Utilization of supportive care medications and opportunities for pre-emptive pharmacogenomic testing in pediatric and young adults with leukemia.

This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective observational study of pediatric leukemia patients admitted between 2009-2019 at a single-center academic children's hospital was conducted to determine PGx-drug exposure within 3 years of diagnosis. Along with baseline demographic and clinical characteristics of these patients, data regarding dates of diagnosis, relapse, death were collected. During the study period, inclusion criteria were met by 714 patients. The most frequently given medications were ondansetron (96.1%), morphine (92.2%), and allopurinol (85.3%) during the study period. In this cohort, 82% of patients received five or more PGx-drugs. Patients diagnosed with acute myeloid leukemia and leukemia unspecified were prescribed more PGx-drugs than other types of leukemia. There was a significant relationship between age at diagnosis and the number of PGx-drugs prescribed. Adolescents and adults both received a median of 10 PGx-drugs, children received a median of 6 PGx-drugs, and infants received a median of 7 PGx-drugs (p < 0.001). Patients with recurrent leukemia had significantly more PGx-drugs prescribed compared to those without recurrent disease, 10 drugs and 6 drugs, respectively (p < 0.001). Patients diagnosed with childhood leukemia are high utilizers of PGx-drugs. There is a vital need to understand how PGx testing may be utilized to optimize treatment and enhance quality of life. Preemptive PGx testing is a tool that aids in optimization of drug therapy and decreases the need for later treatment modifications. This can result in financial savings from decreased health-care encounters.

A survey assessing the impact of COVID-19 and elexacaftor/tezacaftor/ifavacaftor on both physical and mental health in adults with cystic fibrosis.

In this letter to the editor, we report 82 persons with CF (PwCF) self-reported changes in mental and physical health and potential attribution with either the COVID-19 pandemic and the initiation elexacaftor/tezacaftor/ivacaftor (ETI). Emerging evidence has shown an association with ETI and mental health adverse events. The close proximity of ETI FDA approval and prescribing in PwCF and the COVID-19 pandemic present a challenge in determining the cause of mental health decline. We report 33 (40%) of respondents felt that COVID-19 contributed to a worsening of either their anxiety, depression, or both and 7 (9%) of respondents felt that ETI contributed to a worsening in their anxiety, depression, or both. Eighteen (23%) of respondents felt that ETI had contributed to improvement their mental health. This letter highlights multiple factors that could be impacting mental health beyond ETI. As the COVID-19 pandemic is moving toward an endemic phase, future studies may have more success in deciphering ETI effects on mental health.

Enoxaparin adherence for venous thromboembolism prophylaxis in hospitalized patients with sickle cell disease.

BACKGROUND: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with sickle cell disease (SCD). METHODS: This retrospective study assessed adherence to prescribed enoxaparin for VTE prophylaxis in adults with SCD while hospitalized. A total of 172 encounters of 72 unique patients were evaluated between 1 January and 31 December 2019. Patients were grouped based on adherence to prescribed enoxaparin. Group 1 received 100% of doses ordered. Group 2 received between 99% and 1% of doses ordered. Group 3 received 0% of doses ordered. RESULTS: Only 45 encounters (32.3%) received 100% of ordered doses and 81 encounters (47%) did not receive any of the ordered enoxaparin doses. In total, only 37% of all prescribed enoxaparin doses were administered to patients. CONCLUSION: This low level of administered enoxaparin is concerning in a patient population at an increased risk for VTE. VTE prophylaxis adherence needs to be addressed with each admission and, if appropriate, alterative options to enoxaparin should be considered.

Opportunity for pharmacogenetics testing in patients with sickle cell anemia.

Background: Patients with sickle cell disease (SCD) are exposed to numerous drugs over their lifespan, and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for personalized dosing. The authors' aim was to ascertain the number of drugs with CPIC guidelines prescribed to SCD patients. Materials & methods: A search of Indiana University Health affiliated hospitals' electronic medical record identified 957 patients with a diagnosis of SCD. Drugs or drug classes with CPIC actionable guidelines ordered as inpatient and outpatient prescriptions were collected from SCD patients. Results: During the 16-year period, 892 (93%) patients received at least one drug that could have been dosed according to CPIC guidelines. Conclusion: Preemptive pharmacogenetics testing should be considered in SCD patients in order to utilize these data throughout the patient's life.

Pharmacogenomics: a tool to improve medication safety and efficacy in patients with cystic fibrosis.

Cystic fibrosis is a genetic, multiorgan system disease that involves the use of many medications to control symptoms associated with the underlying condition. Many of these medications have Clinical Pharmacogenetics Implementation Consortium evidence-based guidelines for pharmacogenomics that are available to guide dosing. The aim of this article is to review relevant literature and evaluate the utility of preemptive pharmacogenomics testing for persons with cystic fibrosis and propose a pharmacogenomics panel that could be considered standard of care for persons with cystic fibrosis.

Opportunity for pharmacogenomic testing in patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) are exposed to many drugs in their lifetime and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines that are available to guide dosing. Contemporary CF treatments are targeted to specific mutations in the CF transmembrane conductance regulator (CFTR) gene, and thus, require patients to have genetic testing before initiation of modulator therapy. However, aside from CFTR genetic testing, pharmacogenomic testing is not standard of care for CF patients. AIM: The aim of this study is to determine the number of non-CFTR modulator medications with CPIC guidelines that are prescribed to patients with CF. MATERIALS & METHODS: We identified all patients with a diagnosis of CF and queried our hospital electronic medical records (EMR) for all orders, including inpatient and prescriptions, for all drugs or drug classes that have CPIC actionable guidelines for drug-gene pairs that can be used to guide therapy. RESULTS: We identified 576 patients with a diagnosis of CF that were treated at our institution during this 16-year period between June 2005 and May 2021. Of these patients, 504 patients (87.5%) received at least one drug that could have been dosed according to CPIC guidelines if pharmacogenomic results would have been available. CONCLUSIONS: Patients with CF have high utilization of drugs with CPIC guidelines, therefore preemptive pharmacogenomic testing should be considered in CF patients at the time of CFTR genetic testing.

Comparison of Vancomycin Pharmacokinetics in Cystic Fibrosis Patients Pre and Post-lung Transplant.

BACKGROUND: Vancomycin is commonly used to treat acute cystic fibrosis (CF) exacerbations associated with methicillin-resistant Staphylococcus aureus (MRSA). Multiple studies have demonstrated pharmacokinetic differences of antimicrobials in the CF population. Very little data exist regarding pharmacokinetics postlung transplant, but 2 studies have noted changes in tobramycin pharmacokinetics. No such studies exist evaluating vancomycin in CF patients postlung transplant. METHODS: A retrospective cohort review of CF patients who underwent lung transplantation and received vancomycin pre- and posttransplant was conducted. CF patients who underwent transplant between 2007 and 2016 at 4 medical centers throughout the United States were included. The primary endpoint was the change in elimination rate constant. The secondary endpoints were subgroup analyses of patients grouped by age, time posttransplant, and number of nephrotoxic medications. RESULTS: A total of 25 patients were included, of which just under half were pediatric. Patients were significantly older and heavier posttransplant and had higher serum creatinine and number of nephrotoxic medications. The change in elimination rate constant from pre- to posttransplant was -0.50 hr-1 which was statistically significant (P < .001). This significant decrease was consistent among all subgroups of patients evaluated with the exception of pediatric patients. CONCLUSION: Vancomycin pharmacokinetics are significantly altered in CF patients in the posttransplant setting as evidenced by a decrease in elimination rate constant. This decrease may be related to a decrease in renal clearance and higher numbers of nephrotoxic medications posttransplant. Regardless, pretransplant vancomycin regimens may not predict appropriate posttransplant regimens.

Neurotoxicity in adult patients with cystic fibrosis using polymyxin B for acute pulmonary exacerbations.

We present four case reports that describe neurotoxicity experienced in adult patients with cystic fibrosis (CF) receiving intravenous polymyxin B. Paresthesia was observed after the first dose of polymyxin B in all patients. These symptoms resolved after discontinuation of polymyxin B and switching treatment to colistin. All four patients completed therapy with colistin without experiencing additional adverse reactions. This report contributes to the small body of literature currently available on the use of polymyxin B in the CF population.

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

High-dose Cholecalciferol Supplementation in Adults with Cystic Fibrosis.

INTRODUCTION: Despite the availability of consensus guidelines for the treatment of vitamin D deficiency, prospective trials are lacking to examine alternative dosing strategies for adult patients with cystic fibrosis (CF) who do not meet therapeutic goals with standard regimens. OBJECTIVES: The primary objective of this study was to determine the efficacy of high-dose cholecalciferol supplementation in increasing serum vitamin D (25-OHD) levels in adult patients with CF. METHODS: Patients were eligible for inclusion if they were 18 years or older, had baseline 25-OHD levels lower than 30 ng/ml, and were diagnosed with CF and pancreatic insufficiency. Patients were given a single dose of cholecalciferol 300,000 or 500,000 IU based on baseline 25-OHD levels. Response was defined by 25-OHD and ionized calcium levels at 3 months. At 6 months, responders received a second dose of the same strength, and nonresponders were given a weekly supplement of cholecalciferol 50,000 IU in addition to cholecalciferol 500,000 IU. A second 25-OHD level was obtained at 9 months. RESULTS: Of the 46 patients enrolled, 32 patients (70%) completed the study. Baseline levels of 25-OHD significantly increased over time in the per protocol population at 3 and 9 months. A total of 16 patients (50%) were considered nonresponders and required weekly supplementation. CONCLUSION: A protocol using high-dose cholecalciferol or high-dose plus weekly cholecalciferol is safe and effective in treating adult patients with CF and pancreatic insufficiency.