BACKGROUND:Population pharmacokinetic (PK) models can be combined with Bayesian estimation to optimize dosing regimens. The impact of sample collection time on the accuracy and precision of Bayesian predictions was evaluated. METHODS:Data from adult and pediatric patients were used to develop a cefepime population PK model for Bayesian prior use. Holdout data were used for model evaluation. Clinical dosing regimens in the latter cohort were used to conduct optimal sample-time analysis. The accuracy and precision of the Bayesian predictions were assessed as a function of infusion duration and the differences between the observed and optimal sampling times. Analyses were conducted using Pmetrics for R. RESULTS:An allometrically scaled 2-compartment model was fitted (n = 71 patients, 685 observations). In the holdout group (n = 116 patients, 203 observations), the posterior Bayesian fit was acceptable (R2 = 0.923; relative bias -3%; median absolute error, 11.2%; F20, 72%; and F30, 86%). Mid-interval sampling was the optimal 1-sample design for 11/16 regimens. In the 2-sample design, a peak (8/16 regimens) and trough (9/16 regimens) approach was frequently optimal. The 2-sample design yields a lower Bayesian risk of misclassification. For 0.5-hour infusions, Bayesian predictions were similarly accurate but significantly more imprecise when samples were collected >2 hour away from the optimal time versus within ±1 hour of the optimal time (ΔRMSE: 8.98 mg/L, 95% CI: 3.61-15.7 mg/L). For 3 hours infusions, no significant differences in the accuracy or imprecision of the Bayesian predictions were noted. CONCLUSIONS:The nonparametric cefepime population PK model fit as a Bayesian prior in the holdout group. The optimal timing of PK sample collection varied according to regimen type and infusion duration. The precision of Bayesian estimates was lower for 0.5-hour infusions when samples were collected further from the model-predicted regimen-specific optimal collection times.

Abstract Background Clinicians performing beta-lactam therapeutic drug monitoring (TDM) lack evidence on when levels should ideally be drawn after a dose. Herein, we define the optimal timing (i.e., optimal sampling) for cefepime using real-world TDM data to validate our approach.Figure 1.External validation of the Bayesian prior non-parametric population PK model Methods De-identified data from two centers performing routine cefepime TDM were extracted by InsightRX and served as an external validation cohort. Plasma cefepime was quantified using validated LC-MS/MS assays for TDM and dosing was protocolized at each site. CRRT and ECMO patients were included but other dialysis patients were not. Bias (MPE) and precision (RMSE) of a non-parametric prior were assessed. Multiple-model optimal (MM-opt) sampling strategies were estimated for the first 24 hours of treatment. To mirror clinical practice, one- and two-sample designs were evaluated. Dose and covariate values informed optimal sampling times. Bayesian PK exposures were compared using all samples, trough-only sampling, or using a single optimally timed sample. AUCs were calculated from the posteriors. For fT >MIC analysis, the MIC was fixed at 8 mg/L. We used Pmetrics 2.1.1 for R.Figure 2.Distribution of MM-optimal sampling times in external validation data using n=1 sample Results 116 patients (42% female; median age, CRCL, and weight: 62 years, 76 mL/min, and 80 kg, respectively) contributed 235 levels. The PK model demonstrated acceptable bias and precision (-6% MPE, 30.9 RMSE) as a prior for estimating exposures from the TDM data (Fig1). For a one-sample approach, the most common MM-opt sampling times varied (Fig2) but were often a mid-point or trough. In the two-sample approach, sample one was often a mid-point and sample two was often a trough (Fig3). First 24-hr AUC and fT>MIC did not significantly differ using all available samples for analysis vs. limiting sampling to a single optimized time point vs. limiting sampling to a trough-only approach (P >0.05 for all comparisons; Fig4).Figure 3.Distribution of MM-optimal sampling times in external validation data using n=2 samples Conclusion Optimal cefepime sampling times depended on dosing regimen, and renal disposition. When limited to a single sample, optimal sampling times for cefepime TDM were often midpoint/trough levels, but when two samples were obtained the optimal sampling times were often a mid-point followed by a trough. Estimation of PK and PK/PD exposures was not significantly worse when using a validated Bayesian prior and a trough-only sampling approach.Figure 4.First 24 hours PK and PK/PD exposure estimates from Bayesian analysis of all external validation data and Bayesian analysis of n=1 optimally timed samples from the same population Disclosures Nathaniel J. Rhodes, PharmD MS, Apothecademy, LLC: Advisor/Consultant Brandon Smith, MD, PharmD, Melinta Therapeutics: Advisor/Consultant|Shionogi, INC: Advisor/Consultant Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Jasmine Hughes, PhD, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company) Maria-Stephanie Hughes, PharmD, InsightRX: Employee of company|InsightRX: Stocks/Bonds (Private Company) Fekade B. Sime, PhD, S.Aust., Gilead: Grant/Research Support|Pfizer: Grant/Research Support Patrick J. Kiel, PharmD, Amgen: Employee|Amgen: Stocks/Bonds (Public Company) Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Cidara: Advisor/Consultant|DoseMe: Advisor/Consultant|Entasis: Advisor/Consultant|F2G: Advisor/Consultant|GSK: Advisor/Consultant|Lykos: Advisor/Consultant|Roche: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant|Xelia: Advisor/Consultant

PURPOSE:The primary objective of this study was to evaluate the impact of a pharmacist-driven oral antineoplastic (OAN) renewal clinic on medication adherence and cost savings.METHODS:This was a preimplementation and postimplementation retrospective cohort evaluation within a single US Department of Veterans Affairs health care system following implementation of a pharmacist-managed OAN refill clinic. The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from pre- to postimplementation and estimated cost-savings of this clinic. Patients were eligible for inclusion if they had received at least 2 prescriptions of the most commonly prescribed oral antineoplastic agents at the institution between September 1, 2013 and January 31, 2015.RESULTS:Of preimplementation patients, 96 of 99 (96.9%) were male and all patients (n = 35) in the postimplementation group were male. The mean age of the preimplementation group was 69.2 years while the postimplementation group was 68.4 years. Median MPR in the preimplementation group was 0.94, compared with 1.06 in the postimplementation group (P < .001). Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent to their OAN regimen compared with zero patients in the postimplementation group. Estimated total cost savings was $36,335 in the postimplementation period.CONCLUSIONS:Implementation of a pharmacist-driven OAN renewal clinic was associated with a 12% increase in median MPR while saving an estimated $36,335 during the 5-month postimplementation period.

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate a cefepime population pharmacokinetic (PK) model and integrate it into a precision dosing tool for implementation.

Objectives: There has been interest in administering cefepime, a beta-lactam antibiotic, via intravenous push (IVP) as a means to improve time to first-dose antibiotic and reduce cost; however, the downstream impacts on antibiotic exposure and pharmacodynamic efficacy need to be further evaluated. Methods: This study used a population pharmacokinetic model for cefepime and simulated exposures to predict the pharmacodynamic (PD) effect for cefepime regimens administered via IVP or 30-minute intermittent infusion in adults with different renal functions. FDA-approved adult dosages of 1-2 g every 8 or 12 hours were compared. This study aimed to compare the absolute difference in pharmacodynamic probability of target attainment (PTA) between IVP and intermittent infusion, defined as free cefepime concentrations above organism MIC for >= 70% of the time. Results: At MICs of 0.25-0.5 mg/L, absolute differences in PTA were observed, with a reduction as great as 2.3% (89% to 86.7% for 30-minute intermittent infusion and IVP, respectively). At MICs of 1-4 mg/L, 30-minute intermittent infusion and IVP exhibited PTA differences as great as 5.4%, from 89.4% to 84%, respectively. At MICs of >= 8 mg/L, similar absolute differences existed; however, no regimen achieved a PTA >70%. Across renal function strata of 60, 100 and 140 mL/minute (within the same dosing group and MICs), better renal function lowered PTAs. Conclusions: Simulations demonstrated that IVP cefepime resulted in lower PTAs than traditional intermittent infusion among a subset of elevated MICs. Clinicians should exercise caution in IVP strategy, as unintended clinical consequences are possible. (C) 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Fluoropyrimidine drugs, both fluorouracil (FU) and its prodrug capecitabine, are widely used in the treatment of solid tumors such as breast, colorectal, and gastric cancers. Over 2 million patients newly diagnosed with cancer are treated each year with fluoropyrimidines. Between 10% and 40% of these patients develop severe, sometimes life-threatening toxicities, which may include mucositis, neutropenia, nausea, severe diarrhea, vomiting, stomatitis, and hand-foot syndrome. These toxicities can be caused by genetic variants in DPYD, the gene that encodes for dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for FU catabolism.

PURPOSE Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

Recent advancements in molecular testing, the availability of cost-effective technology, and novel approaches to clinical trial design have facilitated the implementation of tumor genome sequencing into standard of care oncology practices. Current models of precision oncology practice include specialized clinics or consultation services based on a molecular tumor board (MTB) approach. MTBs are comprised of interprofessional teams of clinicians and scientists who evaluate tumors at the molecular level to guide patient-specific targeted therapy. The practice of precision oncology utilizing MTB-based models is an emerging approach, transforming precision genomics from a novel concept into clinical practice. This rapid shift in practice from cytotoxic therapy to targeted medicine poses challenges, yet brings exciting opportunities to clinical pharmacists practicing in hematology and oncology. Only a few precision genomics programs in the United States have a strong pharmacy presence with oncology pharmacists serving in leadership roles in research, interpreting genomic sequencing, making treatment recommendations, and facilitating off-label drug procurement. This article describes the experience of the precision medicine clinic at the Indiana University Health Simon Cancer Center, with emphasis on the role of the pharmacist in the precision oncology initiative.

Understanding pharmacokinetic disposition of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of 12 pediatric patients and two separate adult populations were assessed. Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n = 34) on average weighed 82.7 kg and displayed a mean creatinine clearance of 106.7 mL/min. All pediatric subjects (n = 36) had mean weight and creatinine clearance of 16.0 kg and 195.6 mL/min, respectively. A covariate-adjusted two-compartment model described the observed concentrations well (population model R2, 87.0%; Bayesian model R2, 96.5%). In the evaluation subsets, the model performed similarly well (population R2, 84.0%; Bayesian R2, 90.2%). The identified model serves well for population dosing and as a Bayesian prior for precision dosing.

Objective To develop an alternative approach to provide oncology pharmacy practice residents’ education and training in the management of gynecologic malignancies in the absence of a specialist in this area at their institution. Setting Gynecologic oncology is a unique specialty in oncology. There is a need for more oncology clinical pharmacy specialists to participate in the care of patients with gynecologic malignancies as many do not have specific education in this area. Practice description A virtual learning experience was developed that included all aspects of a typical experience with the exception of direct patient care. Postgraduate year 2 oncology pharmacy residents from 3 different programs were included. Practice innovation Although the number of oncology clinical pharmacy specialists who are subspecialized in gynecologic oncology has grown, it is difficult to find experienced preceptors in gynecology oncology. We set to offer a virtual learning environment for programs that did not have a dedicated or highly specialized pharmacist in this area. Evaluation A pre- and postlearning assessment of the resident’s knowledge of gynecologic malignancies was administered. Each trainee independently completed a validated 20-question gynecologic oncology knowledge assessment tool before and again after completion of all sessions. Midpoint and end-of-experience evaluations were completed via the phone with each resident. All evaluations were documented in PharmAcademic (McCreadie Group, Ann Arbor, MI), a required software program for postgraduate residency training programs. Results To date, 7 oncology pharmacy practice residents completed the virtual experience. A 42% improvement in scores pertaining to gynecologic oncology knowledge was identified. Residents were also satisfied with the overall virtual experience. Based on the assessment tool, all the residents gave positive evaluations with “always true” for 6 of the 7 questions. Conclusions This pilot of a virtual experience was a successful platform to provide clinical knowledge and skills for oncology pharmacy residents in gynecologic oncology.

BACKGROUND/AIM:hERG potassium channels enhance tumor invasiveness and breast cancer proliferation. MicroRNA (miRNA) dysregulation during cancer controls gene regulation. The objective of this study was to identify miRNAs that regulate hERG expression in breast cancer.MATERIALS AND METHODS:Putative miRNAs targeting hERG were identified by bioinformatic approaches and screened using a 3'UTR luciferase assay. Functional assessments of endogenous hERG regulation were made using whole-cell electrophysiology, proliferation assays, and cell-cycle analyses following miRNA, hERG siRNA, or control transfection.RESULTS:miR-362-3p targeted hERG 3'UTR and was associated with higher survival rates in patients with breast cancer (HR=0.39, 95%CI=0.18-0.82). Enhanced miR-362-3p expression reduced hERG expression, peak current, and cell proliferation in cultured breast cancer cells (p<0.05).CONCLUSION:miR-362-3p mediates the transcriptional regulation of hERG and is associated with survival in breast cancer. The potential for miR-362-3p to serve as a biomarker and inform therapeutic strategies warrants further investigation.

Study Objective Basiliximab is an immunosuppressive monoclonal antibody used for rejection prevention following solid organ transplantation; the pharmacokinetics (PK) of basiliximab in this setting are known. Basiliximab may also be used for prophylaxis and treatment of graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic cell transplantation (HCT); however, the PK of basiliximab in this setting are not known. Clinical transplant providers expect variation in the volume of distribution and clearance after nonmyeloablative allogeneic transplantation (NMAT) compared with solid organ transplantation. Blood loss, organ site-specific antibody accumulation, and differences in blood product use during the two transplantation approaches may generate differences in basiliximab PK. Therefore, the objective of this study was to describe the PK of basiliximab after its addition to a minimally intense NMAT regimen, in conjunction with cyclosporine, for GVHD prophylaxis in patients with hematologic malignancies. Design Population PK analysis of a single-center, single-arm, phase II clinical trial. Setting Academic cancer research center. Patients Fourteen adults with hematologic malignancies (acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, myelofibrosis, or severe aplastic anemia) and undergoing NMAT with a fully HLA-matched (10 of 10 antigen matched) related or unrelated donor. Measurements and Main Results Basiliximab was used in conjunction with cyclosporine to deplete activated T cells in vivo as GVHD prophylaxis. We developed a novel competitive enzyme-linked immunosorbent assay (ELISA) method using recombinant interleukin-2 receptor alpha-chain (IL-2Ra) and a commercially available soluble sIL-2R ELISA kit to permit the quantification of serum basiliximab concentrations and characterization of the PK properties of the drug in this patient population. Using a nonlinear mixed effects model with NONMEM software, a one-compartment model with first-order elimination best described the PK, as covariate analysis using stepwise covariate modeling did not improve the base model. Conclusion We suggest a one-compartment population model with first-order elimination to capture the PK profile for basiliximab for this patient population.

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

The Clinical Laboratory Improvement Amendments of 1988 require that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a Clinical Laboratory Improvement Amendments-accredited laboratory. Because no known reference materials were available, existing DNA samples were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other Clinical Laboratory Improvement Amendments-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.

Acute myeloid leukemia (AML) is a hematologic malignancy that affects predominantly older patients, with a median age of diagnosis around 67. Overall prognosis is poor; however, novel targeted therapies that can potentially improve outcomes in these patients have emerged in recent years. Mutations in isocitrate dehydrogenase (IDH) occur in 20% of AML diagnoses. IDH2 performs a crucial role in cellular metabolism, and when this enzyme is inhibited, the cell cannot rid itself of endogenous products and is thus marked for apoptosis. The US Food and Drug Administration (FDA) approved the first mutant IDH2 inhibitor, enasidenib, for patients with relapsed or refractory IDH2-mutated AML detected by an FDA-approved test.

Leuprolide acetate depot administered every 3 months is as efficacious and tolerable as a monthly injection in combination with an aromatase inhibitor for premenopausal patients with hormone receptor-positive breast cancer.