense of increased risk of normal-tissue complications. The additional biological damage is mainly attributed to two mechanisms of action, which are the independent cytotoxic activity of chemotherapeutic agents and their interactive cooperation with radiation. The goal of this study is to develop a mathematical framework to obtain drug and radiation administration schedules that maximize the therapeutic gain for concurrent chemoradiotherapy. In particular, we analyze the impact of incorporating these two mechanisms into the radiation fractionation problem. Considering each mechanism individually, we first derive closed-form expressions for the optimal radiation fractionation regimen and the corresponding drug administration schedule. We next study the case in which both mechanisms are simultaneously present and develop a dynamic programming framework to determine optimal treatment regimens. Results show that those chemotherapeutic agents that interact with radiation may change optimal radiation fractionation regimens. Moreover, administration of chemotherapeutic agents possessing both mechanisms may give rise to optimal non-stationary fractionation schemes.

Utilizing temporal variations in chemotherapeutic response to improve breast cancer treatment efficacy

Though survival rates for women with stage I breast cancer have radically improved, treatment options remain poor for the 40% of women diagnosed with later-stage disease. For these patients, improved chemotherapeutic treatment strategies are critical to eradicate any disseminated tumor cells. Despite many promising new drugs <em>in vitro</em>, most ultimately fail in the clinic. One aspect often lost during testing is <em>in vivo</em> circulation half-lives rarely exceed 24 hours, whereas <em>in vitro</em> studies involve drug exposure for 2-3 days. Here, we show how mimicking these exposure times alters efficacy. Next, using this model we show how drug response is highly time-dependent by extending analysis of cell viability out to two weeks. Variations in response both with feeding and time were dependent on drug mechanism of action. Finally, we show that by implementing this temporal knowledge of drug effects to optimize scheduling of drug administration we are able to regain chemosensitivity in a Carboplatin-resistant cell line.

Gene Expression Changes in Colorectal Cancer during Metronomic Chemotherapy and High-Concentration Drug Administration

5-fluorouracil (5-FU) and oxaliplatin, either alone or in combination, are widely used in chemotherapy for advanced colorectal cancer. Among chemotherapeutic strategies, metronomic chemotherapy has recently demonstrated promising efficacy against otherwise chemoresistant neoplasms. However, data on the efficacy of metronomic applications in cancer stem cells are lacking. This cell population is characterized by resistance to most chemotherapeutic models. In this study, we investigated the efficacy of metronomic chemotherapy and compared it with high-concentration administration of 5-FU and oxaliplatin and their combination in colon adenocarcinoma cells and colon cancer stem cells. We assessed changes in expression levels of specific genes involved in 5-FU and oxaliplatin resistance (thymidylate synthase, DNA (cytosine-5)-methyltransferase 1, dihydrofolate reductase, serine hydroxymethyltransferase, DNA excision repair protein, dihydropyrimidine dehydrogenase) in relation to drug administration schedule using quantitative real-time polymerase chain reaction. We also examined changes in cell viability. Metronomic chemotherapy showed greater efficacy in gene expression levels in colorectal cancer cells, while high, single-concentration administration was more effective in colon cancer stem cells. Regarding cell viability, no significant change was observed between metronomic and single-dose treatments. These results suggest that metronomic chemotherapy may be more effective than high-dose chemotherapy in some patients with colorectal cancer, though high, single-concentration administration may be more effective against cancer stem cells.

Once-Weekly Prophylactic Treatment Versus on-Demand Treatment of Nonacog Alfa in Patients with Moderately Severe to Severe Hemophilia B

▪Introduction: Hemophilia B is characterized by a functional deficiency in factor IX (FIX), which results in spontaneous or trauma-induced bleeding into soft tissue, muscles, and joints. Replacing deficient FIX with plasma-derived or recombinant FIX products, either prophylactically or on an on-demand basis, is a mainstay in the prevention and treatment of bleeding episodes in patients with hemophilia B. A previous study of patients with moderately severe to severe hemophilia B compared the efficacy and safety of 2 secondary prophylaxis regimens of a recombinant coagulation FIX product (nonacog alfa, 50 IU/kg twice weekly or 100 IU/kg once weekly) with on-demand treatment. The study found a significant reduction (P<.0001) in the annualized bleeding rate (ABR) for the prophylaxis regimens compared with on-demand therapy. No significant differences in the ABR were observed between the once-weekly and twice-weekly prophylaxis regimens, and safety and tolerability profiles were similar for both.Objective: To demonstrate that once-weekly prophylaxis with nonacog alfa reduces the ABR compared with on-demand treatment in patients with moderately severe to severe hemophilia B.Methods: This open-label, 2-period study enrolled males aged 12 to 65 years with moderately severe to severe hemophilia B (FIX plasma activity ≤2%), ≥100 prior exposure days to FIX products, and no history of or current FIX inhibitor. Patients received on-demand therapy with nonacog alfa for 6 months (dose selected at the investigator’s discretion) followed by prophylactic treatment with nonacog alfa 100 IU/kg once weekly for 12 months. Recovery was assessed on day 1, week 26, and week 78, after a 72-hour washout from any FIX product. Plasma samples were collected before administration and at 30 minutes after nonacog alfa infusion. The primary efficacy end point was the ABR (number of bleeding events/[days on treatment period/365.25]). Secondary end points included the response to on-demand treatment of a bleeding event, incidence of less-than-expected therapeutic effect (LETE) in the prophylaxis setting; and FIX inhibitor development. Safety was also assessed.Results: In total, 25 patients were enrolled and received at least 1 dose of study medication; all patients completed the study. Mean ±SD age was 31.3 ±12.6 years; 5 patients were <18 years; 9 patients were Asian and 16 were white. ABR results are summarized in the Table; ABR for the prophylaxis period was significantly lower (P<.0001) than the ABR for the on-demand period. Of the 507 bleeding events treated over the study, 271 (53.5%) first infusions resulted in an “excellent” response and 177 (34.9%) resulted in a “good” response; the majority of bleeding events (416/507; 82.1%) resolved with 1 infusion. Of the 1254 prophylaxis infusions administered during the study, none were associated with an occurrence of LETE. No patient developed a FIX inhibitor or experienced a thrombotic event during the study. The most commonly reported treatment-emergent AEs (≥20%) were inappropriate schedule of drug administration (24%), arthralgia (20%), upper respiratory tract infection (20%), and toothache (20%) during the prophylaxis period, and headache (32%) and arthralgia (20%) during the on-demand period. Five patients (20%) experienced a total of 6 serious AEs; blood pressure decreased, pain resulting in hospitalization, chicken pox, lipoma, and nephrolithiasis (2 events in 1 patient). Only the serious AE of blood pressure decreased was considered related to study drug. No deaths occurred during the study.Conclusions: Prophylactic treatment with nonacog alfa 100 IU/kg once weekly significantly reduced the number of bleeding events compared with on-demand treatment in patients with moderately severe to severe hemophilia B. Nonacog alfa 100 IU/kg once weekly was well tolerated; no new safety issues were observed.TableComparison of Annualized Bleed Rates Between On-Demand and Prophylaxis RegimensParameterOn-Demand(n=25)100 IU/kg Once-Weekly Prophylaxis(n=25)Over 6 MonthsMean (SD)32.9 (17.4)3.6 (4.6)*Median33.62.0Minimum, maximum6.1, 69.00, 13.8Spontaneous bleeding eventsMean (SD)23.1 (17.1)2.6 (4.1)Median22.41.0Minimum, maximum0, 54.20, 13.8Traumatic bleeding eventsMean (SD)9.9 (14.5)1.0 (1.6)Median4.11.0Minimum, maximum0, 52.20, 6.9*P<.0001 for comparison of on-demand vs prophylaxis treatment. DisclosuresKavakli:Pfizer Inc.: Honoraria; Pfizer Inc.: Scientific Congress Expenses, Scientific Congress Expenses Other; Pfizer Inc.: Research Funding; Pfizer Inc.: Membership on an entity’s Board of Directors or advisory committees. Smith:Pfizer Inc.: Employment; Pfizer Inc.: Stock Ownership, Stock Ownership Other. Korth-Bradley:Pfizer Inc.: Employment; Pfizer Inc.: Stock Ownership, Stock Ownership Other. Fuiman:Pfizer Inc.: Stock Ownership, Stock Ownership Other; Pfizer Inc.: Employment. Zupancic-Salek:Pfizer Inc.: Research Funding. Rendo:Pfizer Inc.: Employment; Pfizer Inc.: Stock Ownership, Stock Ownership Other.