Publications by authors named "Shane J Cross"

17 Publications

  • Page 1 of 1

The Aerogen Solo Is an Alternative to the Small Particle Aerosol Generator (SPAG-2) for Administration of Inhaled Ribavirin.

Pharmaceutics 2020 Nov 29;12(12). Epub 2020 Nov 29.

Department of Infectious Diseases, St. Jude Children Research Hospital, Memphis, TN 38105, USA.

Respiratory syncytial virus (RSV) is associated with adverse outcomes among immunocompromised patients. Inhaled ribavirin has been shown to improve mortality rates. The Small-Particle Aerosol Generator delivery system (SPAG-2) is the only FDA-cleared device to deliver inhaled ribavirin. However, it is difficult to set up and maintain. We developed a method for delivery of this medication using the vibrating mesh nebulizer (Aerogen). We did not observe any adverse events with this method.
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http://dx.doi.org/10.3390/pharmaceutics12121163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760766PMC
November 2020

Pharmacokinetics of alemtuzumab in pediatric patients undergoing ex vivo T-cell-depleted haploidentical hematopoietic cell transplantation.

Cancer Chemother Pharmacol 2020 12 10;86(6):711-717. Epub 2020 Oct 10.

Department of Bone Marrow Transplantation and Cell Therapy, St. Jude Children's Research Hospital, MS 1130, Room I3305, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

Purpose: Alemtuzumab is a humanized monoclonal antibody against CD52 which is predominantly present on T and B lymphocytes. Alemtuzumab has been used as part of conditioning regimens for prophylaxis against rejection and GVHD. While the mechanism of action is well understood, the pharmacokinetics of this drug in children needed to be studied in more detail especially in the setting of ex vivo T-cell-depleted hematopoietic cell transplantation (HCT).

Methods: Serum alemtuzumab levels were measured at various time points in 13 patients who underwent haploidentical HCT utilizing ex vivo donor T-cell depletion. Alemtuzumab was administered subcutaneously at a cumulative dose of 45 mg/m from days - 13 to - 11. A one-compartmental model was used to fit the data using non-linear mixed effects modeling.

Results: We determined the median half-life to be 11 days. Alemtuzumab clearance increased with increasing baseline lymphocyte count (p = 0.008). Additionally, clearance increased with weight and age (p ≤ 0.035). AUC of alemtuzumab did not have any significant relationship with type of leukemia, overall survival, engraftment, immune reconstitution, mixed chimerism or GVHD, although the number of subjects in this pilot study was limited.

Conclusion: Absolute lymphocyte count and body weight affect alemtuzumab clearance. We also demonstrate feasibility of body-surface area-based dosing of alemtuzumab in pediatric HCT patients. Further studies are needed to evaluate the role of monitoring alemtuzumab serum concentrations to balance the prevention of graft rejection and GVHD with the promotion of rapid donor immune reconstitution.
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http://dx.doi.org/10.1007/s00280-020-04160-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735192PMC
December 2020

Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

J Pediatric Infect Dis Soc 2021 Feb;10(1):34-48

Division of Infectious Diseases, Department of Pediatrics, Children's Hospital at Montefiore, New York, New York, USA.

Background: Although coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children.

Methods: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.

Results: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.

Conclusions: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.
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http://dx.doi.org/10.1093/jpids/piaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543452PMC
February 2021

Fluoroquinolone prophylaxis does not increase risk of neuropathy in children with acute lymphoblastic leukemia.

Cancer Med 2020 09 25;9(18):6550-6555. Epub 2020 Jul 25.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.

Background: Fluoroquinolone antibiotics are frequently utilized in pediatric oncology patients as prophylaxis or step-down therapy following broad spectrum beta-lactam therapy for febrile neutropenia. Concerns regarding neurotoxicity limit the use of these agents. No studies have evaluated the association between fluoroquinolone use and neurotoxicity in pediatric oncology patients receiving other neurotoxic agents such as vincristine.

Methods: An observational cohort study comprising patients aged 0-18 at diagnosis enrolled on a prospective study for treatment of acute lymphoblastic leukemia (ALL) at a pediatric comprehensive cancer center between October 2007 and November 2018. Data for neuropathic pain and sensory or motor neuropathy were collected prospectively, and a Cox proportional hazards regression model was used to evaluate associations between administration of fluoroquinolone antibiotics during induction therapy and subsequent development of vincristine-induced peripheral neurotoxicity (VIPN).

Results: A total of 598 participants were enrolled, including 338 (57%) who received fluoroquinolones during induction therapy; of these 470 (79%) were diagnosed with VIPN and 139 (23%) were diagnosed with high-grade (Grade 3+) VIPN. On unadjusted analyses, and analyses adjusted for age and race, there was no evidence of an association between fluoroquinolone exposure and subsequent VIPN (hazard ratio [HR] 0.8, 95% CI 0.5-1.04, P = .08) or high-grade VIPN (HR 1.1, 95% CI 0.4-2.2, P = .87).

Conclusions: The results of this observational study do not show an association between exposure to fluoroquinolone antibiotics during induction therapy for ALL and subsequent development of vincristine-induced peripheral neuropathies, and suggest that a large increase in VIPN is unlikely.
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http://dx.doi.org/10.1002/cam4.3249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520302PMC
September 2020

Multicenter Initial Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

J Pediatric Infect Dis Soc 2020 Dec;9(6):701-715

Department of Pediatrics, Division of Infectious Diseases, Hospital for Sick Children, Toronto, Canada.

Background: Although coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics.

Methods: A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion.

Results: Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available.

Conclusions: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.
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http://dx.doi.org/10.1093/jpids/piaa045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188128PMC
December 2020

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1.

N Engl J Med 2019 04;380(16):1525-1534

From the Departments of Bone Marrow Transplantation and Cellular Therapy (E.M., B.T., W.J., S.G.), Hematology (S.Z., Z.M., J.C., J.D., X.T., B.Y.R., M.J.W., B.P.S.), Therapeutics Production and Quality (T.L., M.M.M.), Immunology (H.A., B.Y.), Pharmaceutical Sciences (S.J.C.), Biostatistics (G.K., C.L.), and Infectious Diseases (G.M.), St. Jude Children's Research Hospital, Memphis, TN; the Allergy and Clinical Immunology Division, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru (J.C.A.B.); the Department of Pediatrics, Allergy-Immunology Division, Children's Hospital Los Angeles, Los Angeles (J.A.C.), and the Department of Pediatrics, Division of Pediatric Allergy-Immunology-Bone Marrow Transplantation, University of California, San Francisco (UCSF) Benioff Children's Hospital, San Francisco (J.R.L.-B., J.M.P., M.J.C.) - both in California; the Department of Pediatrics, Pediatric Allergy and Immunology, University of New Mexico, Albuquerque (E.D.); University of Oklahoma Health Sciences Center, Tulsa (J.T.L.); Departamento de Pediatria da Universidade de Taubaté, Conselho Nacional de Medicina, São Paulo (A.C.M.A.); Copperfield Childcare, Claremont, South Africa (H.W.); and the Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.S.D.R., H.L.M.).

Background: Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.

Methods: We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.

Results: Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.

Conclusions: Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).
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http://dx.doi.org/10.1056/NEJMoa1815408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636624PMC
April 2019

Managing local-regional failure in children with high-risk neuroblastoma: A single institution experience.

Pediatr Blood Cancer 2018 12 30;65(12):e27408. Epub 2018 Sep 30.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Intensification of systemic therapy for high-risk neuroblastoma (HRNB) has resulted in improved local control and overall survival (OS) leaving potential for de-escalation of primary site radiotherapy. The utility of primary site de-escalation should be evaluated in the context of potential for successful local-regional salvage. We evaluated salvage strategies and outcomes in patients with HRNB with local-regional recurrence as a component of first failure.

Methods: Twenty of 89 patients with HRNB experienced local-regional recurrence as a component of first relapse after chemotherapy, radiotherapy, surgery, and stem cell transplant from 1997 to 2013. We reviewed salvage therapy strategies and disease control, and report on the impact of local therapy as salvage for local-regional relapse.

Results: Six of 20 patients with local-regional failure (LRF) were alive after a median follow-up of 13 years (range, 0.9-25.2 years). Median OS was 4.6 years (95% CI, 0.6 to not reached) versus 0.6 years (95% CI, 0.05-2.6) after LRF with and without distant failure, respectively (P = 0.03). OS in patients receiving salvage radiotherapy was comparable to those receiving initial adjuvant but no salvage radiotherapy. Time to first failure and death was significantly impacted by the intensity of frontline systemic therapy (P = 0.03). Salvage radiotherapy reduced the hazard for subsequent LRF (hazard ratio 0.3, 95% CI 0.1-0.9, P = 0.04) but not OS (P = 0.07).

Conclusions: Our study highlights the potential of local control strategies at first failure in patients with LRF when primary site radiotherapy was initially omitted, and delineates potential selection factors which may further improve the therapeutic ratio.
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http://dx.doi.org/10.1002/pbc.27408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192847PMC
December 2018

Haploidentical Donor Transplantation Using a Novel Clofarabine-containing Conditioning Regimen for Very High-risk Hematologic Malignant Neoplasms.

J Pediatr Hematol Oncol 2018 11;40(8):e479-e485

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN.

Recurrent/refractory hematologic malignancies have a poor prognosis, and there is a need for novel treatment regimens that can be tolerated by this heavily pretreated patient group. Clofarabine has antileukemic activity with an acceptable toxicity profile. In a phase I clinical trial (NCT00824135), we substituted clofarabine for fludarabine in a well-established reduced-intensity conditioning regimen for a T cell-depleted, mismatched-related (haploidentical) donor transplant backbone and explored the maximum tolerated dose of clofarabine in this combination in 15 patients undergoing hematopoietic cell transplantation for recurrent/refractory or secondary leukemia. Clofarabine was well tolerated at a dose of 50 mg/m/d for 5 days in this regimen, with minimal treatment-related mortality in a heavily pretreated group of high-risk patients. All patients exhibited quick hematopoietic recovery, with median times to neutrophil and platelet engraftment being 11 and 16 days, respectively. Transient elevation of transaminases was the most common toxicity-observed in 13 patients (86.7%), with 6 (40%) grade III or above. Three patients (20%) developed hepatic veno-occlusive disease. Eleven patients (73.3%) died, with the most common cause of death being disease relapse (in 9 patients [60%]), followed by treatment-related mortality (in 2 patients [13.3%]). Four (26.6%) of the patients are long-term survivors.
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http://dx.doi.org/10.1097/MPH.0000000000001222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197927PMC
November 2018

Selective T-cell depletion targeting CD45RA reduces viremia and enhances early T-cell recovery compared with CD3-targeted T-cell depletion.

Transpl Infect Dis 2018 Feb 16;20(1). Epub 2018 Jan 16.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: T-cell depletion (TCD) effectively reduces severe graft-versus-host disease in recipients of HLA-mismatched allografts. However, TCD is associated with delayed immune recovery and increased infections. We hypothesized that specific depletion of CD45RA+ naive T cells, rather than broad depletion of CD3+ T cells, can preserve memory-immunity in the allografts and confer protection against important viral infections in the early post-transplant period.

Methods: Sixty-seven patients who received TCD haploidentical donor transplantation for hematologic malignancy on 3 consecutive trials were analyzed.

Results: Patients receiving CD45RA-depleted donor grafts had 2000-fold more donor T cells infused, significantly higher T-cell counts at Day +30 post transplant (550/μL vs 10/μL; P < .001), and higher T-cell diversity by Vbeta spectratyping at Day +100 (P < .001). Importantly, these recipients experienced a significant reduction in both the incidence (P = .002) and duration (P = .02) of any viremia (cytomegalovirus, Epstein-Barr virus, or adenovirus) in the first 6 months post transplant. Specifically, recipients of CD3-depleted grafts were more likely to experience adenovirus viremia (27% vs 4%, P = .02).

Conclusion: CD45RA-depletion provided a large number of donor memory T cells to the recipients and was associated with enhanced early T-cell recovery and protection against viremia.
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http://dx.doi.org/10.1111/tid.12823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809307PMC
February 2018

Rotavirus Infection in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients: Clinical Course and Experience Using Nitazoxanide and Enterally Administered Immunoglobulins.

Pediatr Infect Dis J 2018 02;37(2):176-181

From the Department of Infectious Diseases, Department of Pathology, Department of Pharmaceutical Sciences, Department of Bone Marrow Transplantation and Cellular Therapy, and Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Rotaviruses may produce prolonged and severe disease in allogeneic hematopoietic cell transplant (HCT) recipients. Nitazoxanide and enterally administered human immunoglobulins are potential therapeutic options. This retrospective study describes the clinical course of rotavirus infection in pediatric allogeneic HCT recipients and a single-center experience with nitazoxanide and oral immunoglobulins as potential treatment options.

Methods: We identified 36 patients who had positive stool rotavirus antigen assays after allogeneic HCT from May 30, 2012, to July 31, 2015. Clinical, microbiologic and treatment data were collected and analyzed using descriptive statistics.

Results: Forty-nine discrete episodes of rotavirus infection were identified among these 36 patients for a cumulative incidence of 19.7%. For these 49 episodes, the median day to infection after HCT was day 82, and the median duration of diarrhea was 17.5 days (range 4-122). Nitazoxanide and enteral immunoglobulins were prescribed for 41 episodes. The median duration of clinical symptoms after initiation of nitazoxanide was 11 days (range 2-85), 23 days (range 10-107) after enteral immunoglobulins and 26 days (range 6-90) after a combination of nitazoxanide and enteral immunoglobulins (P = 0.1). No adverse effects of either treatment were documented, but efficacy could not be assessed in this patient population.

Conclusions: In pediatric HCT recipients, the clinical illness produced by rotaviruses is prolonged compared with otherwise healthy children. Nitazoxanide appears safe, but its efficacy for this indication requires further study.
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http://dx.doi.org/10.1097/INF.0000000000001740DOI Listing
February 2018

Derivation of new equations to estimate glomerular filtration rate in pediatric oncology patients.

Pediatr Nephrol 2017 09 2;32(9):1575-1584. Epub 2017 Jun 2.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

Background And Objective: Monitoring renal function is critical in treating pediatric patients, especially when dosing nephrotoxic agents. We evaluated the validity of the bedside Schwartz and Brandt equations in pediatric oncology patients and developed new equations for estimated glomerular filtration rate (eGFR) in these patients.

Methods: A retrospective analysis was conducted comparing eGFR using the bedside Schwartz and Brandt equations to measured GFR (mGFR) from technetium-99m diethylenetriamine pentaacetic acid (Tc-DTPA) between January 2007 and August 2013. An improved equation to estimate GFR was developed, simplified, and externally validated in a cohort of patients studied from September 2013 to June 2015. Carboplatin doses calculated from Tc-DTPA were compared with doses calculated by GFR-estimating equations.

Results: Overall, the bedside Schwartz and Brandt equations did not precisely or accurately predict measured GFR (mGFR). Using a data subset, we developed a five-covariate equation, which included height, serum creatinine, age, blood urea nitrogen (BUN), and gender, and a simplified version (two-covariates), which contained height and serum creatinine. These equations were used to estimate GFR in 2036 studies, resulting in precise and accurate predictors of mGFR values. Equations were validated in an external cohort of 570 studies; both new equations were more accurate in calculating carboplatin doses than either the bedside Schwartz or Brandt equation.

Conclusions: Two new equations were developed to estimate GFR in pediatric oncology patients, both of which did a better job at estimating mGFR than published equations.
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http://dx.doi.org/10.1007/s00467-017-3693-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712286PMC
September 2017

Aprepitant reduces chemotherapy-induced vomiting in children and young adults with brain tumors.

J Pediatr Oncol Nurs 2014 Sep-Oct;31(5):277-83. Epub 2014 Jun 27.

St. Jude Children's Research Hospital, Memphis, TN, USA

Purpose: Chemotherapy-induced nausea and vomiting are common and distressing side effects in patients with brain tumors and may be associated with radiation and the administration of highly emetogenic chemotherapy (HEC). Pediatric antiemetic guidelines recommend administration of a 5-hydroxytryptamine-3 (5HT3) receptor antagonists and the addition of aprepitant, a neurokinin 1 (NK1) antagonist with corticosteroids for the treatment of HEC. However, challenges persist in treating chemotherapy-induced nausea and vomiting in patients with brain tumors as corticosteroids are contraindicated due to potential impairment of the blood-brain barrier permeability. The objective was to determine whether a 5HT3 receptor antagonist and the addition of aprepitant, an NK1 antagonist without a corticosteroid, were effective in reducing HEC vomiting in pediatric brain tumor patients.

Method: A retrospective review found that 18 patients with a history of high-grade vomiting during radiation were prescribed a 5HT3 receptor antagonist and aprepitant without a corticosteroid during their first course of HEC. To determine the efficacy of aprepitant without a corticosteroid, each recipient was matched with 2 controls who did not receiv aprepitant.

Results: During HEC, controls without aprepitant were more likely to have Grade 2 or higher vomiting than the aprepitant recipients (P = .03; odds ratio = 4.15; 95% confidence interval = 1.59-10.82), after controlling for radiation-associated vomiting toxicity.

Discussion: Significantly less vomiting was identified in children receiving HEC and prescribed a 5HT3 receptor antagonist and aprepitant. Findings suggest that the addition of an NK1 antagonist may be beneficial to emetic control in this highly vulnerable population.
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http://dx.doi.org/10.1177/1043454214531090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438752PMC
September 2016

Phase I study of the safety and pharmacokinetics of plerixafor in children undergoing a second allogeneic hematopoietic stem cell transplantation for relapsed or refractory leukemia.

Biol Blood Marrow Transplant 2014 Aug 23;20(8):1224-8. Epub 2014 Apr 23.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.

The safety, pharmacokinetics, and biological effect of plerixafor in children as part of a conditioning regimen for chemo-sensitization in allogeneic hematopoietic stem cell transplantation (HSCT) have not been studied. This is a phase I study of plerixafor designed to evaluate its tolerability at dose of .24 mg/kg given intravenously on day -4 (level 1); day -4 and day -3 (level 2); or day -4, day -3, and day -2 (level 3) in combination with fludarabine, thiotepa, melphalan, and rabbit antithymocytic globulin for a second allogeneic HSCT in children with refractory or relapsed leukemia. Immunophenotype analysis was performed on blood and bone marrow before and after plerixafor administration. Twelve patients were enrolled. Plerixafor at all 3 levels was well tolerated without dose-limiting toxicity. Transient gastrointestinal side effects of National Cancer Institute-grade 1 or 2 in severity were the most common adverse events. The area under the concentration-time curve increased proportionally to the dose level. Plerixafor clearance was higher in males and increased linearly with body weight and glomerular filtration rate. The clearance decreased and the elimination half-life increased significantly from dose level 1 to 3 (P < .001). Biologically, the proportion of CXCR4(+) blasts and lymphocytes both in the bone marrow and peripheral blood increased after plerixafor administration.
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http://dx.doi.org/10.1016/j.bbmt.2014.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631218PMC
August 2014

Development and use of active clinical decision support for preemptive pharmacogenomics.

J Am Med Inform Assoc 2014 Feb 26;21(e1):e93-9. Epub 2013 Aug 26.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: Active clinical decision support (CDS) delivered through an electronic health record (EHR) facilitates gene-based drug prescribing and other applications of genomics to patient care.

Objective: We describe the development, implementation, and evaluation of active CDS for multiple pharmacogenetic test results reported preemptively.

Materials And Methods: Clinical pharmacogenetic test results accompanied by clinical interpretations are placed into the patient's EHR, typically before a relevant drug is prescribed. Problem list entries created for high-risk phenotypes provide an unambiguous trigger for delivery of post-test alerts to clinicians when high-risk drugs are prescribed. In addition, pre-test alerts are issued if a very-high risk medication is prescribed (eg, a thiopurine), prior to the appropriate pharmacogenetic test result being entered into the EHR. Our CDS can be readily modified to incorporate new genes or high-risk drugs as they emerge.

Results: Through November 2012, 35 customized pharmacogenetic rules have been implemented, including rules for TPMT with azathioprine, thioguanine, and mercaptopurine, and for CYP2D6 with codeine, tramadol, amitriptyline, fluoxetine, and paroxetine. Between May 2011 and November 2012, the pre-test alerts were electronically issued 1106 times (76 for thiopurines and 1030 for drugs metabolized by CYP2D6), and the post-test alerts were issued 1552 times (1521 for TPMT and 31 for CYP2D6). Analysis of alert outcomes revealed that the interruptive CDS appropriately guided prescribing in 95% of patients for whom they were issued.

Conclusions: Our experience illustrates the feasibility of developing computational systems that provide clinicians with actionable alerts for gene-based drug prescribing at the point of care.
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http://dx.doi.org/10.1136/amiajnl-2013-001993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957400PMC
February 2014

Posaconazole therapeutic drug monitoring in pediatric patients and young adults with cancer.

Ann Pharmacother 2013 Jul-Aug;47(7-8):976-83. Epub 2013 Jun 4.

Department of Pharmacy Practice, St. Louis College of Pharmacy, St. Louis, MO, USA.

Background: Limited information exists regarding the use of posaconazole for treating systemic fungal infections in children, adolescents, and young adults with cancer. At St. Jude Children's Research Hospital, the recommended posaconazole dose in patients weighing less than 34 kg is 18-24 mg/kg daily, given in 4 divided doses. For patients aged 13 years or older or those weighing 34 kg or more, the recommended dose is 800 mg daily, given orally in 4 divided doses.

Objective: To determine whether the current posaconazole dosing guidelines achieve target posaconazole plasma concentrations of 0.7 μg/mL or greater.

Methods: This retrospective clinical study examined data from patients who received treatment-dose posaconazole and had at least 1 posaconazole plasma concentration measurement.

Results: Data from 33 patients who received posaconazole for the treatment of fungal infections were analyzed. The median age of patients was 11.5 years (range 0.5-23.2). Twenty-one of 33 patients (63.6%) had posaconazole concentrations of 0.7 μg/mL or greater (median 1.4; range 0.7-2.98) at the first measurement. The median posaconazole dosage referenced to total body weight in these patients was 20 mg/kg/day. Patients with concentrations less than 0.7 μg/mL (median 0.4; range 0.025-0.69) received lower posaconazole dosages when referenced to body weight (median 12.9 mg/kg/day; p = 0.02). Of the 12 patients with concentrations less than 0.7 μg/mL, 7 (58.3%) were aged 13 years or older.

Conclusions: The current dosing approach for posaconazole yielded therapeutic plasma concentrations more frequently in patients younger than 13 years than in those 13 years or older. This difference may be related to the practice of capping adolescent and young adult doses at the suggested maximum adult daily dose. Therefore, we recommend weight-based dosing in all pediatric, adolescent, and young adult patients with cancer, with routine therapeutic drug monitoring to ensure adequate concentrations.
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http://dx.doi.org/10.1345/aph.1R775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384822PMC
January 2014

Development and implementation of a pharmacist-managed clinical pharmacogenetics service.

Am J Health Syst Pharm 2011 Jan;68(2):143-50

Pharmaceutical Department, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

Purpose: The development and implementation of a pharmacist-managed clinical pharmacogenetics service are described.

Summary: A pharmacist-managed clinical pharmacogenetics service was designed and implemented at an academic specialty hospital to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in the hospital's patients. A series of accredited educational seminars were conducted for our pharmacists to establish competencies in providing pharmacogenetic consults for the genes to be tested by the clinical pharmacogenetics service. The service was modeled after and integrated with an already-established clinical pharmacokinetics service. A steering committee was formed to evaluate the use of available tests, new evidence for implementation of additional tests, and other service quality metrics. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consultation. The consultation includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed. The service has been met with positive clinician feedback. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care.

Conclusion: The development of and experience with a pharmacist-managed clinical pharmacogenetics service are described. The program's success has depended on collaboration between the clinical laboratory and pharmacists, and pharmacists' pharmacogenetic recommendations have been well accepted by prescribers.
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http://dx.doi.org/10.2146/ajhp100113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228517PMC
January 2011

Abacavir and metabolite pharmacokinetics in HIV-1-infected children and adolescents.

J Acquir Immune Defic Syndr 2009 May;51(1):54-9

Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Objectives: Abacavir (ABC) oral clearance, adjusted for body size, is approximately 2 times higher for children than adults with a corresponding difference in dose regimens. However, there are limited data available in the adolescent population. The pharmacokinetics (PKs) of ABC and primary metabolites were determined in HIV-1-infected children and adolescents to evaluate age and patient characteristics as a basis for adjusting ABC dose regimens and to assess the influence of metabolite formation on PK parameters.

Methods: Pediatric subjects 9-18 years of age receiving antiretroviral therapy for HIV-1 infection were stratified by Tanner stage and given a single 8 mg/kg dose of ABC oral solution. Blood samples (n = 10) were obtained over 8 hours and measured for ABC, glucuronide, and carboxylate metabolites using high-performance liquid chromatography. PK parameters for children (Tanner stages 1-2; TS1) and adolescents (Tanner stages 3-5; TS2) were compared.

Results: Twenty-five subjects were enrolled. ABC mean (range) maximum concentration (Cmax; microg/mL), area under the curve (microg.hr/mL), half-life (hours), and apparent clearance (CL/F; mL/min per kg) for TS1 and TS2 were 3.5 (1.2-5.6) vs 3.4 (1.8-5.9), 8.0 (2.1-18.6) vs 8.9 (3.1-17.2), 1.3 (0.7-2.5) vs 1.4 (0.9-1.9), and 22.1 (7.0-59.2) vs 18.4 (7.7-42.9) and not significantly different. Age, Tanner stage, and sex were not correlated with ABC clearance by univariate analysis. The ratios of metabolites to ABC area under the curve were correlated with ABC clearance as were the ratios of metabolites to ABC concentrations at the 6-hour time point.

Conclusions: ABC oral clearance in HIV-1-infected pediatric patients does not change during puberty, is similar to younger children, and is higher than previously published in adults. Therefore, dosing adolescents as adults should be reexamined. Intersubject PK variability is substantial and is not correlated with body size or age but more likely due to differences in metabolite formation that may be genetic in origin.
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http://dx.doi.org/10.1097/QAI.0b013e31819a2257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836884PMC
May 2009