Jennifer Morris

Velaglucerase Alfa for the Management of Type 1 Gaucher Disease

BACKGROUND Gaucher disease (GD) is the most common lysosomal storage disease, (frequency of 1:40,000 to 1:60,000). Ninety-Five percent of patients have type 1 (nonneuropathic type). Symptomatic patients with type 1 GD are treated with enzyme replacement therapy (ERT) to improve disease-induced effects on hemoglobin, platelets, and liver and spleen volume. Currently, several ERTs are available. OBJECTIVE The goal of this article was to review the pharmacology, efficacy, and safety data available for the use of a recently approved ERT, velaglucerase alfa, for the treatment of type 1 GD in symptomatic pediatric and adult patients. METHODS Serial searches of MEDLINE, EMBASE, and Cochrane databases for English-language, peer-reviewed, clinical data (using the search term velaglucerase alfa) were completed, with the final search in November 2011. All identified, peer-reviewed published human data were used for this review. Due to minimal peer-reviewed published data, those data reported via clinical trial registries or in the form of published abstracts were included. The manufacturer was contacted and given the opportunity to submit supplemental data for consideration of inclusion by the author. RESULTS Velaglucerase alfa is produced through gene activation technology and is identical to wild-type enzyme. As with other ERTs for type 1 GD, velaglucerase alfa targets accumulated glucocerebroside primarily within the lysosome of the macrophages in the affected organs and systems. When administered at doses of 60 U/kg intravenously, velaglucerase alfa follows linear pharmacokinetics and is rapidly eliminated, with a mean (SD) residence time or time for 63% of the dose to be cleared from systemic circulation of 14 (4) minutes. Four trials and early access program data reporting efficacy were identified for this review: 5 peer-reviewed publications, 3 clinical trial registry reports, and 1 abstract-only publication. Phase I/II data with an extension phase (n = 12) showed significant improvements (all, P < 0.004) in hemoglobin concentrations (21.7%), platelet counts (157.8%), and hepatic (-42.8%) and spleen (-79.3%) volumes at 48 months. Bone mineral density data reported out to 69 months for this extension population noted significant improvements in z score slope for both lumbar spine (0.14 z score unit per year; P < 0.01) and femoral head (0.08 z score unit per year; P < 0.01). Benchmarking of 7 patients with complete clinical datasets at 57 months identified achievement and maintenance of therapeutic goals set by the International Collaborative Gaucher Group for anemia, platelet counts, hepatosplenomegaly, and bone mineral density. Thirty-eight patients enrolled in an open-label, therapy-switch trial who received velaglucerase alfa at doses consistent with current doses of imiglucerase maintained hemoglobin (-0.101 g/dL [95% CI, -0.272 to 0.07]) and platelet counts (7.04% [95% CI, 0.54% to 13.53%]) at 53 weeks after therapy change. Phase III data evaluating 2 dosing regimens of velaglucerase alfa 60 and 45 U/kg intravenously every other week reported significant improvements in most measured clinical parameters at 12 months: hemoglobin concentrations (60 U/kg, 2.429 [0.324] g/dL [P < 0.0001]; 45 U/kg, 2.438 g/dL [95% CI, 1.488 to 3.389]), platelet counts (60 U/kg, 50.88 × 10(9)/L [95% CI, 23.97 to 77.78]; 45 U/kg, 40.92 × 10(9)/L [95% CI, 11.2 to 70.64]), spleen volumes (60 U/kg, -1.92% of body weight [95% CI, -3.04 to -0.79]; 45 U/kg, -1.87% of body weight [95% CI, -3.17 to -0.57]), and hepatic volumes (60 U/kg, -0.84% of body weight [95% CI, -1.58 to -0.11]). A subanalysis of the pediatric population showed clinical improvements at 12 months in both dosing groups: hemoglobin concentrations (60 U/kg, 1.74 g/dL [95% CI, 0.72 to 2.78]; 45 U/kg, 2.77 g/dL [95% CI, -0.99 to 6.53]), platelet counts (60 U/kg, 49.9 × 10(9)/L [95% CI, -32.1 to 131.9]; 45 U/kg, 60.3 × 10(9)/L [95% CI, -103.1 to 223.7]), spleen volumes (60 U/kg, -2.1 cm(3) [95% CI, -5.3 to 1.1]; 45 U/kg, -0.7 cm(3) [95% CI, -2.6 to 1.2]), and hepatic volumes (60 U/kg, -0.7 cm(3) [95% CI, -1.4 to 0.0]; 45 U/kg, -0.3 cm(3) [95% CI, -1.7 to 1.1]). Data comparing velaglucerase alfa with imiglucerase identified similar changes in hemoglobin concentrations at 1.624 g/dL and 1.488 g/dL, respectively, after 9 months of therapy. Safety was reported in 3 identified studies and in data reported from the early access program: 3 peer-reviewed publications, 3 studies reported in clinical trial registries, and 1 abstract publication. Patients experienced a minimal number of adverse effects, and most reactions were mild to moderate in severity; 1 patient developed an anaphylactoid reaction and was discontinued from the trial. Antibody formation has been described with velaglucerase alfa but when compared with that of imiglucerase, seroconversion is less frequent (1% and 23%, respectively). Dosing regimens, from 30 to 60 U/kg intravenously every other week, have been assessed. Currently, the manufacturer recommends 60 U/kg intravenously every other week; however, further studies and evaluation of current study dosing regimens are needed to determine if there is a lower effective dose. CONCLUSIONS Although a minimal amount of data are available for this relatively new biological agent, velaglucerase alfa reportedly is effective in the achievement and maintenance of therapeutic goals in type 1 GD in both treatment-naive and patients previously treated with imiglucerase. This agent has been reasonably well tolerated in clinical trials and may be considered for use in symptomatic patients with type 1 GD.

Development and Implementation Results of a Venous Thromboembolism Prophylaxis Guideline in a Tertiary Care Pediatric Hospital.

OBJECTIVES Incidence of pediatric venous thromboembolism (VTE) is increasing due to increased survival of children with chronic diseases and use of interventions (eg, central venous lines), with VTE risk. Our objective was to create VTE prophylaxis guidelines with targeted identification of children at high risk to support appropriate mechanical and pharmacologic prophylaxis and integrate into the electronic medical record (EMR) as a hospital-wide quality improvement project. METHODS Patients aged 12 to 17 years were included. We evaluated institutional data regarding VTE incidence and risk factors. We evaluated literature for populations at high risk for VTE. Guidelines were formulated, and an EMR tool to assess risk and support the guidelines was created and implemented. RESULTS The EMR tool was used to screen 48% of qualified admissions for the first month and 81% in the final study month. On average, 69.1% of qualified admissions were screened monthly during the first 18 months of the program. No adverse events were reported due to pharmacologic prophylaxis. CONCLUSIONS Many risk factors are common between children and adults and certain pediatric populations warrant prophylactic consideration. Pediatric VTE prophylaxis guidelines can be successfully implemented into the EMR to identify high-risk populations. Future studies should assess the long-term impact of implementation.

Implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit to reduce medication expenditures.

PURPOSE The implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit (ICU) is described. METHODS This retrospective study compared the use of i.v. chlorothiazide and i.v. ethacrynic acid in pediatric cardiovascular surgery patients before and after implementation of a diuretic stewardship program. All pediatric patients admitted to the pediatric cardiovascular service were included. The cardiovascular surgery service was educated on formal indications for specific diuretic agents, and the diuretic stewardship program was implemented on January 1, 2013. Under the stewardship program, i.v. ethacrynic acid was indicated in patients with a sulfonamide allergy, and i.v. chlorothiazide was considered appropriate in patients receiving maximized i.v. loop diuretic doses. A detailed review of the pharmacy database and medical records was performed for each patient to determine i.v. chlorothiazide and i.v. ethacrynic acid use and expenditures, appropriateness of use, days using a ventilator, and cardiovascular ICU length of stay. RESULTS After implementation of diuretic stewardship, the use of i.v. chlorothiazide decreased by 74% (531 fewer doses) while i.v. ethacrynic acid use decreased by 92% (47 fewer doses), resulting in a total reduction of

Vancomycin associated acute kidney injury in pediatric patients

91,398 in expenditures on these diuretics over the six-month study period and an estimated annual saving of over

Antimicrobial Prophylaxis for External Ventricular Drains in Pediatric Neurosurgical Patients

182,000. The median number of days using a ventilator and the length of ICU stay did not differ significantly during the study period. CONCLUSION Implementation of a diuretic stewardship program reduced the use of i.v. chlorothiazide and i.v. ethacrynic acid without adversely affecting clinical outcomes such as ventilator days and length of stay in a pediatric cardiovascular ICU.

Population Pharmacokinetic Analysis of Gentamicin in Pediatric Extracorporeal Membrane Oxygenation

Introduction Vancomycin associated acute kidney injury (vAKI) is a well known complication in pediatric patients. Identification and characterization of the incidence and risk factors for vAKI in the pediatric population would assist clinicians in potentially preventing or mitigating vAKI. Methods and materials A 6 year retrospective cohort study was designed. Patients were included if they were < 19 years of age, received vancomycin as inpatients, and had a baseline SCr and one other SCr drawn during and up to 72 hours after the discontinuation of vancomycin. Data collection included patient demographics, vancomycin doses and length of therapy, vancomycin serum concentrations, and concomitant medications. The Kidney Disease Improving Global Outcomes (KDIGO) criteria were used to characterize acute kidney injury. Descriptive statistical methods were used and ordinal logistic regression was employed to determine variables significantly associated with vAKI. Results A total of 7,095 patients met study criteria (55.4% male, median age 4.1 years (IQR 0.67–11.2 years)). Mechanical ventilation was used in 7.9% (n = 563) and mortality was 4.9% (n = 344). A total of 153 concomitant medications were identified. A median of 5 (IQR 3–7) SCr values were obtained and median SCr prior to vancomycin was 0.39 (IQR 0.28–0.57) mg/dL (CrCl 134±58 mL/min/1.73m2). Vancomycin was administered for a median of 2 (IQR 1–3) days (14.9±1.6 mg/kg/dose). vAKI was present in 12.2% (n = 862: KDIGO stage 1 (8.30%, n = 589), KDIGO stage 2 (1.94%, n = 138) KDIGO stage 3 (1.89%, n = 134)). Mean vancomycin serum concentration at 6–8 hours after a dose for patients with vAKI (10.7±8.9 mg/L) was significantly, but not clinically different for patients with no vAKI (7.5±6.3 mg/L). (p<0.05) Ordinal logistic regression identified total dose of vancomycin, vancomycin administration in the intensive care unit, and concomitant medication administration as significant for vAKI. In particular, concomitant administration of several different medications, including nafcillin, clindamycin, and acetazolamide, were noted for strong associations with vAKI. (p<0.05) Conclusions Moderate to severe acute kidney injury due to vancomycin is infrequent in children and associated with concomitant medication use and total dose of vancomycin. Serum vancomycin concentrations are not useful predictors of vAKI in the pediatric population.