Body Surface Area-based Dosing Research Articles

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study.

Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited population pharmacokinetic (PPK) data are available for pediatric HSCT patients. This study aimed to develop a PPK model and recommend optimal oral MMF dosage in pediatric HSCT patients. This prospective study involved pediatric HSCT patients at a tertiary academic institution. Patients received oral MMF 15-20 mg/kg twice daily for aGVHD prophylaxis and treatment. The PPK analysis was conducted using a nonlinear mixed-effects modeling method. Simulation was performed considering different body surface areas (BSAs) (0.5 m2, 1.0 m2, 1.5 m2) and dosing (400 mg/m2, 600 mg/m2, 900 mg/m2 twice daily). Based on the simulation, an optimal dosage of oral MMF was suggested. A total of 20 patients and 80 samples were included in the PPK model development. A one-compartment model with first-order absorption adequately described the pharmacokinetics of mycophenolic acid (MPA). BSA was a statistically significant covariate on Vd/F. Simulation suggested the optimal dosage of oral MMF as 900 mg/m2 twice daily, respectively. A reliable PPK model was developed with good predictive performance. This model-informed optimal MMF dosage in pediatric HSCT patients can provide valuable dosing guidance in real-world clinical practice.

Body Surface Area Valganciclovir Prophylactic Dosing is Associated with a Higher Rate of Drug-Associated Toxicities Compared to Body Weight Dosing in Pediatric Solid Organ Transplant Recipients

Abstract Background Valganciclovir (VGCV) is used for prevention of cytomegalovirus (CMV) in pediatric solid organ transplant (SOT) recipients who are at moderate or high risk for CMV infection or reactivation. Optimal dosing is not well defined, and both weight-based (WB) (15 mg/kg/dose) and body surface area-based (BSA) dosing (7 x BSA x creatinine clearance with an upper limit of 150 mL/min/1.73 m2) are used. We used a recently completed retrospective study on VGCV toxicity to compare the effects of these 2 dosing strategies on the proportion and the odds of CMV DNAemia, neutropenia, lymphopenia, and toxicity-related VGCV discontinuation or dose modification. Methods Data was collected from 6 US centers. Inclusion criteria were SOT recipients <20 years of age transplanted between January 2016 and December 2019, anticipated to receive VGCV prophylaxis with either dosing method for >/=3 months, and availability of >/=6 months of follow-up data post-transplant. Neutropenia and lymphopenia were defined as absolute neutrophil or lymphocyte count <1000 cells/microL. The number of patients who had premature discontinuation or dosing modification attributed to leukopenia or acute kidney injury (AKI) was quantified. Anticipated VGCV duration, dosing strategy, and threshold for making VGCV changes were at the discretion of each center for each patient. Cytopenias or toxicities that occurred within 15 days of SOT were excluded. Data were collected for one-year post-transplant and analyzed using Stata version 17.0. Groups were compared using Mann Whitney U test for continuous variables and chi-square test for categorical variables; logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) with multivariable analysis. Results 412 patients met inclusion criteria. 312 patients were treated with WB and 100 with BSA dosing. Median age at transplantation was 5.1 (IQR 1.8-11.8) years and 42.7% were female. Transplanted organs included: liver 35.4%, kidney 33.5%, heart 22.3%, lung 6.6%, and other 2.2%. Within one year of transplantation, 23.4% and 12.2% of the WB group and 31.0% and 16% of the BSA group had at least one episode of CMV DNA detection in the plasma (DNAemia) and breakthrough CMV DNAemia while on VGCV prophylaxis, respectively (p=0.1 and p=0.3). There was no statistically significant difference in the odds of CMV DNAemia or breakthrough CMV DNAemia between dosing groups at one year when adjusted for: transplanted organ, CMV risk based on pre-transplant serostatus, duration of anticipated prophylaxis, age, receipt of CMV immunoglobulin, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid (aOR=1.1, 95% CI: 0.6-1.8, p=0.8 and aOR=1.4, 95% CI: 0.6-2.9, p=0.4). However, the risk of all drug toxicity while on prophylaxis were significantly greater in BSA compared to WB group: neutropenia (50.0% vs 29.3%), lymphopenia (51.0% vs 15.0%), and toxicity-related VGCV discontinuation or modification (21% vs 6.7%) (each p<0.001). The BSA group had higher odds of neutropenia (aOR=2.3, 95% CI: 1.4-3.7, p=0.001), lymphopenia (aOR=7.0, 95% CI: 3.9-12.4, p<0.001), and toxicity-related VGCV discontinuation or modification (aOR=4.6, 95% CI: 2.2-9.3, p<0.001) while on prophylaxis when adjusted for age, organ, anticipated VGCV duration, and receipt of trimethoprim-sulfamethoxazole, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid. Conclusions Results of this study indicate that BSA dosing of VGCV is associated with a significantly greater risk of toxicity without a decrease in CMV DNAemia.

Body Surface Area-Based Dosing of Infliximab is Superior to Standard Weight-Based Dosing in Children With Very Early Onset Inflammatory Bowel Disease

Children with very early onset inflammatory bowel disease (VEO-IBD) are uniquely at risk of inadequate infliximab (IFX) exposure. We studied the association between standard body weight (BW)-based and body surface area (BSA)-based dosing strategies and outcomes. We identified VEO-IBD patients treated with IFX before 9 years at a single center. Patients were separated into those that received a BSA-based dose (200 mg/m2) and standard BW dosing (5 mg/kg). IFX drug levels, dose intensification, time on steroids, and long-term outcomes were compared. Receiver operator characteristic curves determined the optimal BW- and BSA-based dose to achieve a trough ≥10 μg/ml at dose 4 (IFX#4). Forty-three children with VEO-IBD were identified. Receiver operator characteristic curves demonstrated optimal BW- and BSA-based doses to achieve IFX trough ≥10 μg/ml at IFX#4 were 7.5 mg/kg and 180mg/m2. Children were classified to standard BW dosing (22/43) and BSA dosing (10/43). IFX#4 trough was significantly higher in those who received BSA dosing (BSA 18.6 μg/ml [interquartile range 10.8-28.1] vs BW 5.1 μg/ml [interquartile range 2.6-10.7], P= .04). BSA dosing was more likely to achieve a target drug level >10μg/ml at IFX#4 (BSA 70% vs BW 18%, P= .02). BW dosing was associated with a greater likelihood of dose escalation (BW 82% vs BSA 30%, P < .01) and a shorter time to first escalation. BSA dosing was associated with shorter time spent on steroids (P= .02). Young children require higher IFX dosing to achieve adequate drug exposure. Our data support the use of a BSA-based dose of 200 mg/m2 or, if a BW-based approach is used, 7.5 mg/kg. BSA dosing allows the use of a consistent dose over the age and weight spectrum.

Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis.

Obesity (body mass index [BMI] ≥30kg/m2 ) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60years or older). Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate-risk cytogenetics group (p=.008), poorer performance status (p=.01), and a trend toward older age (p=.06). Obesity was not associated with somatic mutations among a selected 18-gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high-dose (90mg/m2 ) daunorubicin arm (p=.002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90-2.13; p=.14). Obesity is associated with unique clinical and disease-related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area-based dosing is not necessary because dose adjustments do not affect outcomes.

Population Pharmacokinetics of Melphalan in a Large Cohort of Autologous and Allogeneic Hematopoietic Cell Transplantation Recipients: Towards Individualized Dosing Regimens.

High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing. Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM. Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m2, a two-compartment population-pharmacokinetic model was developed. Fat-free mass was a covariate for clearance, central volume of distribution, and inter-compartmental clearance, while glomerular filtration rate predicted clearance. Simulation studies showed that based on fixed body surface area-based dosing, renal impairment has a higher impact in increasing melphalan exposure compared with obesity. The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.

Measurement of 5- fluorouracil, capecitabine and its metabolite concentrations in blood using volumetric absorptive microsampling technology and LC-MS/MS

5-fluorouracil (5-FU) and its oral formulation, capecitabine, are widely used in treating a range of malignancies, either alone or in combination with other antineoplastic drugs. Body surface area-based dosing is used for these agents, despite this approach leading to substantial variability in drug exposure and often resulting in either toxicity or treatment failure. Tailoring therapeutic regimens for individual patients using therapeutic drug monitoring (TDM) has been shown to significantly reduce toxicity and improve cancer outcomes. However, for optimum TDM, sample timing is crucial, along with the need for a venepuncture blood sample to obtain the plasma currently used for 5-FU measurement. In addition to complex blood sample handling requirements, large sample volume and frequent sampling required for pharmacokinetic analysis is another barrier to successfully implementing TDM in a healthcare setting. Microsampling is an alternative collection method to venepuncture, which, combined with the now readily available liquid chromatography mass spectrometry (LC-MS/MS) technology, overcomes the plasma-associated issues. It also has the significant advantage of enabling at home and remote sampling, thus facilitating 5-FU TDM in clinical practice.A LC-MS/MS method for simultaneous measurement of capecitabine, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine and 5-FU using Mitra® microsampling devices for sample collection was developed. A Shimadzu 8060 LC-MS/MS equipped with electrospray ionisation source interface, operated in positive and negative ion modes, with reversed-phase chromatographic separation was employed for sample analysis. Samples were extracted from Mitra® devices using acetonitrile containing stable isotope-labelled internal standards, sonicated, evaporated under vacuum and resuspended in 0.1 % formic acid before injection into the LC-MS/MS. Chromatographic separation was on a Luna Omega Polar C18 (100 × 2.1 mm, 1.6 µm) column with gradient elution of 0.1 % formic acid in water and acetonitrile. Total run time was 5 min, with the injection volume of 1 µL. The intra and inter-day imprecision ranged from 3.0 to 8.1 and 6.3–13.3 % respectively. Accuracy ranged from 95 −114 % for all analytes. Lower limit of quantification with imprecision of < 19 % and accuracy between 89 and 114 % was 0.05 mg/L for 5-FU and 10 µg/L for other analytes. Assays were linear from 0.05 to 50 mg/L for 5-FU and 10–10,000 µg/L for all other analytes. Analytes were stable on Mitra® devices for up to 9 months at room temperature, 2 years at −30 ℃ and 3 days at 50 ℃. The method was successfully applied for the analysis of samples from patients undergoing cancer treatment with 5-FU and capecitabine. Microsampling using volumetric absorptive microsampling proved to be as reliable as conventional blood collection for 5-FU and capecitabine. This sampling technique may lead to less invasive and better-timed sample collection for TDM, supporting dose optimization strategy.

A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication.

Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients. Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation. Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours [13%]; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 hour-1 [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 15.4 L/h [24%] (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day). Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.

Does oxaliplatin pharmacokinetics (PKs) explain associations between body composition and chemotherapy toxicity risk in older adults with gastrointestinal (GI) cancers?

3095 Background: Considerable inter-individual variability in oxaliplatin toxicity exists in older adults with GI cancers. Low lean body mass (LBM), commonly known as sarcopenia, influences toxicity and is not incorporated in standard body surface area-based dosing, which may affect oxaliplatin PK and tolerability, but has not been examined systematically. Methods: We examined oxaliplatin PK in 26 older adults (103 concentrations) with GI cancers (NCT03998202). Using the transverse section at L3, skeletal muscle area (SMA) and total adipose tissue (TAT) were quantified (Slice-O-Matic software) and LBM was calculated (LBM = 0.30 × SMA + 6.06). Noncompartmental methods (WinNonlin 7.0) were used for PK estimates and a one compartment population PK model (PopPK) was developed. Covariates included age, sex, LBM, TAT, weight, BMI, creatinine clearance, BSA, serum albumin, and body composition phenotypes (i.e. low LBM-high TAT, etc.). Results: Median age was 68yrs, 69% male, 88% white, and mostly colorectal (62%) and pancreatic (27%) cancers. There was wide variability in oxaliplatin volume of distribution (Vd: 12.5-259L), peak concentrations (Cmax: 404-3642ng/mL), and clearance (CL: 26.7-270L/hr). Participants with lower LBM had lower Vd (r = 0.51, p&lt; 0.01); those with higher TAT had higher Cmax (r = 0.53, p&lt; 0.01). Higher albumin was associated with lower Cmax (r = -0.49, p= 0.01) and higher CL (r = 0.47, p= 0.01). The phenotype of low LBM + high TAT had the lowest Vd (Relative Risk [RR] 0.32, p= 0.01), lowest CL (RR 0.39, p&lt; 0.01), and highest Cmax (RR 3.3, 95% CI 1.7-6.5, p&lt; 0.01). Eleven patients (44%) had grade 3-5 chemotoxicity. Vd (r = -0.46, p= 0.02) and Cmax (r = 0.44, p= 0.03) were associated with grade 3-5 chemotoxicity. The phenotype of low LBM + high TAT was associated with a 45% higher risk of grade 3-5 chemotoxicity (RR = 1.45, 95% CI 1.1-2.1, p= 0.04), while BSA was not (r = -0.04, p= 0.9). In the popPK model, body composition was associated with PK (TAT with Vd [p = 0.006] and CL [p &lt; 0.001]), as was albumin (Vd p = 0.004; CL p = 0.002), while BSA was not (Vd p = 0.08; CL p = 0.2). Compared to BSA, an additional 11-17% in oxaliplatin PK variability was explained by LBM (11%), TAT (14%), and albumin (17%). Conclusions: Relationships between body composition, oxaliplatin PK, and severe chemotoxicity suggest the need for novel dosing strategies that incorporate body composition to reduce chemotoxicity and improve outcomes. Clinical trial information: NCT03998202.

Comparison of Individualized Versus MAP-Bayesian Predicted AUC of Busulfan in FluBu4 Treated Patients Undergoing Allogeneic Transplant

Although myeloablative fludarabine/busulfan (FluBu4) has been widely adopted in clinical practice, considerable interpatient variability exists in systemic busulfan exposure (AUC) when using body weight or body surface area based-dosing, leading to decreased efficacy (i.e. relapse) or increased toxicity (i.e., mucositis, veno-occlusive disease). This well-defined dose-exposure-outcome relationship has led to the widespread clinical implementation of therapeutic drug monitoring (TDM). However, individualized TDM can be time and labor intensive as well as potentially biased due to the lack of incorporation of any previously established PK data (Bayesian prior). In contrast, Bayesian maximum a posteriori (MAP) PK models consider the Bayesian prior and individualized TDM to generate a revised probability distribution (Bayes conditional posterior) to more accurately and rapidly estimate the AUC with reduced bias. There are a paucity of data comparing busulfan AUCs using individualized PK versus MAP-Bayesian-based models in adults although these more sophisticated approaches may assist in optimizing dosing of busulfan in this vulnerable population. This was a retrospective, single-center study of patients who received FluBu4 with busulfan TDM between January 1999 and September 2019. 109 patients diagnosed with a hematologic malignancy who received either sequential (n=46) or concurrent (n=63) FluBu4 were analyzed. The median age was 48 (range: 18-66), and were Hispanic (n=38), White (n=46) or African-American (n=14). TDM was performed either after a test dose of 0.8 mg/kg (n=52) or after the first dose (3.2 mg/kg) of busulfan administered during the preparative regimen (n=71), with dosing was based on actual or adjusted body weight. For PK analysis, plasma busulfan concentrations were analyzed via gas chromatography with mass selective detection. Individualized PK data were generated using WinNonlin while the MAP-Bayesian approach utilized the Bayesian prior developed from McCune et al (Clin Cancer Res, 2014). An AUC of 4800 µM˖min/24 hours was targeted based on previous literature. Based on individualized PK data, total recommended busulfan doses ranged from 9.3-21.3 mg/kg (-27.1% to +66.7% compared to FDA labeled dose of 12.8 mg/kg). When first-dose busulfan PK was compared between busulfan given sequentially versus concurrently with fludarabine there was a trend towards a higher AUC with concomitant administration (4651 vs. 4988 µM˖min; p=0.13). A strong correlation between the AUC generated from both the individualized PK an MAP-Bayesian models was observed with both the test dose (R2=0.91) and first dose (R2=0.86) of busulfan. Using the MAP Bayesian model, AUC predictions were on average higher (mean AUC 5069 versus 4886 µM˖min, p&amp;lt;0.0001) compared to the patient-specific individualized PK estimates. Figure 1 shows the Bland Altman plots for comparison of the individualized AUC vs. MAP-Bayesian estimates for test dose and first dose. Our individualized busulfan PK approach generated relatively similar AUC values compared to MAP-Bayesian estimates, although the higher AUC generated via MAP-Bayesian predictions may allow for lower doses of busulfan to be administered thereby potentially reducing toxicity while maintaining efficacy. Further, use of the MAP-Bayesian method may allow for more rapid dose optimization and a decreased number of serum concentrations. Further prospective studies including more patients are warranted to confirm these findings. Figure 1 Disclosures Calip: Flatiron Health: Current Employment. Patel:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

Systemic exposure to 5-fluorouracil and its metabolite, 5,6-dihydrofluorouracil, and development of a limited sampling strategy for therapeutic drug management of 5-fluorouracil in patients with gastrointestinal malignancy.

5-Fluorouracil (5-FU) is widely used in combination chemotherapy, and literature suggests pharmacokinetic-guided dosing to improve clinical efficacy and reduce toxicity. This study aimed to determine the pharmacokinetic exposure of both 5-FU and its metabolite, 5,6-dihydrofluorouracil (DHFU), in patients with gastrointestinal malignancy and to establish a simplified strategy to assist in therapeutic drug management for dose optimization. This was a prospective, observational study, performed in 27 patients diagnosed with gastrointestinal malignancy who were prescribed 5-FU. Multiple samples were collected per patient over the slow bolus (15-20 min) and continuous infusion period (over 44 h) in doses 1 and 3, and the concentrations of 5-FU and DHFU were measured. A higher proportion of patients had exposures within the therapeutic range in dose 3 (50%) as compared to dose 1 (37.5%) with 5-FU. There was an association between delayed time to maximum concentration of DHFU and a high maximum concentration of 5-FU. A limited sampling strategy was developed with 4 samples, 2 during the bolus period and 2 during the continuous period (at 18 h and the end of infusion), which accurately predicted the total area under the curve of 5-FU. Using body surface area-based dosing with 5-FU, 50-60% of patients were outside of the therapeutic range. In the absence of genotype testing, measurement of the metabolite DHFU could be a phenotypical measure of dihydropyrimidine dehydrogenase enzyme activity. A limited sampling strategy was developed in patients who were prescribed a combination regimen of slow bolus, followed by a 44-hour continuous infusion of 5-FU to assist in the therapeutic drug management of patients.

Development of a method for clinical pharmacokinetic testing to allow for targeted Melphalan dosing in multiple myeloma patients undergoing autologous transplant.

High dose melphalan (HDM) and autologous stem cell transplant (ASCT) is standard of care for multiple myeloma (MM), but there is significant variability in melphalan exposure (area under the plasma drug concentration-time curve, AUC) when using body surface area-based dosing. Our aim was to establish a method of pharmacokinetic (PK) testing for real-time melphalan dose adjustments. We performed a prospective PK study of melphalan 140 or 200 mg/m2 in MM patients undergoing ASCT. Twenty MM patients were administered HDM on days -2 and - 1, with PK sampling at 8-10 time points. PK testing was performed on day -2 in all patients, and on day -1 in 5 patients. Less than 20% interpatient variation in the day -2 and - 1 AUC was observed. The day -2 range in AUC (4.95-11.28 mg h/L) confirmed significant interpatient variability. The hypothetical total dose ranged from 133-302 mg/m2 to achieve the total median AUC. A 4-time point AUC (0, 30, 150 and 240 min) highly correlated with the AUC from the 8-time point schedule. A higher AUC correlated with increased risk of febrile neutropenia (P = .05). Here we outline the methods to establish novel melphalan dosing using PK testing in MM patients undergoing ASCT to target a desired melphalan AUC.

Successful Personalization of Propylene Glycol Free Melphalan (PGF-MEL) for Multiple Myeloma (MM) and AL Amyloidosis (AL) Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT) Using Pharmacokinetic (PK)-Directed Dosing

Background Body surface area-based dosing of melphalan prior to AHCT for MM and AL patients causes inter-patient variability in exposure measured by area under the curve (AUC). Higher AUC is associated with increased toxicity, but prolonged survival (Shaw et al., BBMT 2012). Using Evomela (PGF-MEL, Acrotech Biopharma LLC), a more stable and possibly less toxic intravenous formulation of melphalan, we examined the feasibility of PK-directed dosing to individualize and optimize therapy. Methods Prospectively, patients received 100mg/m2 of PGF-MEL on day -2 prior to AHCT. Serum samples were collected at 5, 15, 30, 40, 75, and 150 min after the dose and AUC PK modeling (Phoenix WinNonlin v6.4) was used to determine the dose required to achieve a target AUC of 13.5mg/L*h (+/-1). On day -1, patients received the balance of the calculated dose with samples collected at the same timepoints to calculate the total AUC. After 5 patients were enrolled, the protocol was amended to increase the maximum allowable dose to the equivalent of 260mg/m2 from 220mg/m2. On day +1, 6, 11, 30, 60, and 90, patients reported symptom burden was collected using the MD Anderson Symptom Inventory – MM (MDASI-MM). Results Results of 15 patients are presented with 11 having MM and 4 AL, 60% male, median age 62yr (range 48-71), median body surface area 1.9 (range 1.5-2.2), and median creatinine on day of Mel 0.8mg/dL (range 0.7-1.6). Target doses were calculated and given in 100% of patients. Thirteen of 15 patients (87%) achieved the target AUC. The median AUCs on day -2 and day -1 were 6.3 mg/L*h (range 4.2-11.4) and 5.6 (range 3.1 – 8.4) respectively, with a median total AUC of 13.2 (range 9.6-15.2, Figure 1). Three patients received the capped dose of 220mg/m2 prior to the amendment and achieved their predicted AUC; 1 patient received the minimum 140mg/m2 and also achieved the predicted AUC which was higher than the target AUC, as expected. 9/15 patients had AUCs between 12.5-14.5 with 4/6 patients out of range for the above reasons. Neutropenic fevers occurred in 40% and grade 2 diarrhea for at least 1 day in 80% (median 2 days, range 0-7). Median time to neutrophil engraftment was 9 days (range 9-12). The median number of red cell and platelet transfusions required were 0 (range 0-3) and 1 (range 0-8), respectively. Engraftment syndrome was seen in 30% of patients. The hematologic response rate post AHCT was 100%, including complete remission in 20% and ≥ very good partial response 73%. With median follow-up of 6.4 months (range 2.8-13.1 months), one patient with MM whose AUC was below the target (10.1 units) has relapsed. No patient has died. Conclusion We show for the first time that personalization of therapy to a target AUC using PK-directed PGF-MEL was logistically feasible and prevented underdosing. Full trial results for 35 patients, as well as patient-reported outcomes and toxicities will be presented at the meeting.

OUTCOMES OF TREATMENT FOR OBESE PATIENTS WITH ADVANCED HODGKIN LYMPHOMA IN THE RATHL TRIAL (CRUK/07/033)

Introduction: With obesity levels increasing, optimal chemotherapy (CT) dosing for overweight patients is a significant issue. Although guidelines recommend obese patients should be dosed on full body weight, clinicians continue to cap doses through fear of excess toxicity. It is not clear whether this affects treatment outcomes, particularly in diseases treated in anticipation of cure, such as Hodgkin lymphoma (HL), where the role of body mass index (BMI) on survival is unknown. Methods: Adult patients (pts) with newly diagnosed HL (Ann Arbor stages IIB–IV, or IIA with bulk or ≥3 involved sites) underwent paired baseline and interim PET-CT scans after 2 cycles of ABVD (PET2). Treatment was intended to be given at full dose and on schedule, irrespective of blood counts, provided pts were well. Pts with negative PET2 were randomized to ABVD or AVD for 4 more cycles. Pts with positive PET2 proceeded to intensification with BEACOPP-14 or escalated BEACOPP. BMI was recorded at trial entry, individual drug doses administered, and toxicity scores were recorded for each cycle. Results: BMI data was analysed for 1199 eligible pts. A total of 25.4% were overweight (BMI 25-30), 14.9% obese (BMI 30-40), and 1.3% very obese (BMI 40+). CT doses of <90% were given significantly more often to pts with BMI ≥ 30 in almost all cycles. For example in cycle 1: at least one drug was given at <90% in 20% pts with BMI ≥ 30, versus 12.4% of pts with BMI <30 (P = .008). Grade III/IV neutropenia was not significantly different according to BMI however, nor was the use of G-CSF. Among 190 obese/very obese pts, dose reductions to <90% did not significantly affect the risk of grade III/IV haematologic toxicity, but the PET2 results showed a trend towards more positive scans (19.4% vs 9.9%, P = .1). PFS and OS were not affected by dose reduction among the obese group, either across all pts or selecting only those with negative PET2. No significant difference in PFS or OS was detected when analysing the whole study population according to BMI. Conclusion: Elective dose reductions were more common in pts with BMI ≥ 30, but this did not reduce their risk of grade III/IV neutropenia. Conversely, administering full body surface area-based dosing for weight did not result in a higher incidence of grade III/IV haematology toxicity. Among obese pts, modest dose reductions do not appear to lessen the risk of myelosuppression or to adversely affect treatment outcomes, and in this study which mandated close adherence to dose intensity, there was no evidence of worse outcomes among obese pts. Keywords: ABVD; Hodgkin lymphoma (HL); positron emission tomography (PET)

Chemotherapy safety standards: A pediatric perspective.

Chemotherapy safety standards: A pediatric perspective.

Population Pharmacokinetics of Necitumumab in Cancer Patients.

Necitumumab is a second-generation, recombinant, human immunoglobulin G1, epidermal growth factor (EGFR) receptor antibody that specifically blocks the ligand binding site of EGFR. Necitumumab potentially acts by blocking ligand epidermal growth factor (EGF) binding-mediated activation of the EGFR signaling pathway, inhibiting tumor growth, angiogenesis, and anti-apoptotic mechanisms. Necitumumab inhibited the interaction of EGF and EGFR with a concentration that inhibits binding by 50 % of approximately 0.9 nM (0.13 mg/L) and demonstrated antitumor activity during in vivo experiments associated with trough plasma concentrations of approximately 40 mg/L. This work describes the population pharmacokinetics of necitumumab in cancer patients when administered with or without concomitant chemotherapy and evaluates patient characteristics that may guide dosing. Nonlinear mixed-effects modeling of serum concentration data across five clinical studies (phases I–III) indicated that necitumumab exhibited target-mediated drug disposition, commonly observed with monoclonal antibodies, and that pharmacokinetics were expected to be linear in the studied dose ranges when administered as repeated infusions. No age, sex, race, or concomitant medication factors were found influential, while weight was a statistically significant factor for both distribution and elimination. Simulations from the final model indicated that only a limited reduction in patient drug exposure variability would be achieved by weight- or body surface area-based dosing. Necitumumab effective half-life was estimated to approximately 2 weeks, and steady state was achieved within three to four cycles of treatment. The phase III dosing schedule of 800 mg dosed on days 1 and 8 of a 21-day schedule resulted in serum concentrations that exceeded the 40-mg/L threshold indicated by preclinical experiments.

Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice

BackgroundStudies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice. Patients and MethodsA total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data. ResultsThe average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU–related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses. ConclusionPersonalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU–related toxicities.

Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

Background:Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patient’s dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria.Methods:Three BSA bands were defined: BSA<1.7 m2, 1.7 m2⩽BSA<1.9 m2, BSA⩾1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug.Results:For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between −14% and +22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P<0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs.Conclusion:For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure.

Drug Dosing Based on Weight and Body Surface Area: Mathematical Assumptions and Limitations in Obese Adults

The average weight of adults in the United States has increased by 25 pounds (11 kg) over the past 50 years, with a marginal change in height. Drugs are generally dosed according to one of three approaches: fixed dosing, weight-based dosing, or body surface area-based dosing. Dosing based on body weight or body surface area assumes that drug pharmacokinetic parameters increase in proportion with increasing body size. In contrast, dosing drugs on a fixed basis assumes that drug pharmacokinetic parameters do not increase with body size. Unfortunately, early stages of clinical drug development tend to include adults within a narrow range of body size. This study population does not reflect the current U.S. population distribution and does not permit evaluation of the correct relationship between body size and drug clearance. As a consequence, a weight-based or body surface area-based dosing regimen defined during drug development may not be applicable to U.S. patient populations. These dosing strategies are more likely to result in drug overexposure (weight-based approach) or underexposure (body surface area-based approach) among obese patients. Alternate weight descriptors such as ideal body weight, adjusted body weight, fat-free weight, and lean body weight are used to prevent drug overexposure with weight-based dosing, but their benefits and limitations must be understood. Reappraisal of the drug dosing paradigm is needed in this era of rising obesity; however, until drug-specific reviews can be performed, clinical studies must include patients at the extremes of the weight continuum to ensure applicable dose extrapolation for body size.

Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: Good tolerance profile and efficacy in rhabdomyosarcoma – A report from the Société Française des Cancers et leucémies de l’Enfant et de l’adolescent (SFCE)

AimThis phase II study evaluated efficacy, safety and pharmacokinetics (PK) profile of combination intravenous vinorelbine (VNL) and continuous low doses oral cyclophosphamide (CPM) combination in children and young adults with a recurrent or refractory solid tumour. MethodsA total of 117 patients (median age, 12years) within six disease strata received intravenous VNL 25mg/m2 on days 1, 8 and 15 of each 28-day cycle combined with continuous daily oral CPM 25mg/m2. Tumour response was assessed every two cycles according to WHO (World Health Organisation) criteria. PK of VNL was investigated in a subset of 18 patients aged 4–15years. ResultsIn rhabdomyosarcoma (RMS) (n=50), the best overall response rate (ORR) was 36% with four complete (8%) and 14 partial responses (28%). The best ORR was 13% in Ewing’s sarcoma (n=15), 6% in non-RMS soft tissue sarcoma (n=16) and 6% in neuroblastoma (n=16). No response was observed in osteosarcoma (n=10) and medulloblastoma (n=7). The main grade 3/4 toxicity was neutropenia (38%). Other severe toxicities were limited with 3% of peripheral neuropathy and no haemorrhagic cystitis. The PK analysis revealed equivalent blood exposure to VNL between children >4years and adult series when the VNL dose was based on the body surface area-based dosing. Concluding statementIn heavily pre-treated children, VNL combined with CPM showed an interesting response rate in RMS and an acceptable toxicity profile supporting further evaluation of these agents in phase III trials.

Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients

There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD. Pharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi's sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined. There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean±SD clearance for patients <60years old and ≥60years old were 54.6±28.5 and 23.3±10.8mL/h/m(2), respectively (P<0.0001), and for female and male patients were 23.7±18.8 and 55.6±26.8mL/h/m(2), respectively (P<0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance. Age, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents.