Single Daily Dose of I.V. Busulfan (BU) in Pediatric Patients. Feasibility, Pharmacokinetics (PK) and Toxicity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1151-1151 ◽  
Author(s):  
Morris Kletzel ◽  
David Jacobsohn ◽  
William Tse ◽  
Reggie Duerst
Keyword(s):  
Pediatric Patients ◽  
Prospective Trial ◽  
Young Patients ◽  
Area Under The Curve ◽  
Test Dose ◽  
Single Daily Dose ◽  
Severe Combined Immune Deficiency ◽  
Stem Cell Source ◽  
Daily Dose ◽  
Improve Compliance

Abstract Administration of oral BU is a challenge in pediatric patients. The I.V preparation can improve compliance and eliminate variability in absorption. The metabolism and clearance of BU is age dependant. A prospective trial using a single daily dose of I.V. BU as part of a reduced Intensity Regimen was undertaken. Patients were enrolled after proper informed consent was signed... The regimen consisted of a test dose of BU (0.8mg/kg as a 2 hr infusion) on day -10, Fludarabine 25mg/m2/day from day-10 to -5, BU 3.2 mg/Kg/Day on days -5 ,-4.and rabbit ATG 2mg/kg daily on days -4 to-1. Cells were infused on day 0. The stem cell source were UCB (n=4), MUD (n=7) and MSD (n=1). PK samples (2, 4, 6,8,12 hrs) were obtained and submitted to the Seattle Cancer Care Alliance for determination of the Area Under the Curve (AUC) and clearance for BU. Twelve patients were enrolled (8F, 4M), median age 8 (0.5–16), median weight 22.6 kg (4.3–58.8) with the following diagnoses: Neuroblastoma (n=3), ALL (n=3), CML (n=2), Aplastic Anemia and X linked Lymphoprolipherative Disease, Ommen’s syndrome, Severe Combined Immune Deficiency. An AUC of 800–1200 and 3200–4800 uMol*min were targeted for the test dose and the single daily dose respectively. The median AUC for the test dose was 1003 uMol*min (804–1315), and the median clearance was 3.1 (ml/min)/Kg (2.4–7.3). The median AUC for the single daily dose was 3512 uMol*min (1511–4097) and the clearance 3.4 (ml/min)/kg (2.8–6.8). After the test dose 4 patients had their dose adjusted (2 patients lower and 2 patients higher). In the very young patients (< 1 year of age) the AUC of the single daily dose could not be predicted due to abnormal clearance. No instances of VOD or seizures were observed. Full donor chimerism was achieved in 8 patients in a median of 23 days (14–53), 2 patients developed graft failure, 1 patient was not evaluable for engraftment due to early TRM from pre-existing CMV pneumonia and 1 patient is too early. In conclusion, a single daily dose of I.V. BU is feasible, a test dose can be a predictor of the single daily dose AUC except in the very young, No regimen related toxicity was observed and engraftment was prompt and complete in 8 evaluable patients.

Age-Dependent Pharmacokinetic Profile of Single Daily Dose Intravenous Busulfan in Children Undergoing Reduced-Intensity Conditioning Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 796-796
Author(s):  
William T. Tse ◽  
Reggie Duerst ◽  
Jennifer Schneiderman ◽  
Sonali Chaudhury ◽  
David Jacobsohn ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Test Dose ◽  
Single Daily Dose ◽  
Daily Treatment ◽  
Reduced Intensity Conditioning ◽  
Treatment Dose ◽  
Daily Dose ◽  
Age Dependent ◽  
Group 2 ◽  
Group 1

Abstract Busulfan, an important agent used in conditioning regimens before hematopoietic stem/progenitor cell (HSPC) transplantation, has a “narrow” therapeutic index. Targeted dosing of busulfan based on its pharmacokinetic (PK) profile is often used. We studied the age-dependent PK profile of single daily dose intravenous Bu (IV Bu) in pediatric patients and determined a target range of Bu exposure that is appropriate for children undergoing reduced-intensity conditioning (RIC) HSPC transplantation. The RIC regimen included: fludarabine 30 mg/m2 per day for 6 days (days –10 to –5); single daily treatment doses of IV Bu given over 3 hours each day for 2 days (days –5 and –4), with individualized Bu dosing based on the PK results of a test dose; and rabbit ATG (2 mg/kg/day) or equine ATG (40 mg/kg/day) for 4 days (days –4, –3, –2 and –1). In 2 variations of the regimen, ATG was either eliminated or replaced with extracorporal photopheresis. Allogeneic HSPC were infused on day 0. Cyclosporin A and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. An initial cohort of 52 patients was studied. The median age of the cohort was 7.7 years (range 0.06–17.6), with 19 patients less than 4 years of age (group 1) and 33 patients older than 4 years (group 2). Patients had either malignant or non-malignant diseases (immunodeficiency (n=14), metabolic disease (2), marrow failure (6), histiocytosis (1), ALL (9), AML (5), CML (4), MDS (2), lymphoma (5)), neuroblastoma (4)). Patients received a test dose of IV Bu (0.8 mg/kg) five days before the treatment doses. After the test dose, the median AUC attained was 886 μM·min in group 1 (range 439–1828) and 965 μM·min in group 2 (range 579–1970). Only 59% of the patients in both groups attained a plasma concentration-time “area-under-the-curve” (AUC) within the expected range of 800–1200 μM·min. Based on the test dose PK, patients received individualized treatment doses adjusted to target an AUC of 4000 μM·min per day for 2 days (range 3200–4800 μM·min). The median daily treatment dose of IV Bu given was 3.45 mg/kg in group 1 (range 0.8–7.2) and 3.20 mg/kg in group 2 (range 0.9–5.4), with a distinct and linear inverse-relationship between the weight-normalized treatment dose required and the weight of the patient (treatment dose = 4.0 mg/kg - 0.01*weight in kg, p=0.001). After the adjusted treatment dose, patients who achieved AUC within the targeted range increased to 67% in group 1 and 84% in group 2. Despite the dose adjustment, group 1 attained a lower median treatment dose AUC (3568 μM·min) as compared to group 2 (4035 μM·min) (p=0.001). All patients in this cohort tolerated the conditioning regimen. No patient developed seizures or hepatic veno-occlusive disease. Stable donor chimerism, however, was achieved in only 56% of patients in group 1 and 79% in group 2. Eight patients received a second transplantation because of primary or secondary graft failure. Eight patients died of transplantation-related causes. Because of the concern that a low AUC correlated with an adverse clinical outcome, a second cohort of 23 patients followed a modified protocol in which a treatment dose AUC of 5000 μM·min was targeted (range 4200–5800 μM·min). The median age of the second cohort was 2.1 years (range 0.3–21), with 13 patients less than 4 years and 10 patients older than 4 years. The median daily treatment dose given in this cohort was 4.5 mg/kg (range 2.6–6.5). All patients tolerated the higher Bu treatment dose with minimal regimen-related toxicity. After the treatment dose, patients attained a higher median AUC of 4825 μM·min (range 3719–5900), with over 90% of the patients achieving AUC within the targeted range of 4200–5800 μM·min. The number of patients who achieved stable donor chimerism also increased to 91%. One patient died of a transplantation-related cause. In conclusion, our results showed that RIC regimens utilizing 2 single daily doses of IV Bu were effective and well tolerated in children. An age-dependent variability in the PK profile of IV Bu could have contributed to a higher rate of graft failure in the younger patients after they received the Bu doses targeted to achieve an AUC of 4000 μM·min per day. Since there appears to be a wide safety margin in the upper limit of the Bu therapeutic range in RIC transplantation, a targeted AUC of 5000 μM·min per day for two days is recommended in pediatric patients, especially those less than 4 years of age.

Once-Daily Dosing with Phenobarbital in Children with Seizure Disorders

PEDIATRICS ◽  
1981 ◽  
Vol 68 (6) ◽  
pp. 824-827
Author(s):  
Anne G. Davis ◽  
Kelly D. Mutchie ◽  
Joel A. Thompson ◽  
Garth G. Myers
Keyword(s):  
Adverse Reactions ◽  
Pediatric Patients ◽  
Seizure Activity ◽  
Single Daily Dose ◽  
Daily Regimen ◽  
Serum Concentrations ◽  
Once Daily ◽  
Seizure Disorders ◽  
Daily Dose

In nine pediatric patients with seizure disorders, aged 8 months to 16½ years, a single daily dose of phenobarbital was as effective in maintaining therapeutic serum concentrations as twice-daily dosing. There were no adverse reactions to the once-daily regimen, and no seizure activity occurred during the study as a result of the change in dosing pattern.

scholarly journals Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2357-2362 ◽  
Author(s):  
PJ Shaw ◽  
CE Scharping ◽  
RJ Brian ◽  
JW Earl
Keyword(s):  
Acute Leukemia ◽  
Dose Regimen ◽  
Peak Plasma ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Single Daily Dose ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Peak Plasma Level ◽  
Daily Dose

Abstract The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.

scholarly journals Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2357-2362
Author(s):  
PJ Shaw ◽  
CE Scharping ◽  
RJ Brian ◽  
JW Earl
Keyword(s):  
Acute Leukemia ◽  
Dose Regimen ◽  
Peak Plasma ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Single Daily Dose ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Peak Plasma Level ◽  
Daily Dose

The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.

scholarly journals D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3622
Author(s):  
Jonathan Barra ◽  
Javier Cerda-Infante ◽  
Lisette Sandoval ◽  
Patricia Gajardo-Meneses ◽  
Jenny F. Henriquez ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Akt Signaling ◽  
Single Daily Dose ◽  
Mutant P53 ◽  
Inhibitory Pathway ◽  
Recycling Endosomes ◽  
Oncogenic Pathways ◽  
Daily Dose ◽  
High Concentrations ◽  
Novel Therapeutic

Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display invasive migration and AKT-mediated survival associated with enhanced EGFR recycling. D-Propranolol (D-Prop), the non-beta blocker enantiomer of propranolol, was previously shown to induce EGFR internalization through a PKA inhibitory pathway that blocks the recycling of the receptor. Here, we first show that D-Prop decreases the levels of EGFR at the surface of GOF mutp53 cells, relocating the receptor towards recycling endosomes, both in the absence of ligand and during stimulation with high concentrations of EGF or TGF-α. D-Prop also inactivates AKT signaling and reduces the invasive migration and viability of these mutp53 cells. Unexpectedly, mutp53 protein, which is stabilized by interaction with the chaperone HSP90 and mediates cell oncogenic addiction, becomes destabilized after D-Prop treatment. HSP90 phosphorylation by PKA and its interaction with mutp53 are decreased by D-Prop, releasing mutp53 towards proteasomal degradation. Furthermore, a single daily dose of D-Prop reproduces most of these effects in xenografts of aggressive gallbladder cancerous G-415 cells expressing GOF R282W mutp53, resulting in reduced tumor growth and extended mice survival. D-Prop then emerges as an old drug endowed with a novel therapeutic potential against EGFR- and mutp53-driven tumor traits that are common to a large variety of cancers.

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