A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization.

The quality of warfarin treatment may be improved if management is guided by the use of models based upon pharmacokinetic-pharmacodynamic theory. A prospective, two-armed, single-blind, randomized controlled trial compared management aided by a web-based dose calculator (NextDose) with standard clinical care. Participants were 240 adults receiving warfarin therapy following cardiac surgery, followed up until the first outpatient appointment at least 3 months after warfarin initiation. We compared the percentage of time spent in the international normalized ratio acceptable range (%TIR) during the first 28 days following warfarin initiation, and %TIR and count of bleeding events over the entire follow-up period. Two hundred thirty-four participants were followed up to day 28 (NextDose: 116 and standard of care: 118), and 228 participants (114 per arm) were followed up to the final study visit. Median %TIR tended to be higher for participants receiving NextDose guided warfarin management during the first 28 days (63 vs. 56%, P = 0.13) and over the entire follow-up period (74 vs. 71%, P = 0.04). The hazard of clinically relevant minor bleeding events was lower for participants in the NextDose arm (hazard ratio: 0.21, P = 0.041). In NextDose, there were 89.3% of proposed doses accepted by prescribers. NextDose guided dose management in cardiac surgery patients requiring warfarin was associated with an increase in %TIR across the full follow-up period and fewer hemorrhagic events. A theory-based, pharmacologically guided approach facilitates higher quality warfarin anticoagulation. An important practical benefit is a reduced requirement for clinical experience of warfarin management.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of therapies, both currently marketed and under clinical development, may be directly impacted by the physiological alterations that occur secondary to the occurrence of chronic excess body weight. The increased prevalence of this disease should not be ignored. Both private and federal institutions involved in drug research and development should consider, as appropriate, a greater inclusion of individuals who are obese in clinical trials throughout the entirety of drug development, and leverage the available PK, PD, safety, and efficacy data to make more informed dosing recommendations.

Equivalent doses for anticancer agents used in pediatric oncology: A literature review and evaluation of a novel approach for conversion factors.

BACKGROUND: Epidemiological research on late effects of therapy shows the necessity to aggregate chemotherapy agents to substance classes. This requires using conversion factors by substance classes. AIMS: The aim of this study was to identify previously used conversion factors from the literature, to present a novel approach for additional factors, and to compare these approaches. METHODS AND RESULTS: A literature review was performed, which identified two main principles of deriving conversion factors: effect-equivalence and equimolar. Thirty-five articles presenting effect equivalence-based factors in the widest sense were found in the literature. Ten articles presented the equimolar approach which can be applied to almost all chemotherapy substances. Based on a comprehensive list of treatment protocols used in German pediatric oncology, we derived alternative conversion factors from typical doses. We compared the conversion factors using Pearson correlation coefficients and linear regression. At least two types of conversion factor were available for each of the 49 substances included. The equivalent effect-based and the typical dose-based factors were highly correlated with a regression coefficient close to 1. The equimolar factors are independent. CONCLUSIONS: For substances for which no conversion factor based on some type of effect equivalence has been published so far, a factor based on a typical doses-approach may be used in epidemiological late effects research. Doses aggregated based on the equimolar approach may not be compatible with doses aggregated based on equivalent effects.

Manipulations and age-appropriateness of oral medications in pediatric oncology patients in Sweden: Need for personalized dosage forms.

Due to the lack of age-appropriate formulations for children, healthcare professionals and caregivers frequently manipulate dosage forms to facilitate oral administration and obtain the required dose. In this study, we investigated drug manipulation and age-appropriateness of oral medications for pediatric oncology patients with the aim of identifying the therapeutic needs for personalized dosage forms. An observational study at a pediatric oncology ward, combined with analysis of the age-appropriateness of the oral medications, was performed. Nurses frequently manipulated solid dosage forms to administer them via enteral feeding tubes. Of the active pharmaceutical ingredients (APIs) assessed for age-appropriateness, 74% (29 of 39) were identified to need personalization, either because of lack of child-friendly dosage form, suitable dosage strength, or both. Most APIs, due to limited solubility, were sensitive to formulation changes, such as drug manipulation. This study demonstrates problems and therapeutic needs regarding oral dosage forms in treatment of children with cancer. Expertise in formulation design, new manufacturing technologies, and patient-centered information are needed to address age-appropriate formulations for children.

Medications and dosages used in medical assistance in dying: a cross-sectional study.

BACKGROUND: There is little evidence describing the technical aspects of medical assistance in dying (MAiD) in Canada, such as medications, dosages and complications. Our objective was to describe clinical practice in providing MAiD in Ontario and Vancouver, Canada, and explore relations between medications used, time until death and complications. METHODS: We conducted a retrospective cohort study of a sample of adult (age ≥ 18 yr) patients who received MAiD in Ontario between 2016 and 2018, and patients who received MAiD in 1 of 3 Canadian academic hospitals (in Hamilton and Ottawa, Ontario, and Vancouver, British Colombia) between 2019 and 2020. We used de-identified data for 2016-2018 from the Office of the Chief Coroner for Ontario MAiD Database and chart review data for 2019-2020 from the 3 centres. We used multivariable parametric survival analysis to identify relations between medications, dosages and time from procedure start until death. RESULTS: The sample included 3557 patients (1786 men [50.2%] and 1770 women [49.8%] with a mean age of 74 [standard deviation 13] yr). The majority of patients (2519 [70.8%]) had a diagnosis of cancer. The medications most often used were propofol (3504 cases [98.5%]), midazolam (3251 [91.4%]) and rocuronium (3228 [90.8%]). The median time from the first injection until death was 9 (interquartile range 6) minutes. Standard-dose lidocaine (40-60 mg) and high-dose propofol (> 1000 mg) were associated with prolonged time until death (prolonged by a median of 1 min and 3 min, respectively). Complications occurred in 41 cases (1.2%), mostly related to venous access or need for administration of a second medication. INTERPRETATION: In a large sample of patients who died with medical assistance, certain medications were associated with small differences in time from injection to death, and complications were rare. More research is needed to identify the medication protocols that predict outcomes consistent with patient and family expectations for a medically assisted death.

Semi-Mechanistic PK/PD Modeling and Simulation of Irreversible BTK Inhibition to Support Dose Selection of Tirabrutinib in Subjects with RA.

Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.

Enoxaparin titrated by anti-Xa levels reduces venous thromboembolism in trauma patients.

BACKGROUND: Trauma is a major risk factor for the development of a venous thromboembolism (VTE). After observing higher than expected VTE rates within our center's Trauma Quality Improvement Program data, we instituted a change in our VTE prophylaxis protocol, moving to enoxaparin dosing titrated by anti-Xa levels. We hypothesized that this intervention would lower our symptomatic VTE rates. METHODS: Adult trauma patients at a single institution meeting National Trauma Data Standard criteria from April 2015 to September 2019 were examined with regards to VTE chemoprophylaxis regimen and VTE incidence. Two groups of patients were identified based on VTE protocol-those who received enoxaparin 30 mg twice daily without routine anti-Xa levels ("pre") versus those who received enoxaparin 40 mg twice daily with dose titrated by serial anti-Xa levels ("post"). Univariate and multivariate analyses were performed to define statistically significant differences in VTE incidence between the two cohorts. RESULTS: There were 1698 patients within the "pre" group and 1406 patients within the "post" group. The two groups were essentially the same in terms of demographics and risk factors for bleeding or thrombosis. There was a statistically significant reduction in VTE rate (p = 0.01) and deep vein thrombosis rate (p = 0.01) but no significant reduction in pulmonary embolism rate (p = 0.21) after implementation of the anti-Xa titration protocol. Risk-adjusted Trauma Quality Improvement Program data showed an improvement in rate of symptomatic pulmonary embolism from fifth decile to first decile. CONCLUSION: A protocol titrating prophylactic enoxaparin dose based on anti-Xa levels reduced VTE rates. Implementation of this type of protocol requires diligence from the physician and pharmacist team. Further research will investigate the impact of protocol compliance and time to appropriate anti-Xa level on incidence of VTE. LEVEL OF EVIDENCE: Therapeutic/care management, Level IV.

Effective use of weight-based enoxaparin for deep vein thrombosis chemoprophylaxis in patients with traumatic brain injury.

BACKGROUND: Enoxaparin is the recommended agent for deep vein thrombosis (DVT) chemoprophylaxis in trauma patients. Current literature suggests weight-based dosing is superior to standard dosing for adequate chemoprophylaxis. Literature regarding the use of weight-based enoxaparin in the setting of traumatic brain injury (TBI) however is limited. METHODS: A retrospective analysis of adult trauma patients admitted between January 1, 2018 to February 28, 2019 was performed. Sixty-six patients with TBI receiving weight-based enoxaparin met inclusion criteria. Incidence of intracranial hemorrhage (ICH) expansion was the primary endpoint. Newly diagnosed venous thromboembolism (VTE) and death were secondary endpoints. RESULTS: Two patients, out of sixty-six, had progression of their TBI requiring surgical intervention. Newly diagnosed VTE occurred in one patient. No deaths were due to ICH expansion or VTE. CONCLUSIONS: Use of weight-based enoxaparin dosing in the setting of TBI shows promise without an increased incidence of ICH expansion when compared to other studies. Level of Evidence and Study Type: Level IV, Therapeutic.

Weight-based cefuroxime dosing provides comparable orthopedic target tissue concentrations between weight groups - a microdialysis porcine study.

Antibiotic prophylaxis is a key element in prevention of surgical site infections. For the majority of orthopedic procedures, antibiotic administration follows fixed dosing regimens irrespective of weight. However, this may result in insufficient antibiotic target tissue concentrations and higher risk of surgical site infections in obese individuals. The aim of this study was to investigate the effect of weight-based cefuroxime dosing on plasma and target tissue concentrations. Eighteen female pigs were allocated into three groups differentiated by weight: 53-57 kg, 73-77 kg, and 93-97 kg. Microdialysis catheters were placed for continuous sampling in bone, muscle, and subcutaneous tissue during an 8h sampling interval. Blood samples were collected as reference. Cefuroxime was administered intravenously as a bolus according to weight (20 mg/kg). The primary endpoint was the time above the cefuroxime minimal inhibitory concentration for Staphylococcus aureus (T > MIC (4 µg/mL)). Comparable target tissue T > MICs (4 µg/mL) were found between weight groups. Mean T > MIC ranged between 116-137 min for plasma, 118-154 min for bone, 109-146 min for the skeletal muscle, and 117-165 min for subcutaneous tissue across the groups. Weight-based cefuroxime (20 mg/kg) dosing approach provides comparable perioperative plasma and target tissue T > MIC (4 µg/mL) in animals between 50-100 kg body weight, and thus a comparable prophylaxis of surgical site infections.

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through Week 24 or Week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union.

phase1RMD: An R package for repeated measures dose-finding designs with novel toxicity and efficacy endpoints.

Traditional dose-finding designs are substantially inefficient for targeted agents and cancer immunotherapies by failing to incorporate efficacy signals, mild and moderate adverse events, and late, cumulative toxicities. However, the lack of user-friendly software is a barrier to the practical use of the novel phase I designs, despite their demonstrated superiority of traditional 3+3 designs. To overcome these barriers, we present an R package, phase1RMD, which provides a comprehensive implementation of novel designs with repeated toxicity measures and early efficacy. A novel phase I repeated measures design that used a continuous toxicity score from multiple treatment cycles was implemented. Furthermore, in studies where preliminary efficacy is evaluated, an adaptive, multi-stage design to identify the most efficacious dose with acceptable toxicity was demonstrated. Functions are provided to recommend the next dose based on the data collected in a phase I trial, as well as to assess trial characteristics given design parameters via simulations. The repeated measure designs accurately estimated both the magnitude and direction of toxicity trends in late treatment cycles, and allocated more patients at therapeutic doses. The R package for implementing these designs is available from the Comprehensive R Archive Network. To our best knowledge, this is the first software that implement novel phase I dose-finding designs that simultaneously accounts for the multiple-grade toxicity events over multiple treatment cycles and a continuous early efficacy outcome. With the software published on CRAN, we will pursue the implementation of these designs in phase I trials in real-life settings.

A framework for economic evaluation of therapeutic drug monitoring-guided dosing in oncology.

The standard approach for dose individualization of chemotherapy in the oncology setting has long been based on body surface area (BSA) as a measure of body size. However, for many anticancer drugs, administration of dosages based on BSA may result in some patients receiving supratherapeutic or subtherapeutic concentrations due to substantial interindividual pharmacokinetic variability. Therapeutic drug monitoring (TDM)-guided dosing aims to ensure that the patient's serum drug concentration is in a target range which has been shown to produce optimal clinical outcomes. The management of several malignancies is now moving away from using traditional intravenous chemotherapy to longer-term treatment with targeted molecular therapies. These targeted anticancer drugs are currently dosed based on a fixed dose for all patients. The pharmacokinetic characteristics of most of these drugs (e.g., tyrosine-kinase inhibitors) support implementation of individualized dosing via TDM. However, prior to adopting TDM-guided dosing in oncology settings, the economic efficiency and value for money of introducing TDM interventions should be critically and systematically examined along with the impacts on patient care and outcomes. Yet, current evidence in this area is limited, and more generally, there is lack of methodological guidance on how to identify, estimate and value clinical and cost information necessary to conduct economic evaluations of TDM interventions. In this paper, we propose a coherent framework for conducting economic evaluation of TDM interventions in oncology settings and discuss some practical challenges of conducting economic evaluations of TDM.

Therapeutic Effects of GGsTop® Gel in a Mouse Model of 5-Fluorouracil-induced Oral Mucositis With Reduced White Blood Cells.

BACKGROUND/AIM: In order to produce an animal model for oral mucositis induced by anticancer drugs, it is necessary to maintain an immunosuppressive state. We determined the optimal dose and frequency of 5-fluorouracil for a model mouse production. In addition, we used this model to investigate the effect of GGsTop® gelation on the therapeutic effect of oral mucositis. MATERIALS AND METHODS: Changes in body weight and white blood cell count were measured to determine the optimal dosing schedule. The therapeutic effect of GGsTop® gel using chitosan was evaluated by observing changes in the ulcer area for three weeks and measuring collagen and glutathione concentrations in oral mucosal tissue. RESULTS: The optimal dose and frequency of 5-fluorouracil were found to be 50 mg/kg every four days. It was revealed that the therapeutic effect of GGsTop® was enhanced by gelation. CONCLUSION: GGsTop® gel is suggested to be a promising formulation for the treatment of oral mucositis.

Financial Burden of Discarded Weight-based Antineoplastic Drugs to Payers and Patients in the Private Insurance Market.

Background: Our study estimated insurance payments and patient out-of-pocket (OOP) expenses associated with discarded weight-based intravenous antineoplastic drugs for privately insured US adult patients with cancer. Methods: We identified patients who received weight-based antineoplastic drugs from a 2017 MarketScan health risk assessment (IBM Corp, Armonk, NY) linked to claims data. Using weight information in the health risk assessment, we derived the recommended dose and calculated the percentage of drugs discarded. We applied ß-regression to determine factors associated with the discarded percentages. To compare patients with and without high-deductible plans, we employed a generalized linear model and a 2-part model to examine insurance payment and OOP expense, respectively. All statistical tests were 2-sided. Results: Of 27 350 claims for 58 weight-based antineoplastic drugs from 1970 patients, the median discarded percentage was 9.8% (mean [SD] = 12.8% [10.5%]). Aside from drug and tumor type, statistically significantly higher discarded percentages were found for patients in the lowest weight group (5.5% [95% confidence interval = 4.7% to 6.4%]; P < .001; weight <150 lb [68.0 kg] vs ≥200 lb [90.7 kg]). Private payers spent $5090 per patient in 2017 on discarded weight-based antineoplastic drugs, and patients' mean OOP expense on discarded drugs was $63. In total, 39.7% of patients had high-deductible plans. The adjusted mean OOP expense for discarded drugs was statistically significantly higher for those in high-deductible plans ($95 vs $47; P < .001). Conclusions: Private insurers incurred substantial financial burden from discarded weight-based antineoplastic drugs. Although the OOP expenses of discarded drugs were modest for most privately insured patients with cancer, approximately 5% spent more than $400 on the discarded drugs. Policies designed to reduce drug waste from single-dose, weight-based antineoplastic drugs should evaluate their financial consequences for payers and patients.

Effect of removing race from glomerular filtration rate-estimating equations on anticancer drug dosing and eligibility: a retrospective analysis of National Cancer Institute phase 1 clinical trial participants.

BACKGROUND: Kidney function assessment by estimated glomerular filtration rate (eGFR) equations, such as the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, is important to determine dosing and eligibility for anticancer drugs. Inclusion of race in eGFR equations calculates a higher eGFR at a given serum creatinine concentration for Black patients versus non-Black patients. We aimed to characterise the effect of removing race from the CKD-EPI equation on dosing and eligibility of anticancer drugs with kidney function cutoffs. METHODS: We did a retrospective analysis of patients enrolled in phase 1 studies sponsored by the Cancer Therapy Evaluation Program between January, 1995, and October, 2010. eGFR based on creatinine (eGFRCr) was calculated by the CKD-EPI equation and a version of the CKD-EPI equation without the race term (CKD-EPIwithout race). Estimated creatinine clearance (eClCr) was calculated by the Cockcroft-Gault equation. Dosing simulations based on each assessment of kidney function were done for ten anticancer drugs with kidney function cutoffs for dosing (oxaliplatin, capecitabine, etoposide, topotecan, fludarabine, and bleomycin) or eligibility (cisplatin, pemetrexed, bendamustine, and mitomycin) based on labelling approved by the US Food and Drug Administration or consensus guidelines. The absolute proportion of patients eligible or in each renal dosing range was calculated for each drug. Eligibility and dosing discordance rates were also calculated. FINDINGS: Demographics and laboratory values from 340 Black patients (172 men and 168 women) were used. Median age was 57 years (IQR 47-64), median bodyweight was 78·1 kg (67·0-89·8), median body surface area was 1·91 m2 (1·77-2·09), and median serum creatinine concentration was 0·9 mg/dL (0·8-1·1). Median eGFRCr or eClCr was 103 mL/min (85-122) calculated by CKD-EPI, 89 mL/min (73-105) by CKD-EPIwithout race, and 90 mL/min (72-120) by Cockcroft-Gault. Black patients were recommended to receive dose reductions or were rendered ineligible to receive drug more frequently when using CKD-EPIwithout race than when using CKD-EPI, but at a similar rate as when using Cockcroft-Gault. The number of patients ineligible for therapy or recommended to receive any renal dose adjustment when CKD-EPIwithout race versus CKD-EPI was used increased by 72% (from 25 of 340 to 43 of 340 patients) for cisplatin, by 120% (from five to 11) for pemetrexed, by 67% (from three to five) for bendamustine, by 150% (from ten to 25) for capecitabine, by 150% (from ten to 25) for etoposide, by 67% (from three to five) for topotecan, by 61% (from 74 to 119) for fludarabine, and by 163% (from eight to 21) for bleomycin. Up to 18% of patients had discordant recommendations using CKD-EPIwithout race versus CKD-EPI. INTERPRETATION: Removing race from the CKD-EPI equation will calculate a lower eGFR for Black patients and exclude more patients from receiving anticancer therapy, which could lead to undertreatment of Black patients with cancer and adversely affect their outcomes. FUNDING: National Institutes of Health.

Would the Recommended Dose Have Been Different Using Novel Dose-Finding Designs? Comparing Dose-Finding Designs in Published Trials.

Simulation studies have shown that novel designs such as the continual reassessment method and the Bayesian optimal interval (BOIN) design outperform the 3 + 3 design by recommending the maximum tolerated dose (MTD) more often, using less patients, and allotting more patients to the MTD. However, it is not clear whether these novel designs would have yielded different results in the context of real-world dose-finding trials. This is a commonly mentioned reason for the continuous use of 3 + 3 designs for oncology trials, with investigators considering simulation studies not sufficiently convincing to warrant the additional design complexity of novel designs. METHODS: We randomly sampled 60 published dose-finding trials to obtain 22 that used the 3 + 3 design, identified an MTD, published toxicity data, and had more than two dose levels. We compared the published MTD with the estimated MTD using the continual reassessment method and BOIN using target toxicity rates of 25% and 30% and toxicity data from the trial. Moreover, we compared patient allocation and sample size assuming that these novel designs had been implemented. RESULTS: Model-based designs chose dose levels higher than the published MTD in about 40% of the trials, with estimated and observed toxicity rates closer to the target toxicity rates of 25% and 30%. They also assigned less patients to suboptimal doses and permitted faster dose escalation. CONCLUSION: This study using published dose-finding trials shows that novel designs would recommend different MTDs and confirms the advantages of these designs compared with the 3 + 3 design, which were demonstrated by simulation studies.

Clinical Benefit of Therapeutic Drug Monitoring in Colorectal Cancer Patients Who Received Fluorouracil-Based Chemotherapy.

BACKGROUND The impact of therapeutic drug management (TDM) on reducing toxicity and improving efficacy in colorectal cancer (CRC) patients receiving fluorouracil-based chemotherapy is still unclear. MATERIAL AND METHODS A total of 207 patients (Study Group n=54, Historical Group n=153) with metastatic colorectal cancer were enrolled. All of them received 6 administrations of the 5-FU based regimens. Initial 5-FU dosing of all patients was calculated using body surface area (BSA). In the Study Group, individual exposure during each cycle was measured using a nanoparticle immunoassay, and the 5-FU blood concentration was calculated using the area under the curve (AUC). We adjusted the 5-FU infusion dose of the next cycle based on the AUC data of the previous cycle to achieve the target of 20-30 mg×h/L. RESULTS In the fourth cycle, patients in the target concentration range (AUC mean, 26.3 mg×h/L; Median, 28 mg×h/L; Range, 14-38 mg×h/L; CV, 22.4%) accounted for 46.8% of all patients, which were more than the ones in the first cycle (P<0.001). 5-FU TDM significantly reduced the toxicity of chemotherapy and improved its efficacy. The Study Group (30/289) showed a lower percentage of severe adverse events than that in the Historical Group (185/447) (P<0.001). The incidences of complete response and partial response in the Study Group were higher than those in the Historical Group (P=0.032). CONCLUSIONS TDM in colorectal cancer can reduce toxicity, improve efficacy and clinical outcome, and can be routinely used in 5-FU-based chemotherapy.