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Pharmacokinetic and Clinical Outcomes When Ideal Body Weight is Used to Dose Busulfan in Obese Hematopoietic Stem Cell Transplant Recipients
S388
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
563 Pharmacokinetic and Clinical Outcomes When Ideal Body Weight is Used to Dose Busulfan in Obese Hematopoietic Stem Cell Transplant Recipients Shawn Griffin 1,2, Ashley Richards 3, Sarah Wheeler 3, Laura Wiggins 3. 1 Indiana University Health, Indianapolis, IN; 2 Indiana University Simon Cancer Center, Indianapolis, IN; 3 UF Health Shands Hospital, Gainesville, FL Background: Intravenous busulfan (BU) is widely used in conditioning chemotherapy prior to stem cell transplantation at an initial dose of .8 mg/kg and is then adjusted to achieve a pre-defined goal drug exposure. A variety of dosing weights have been described in the literature. The primary objective of this study was to determine the impact on steadystate concentrations when ideal body weight (IBW) was used to dose BU in obese transplant recipients compared to nonobese patients. The secondary objectives were to determine the impact on survival and to describe the use of alternative dosing weights. Methods: This was a retrospective, IRB-approved, singlecenter analysis of all adult stem cell transplant recipients who received BU between August 1, 2007 and October 31, 2014. The obese and non-obese cohorts were based on a cutoff of 130% IBW. P values <.05 were considered statistically significant. Results: There were 63 patients included in the obese cohort and 82 patients included in the non-obese cohort. The mean steady-state concentration after the first dose of BU was 673.7 ng/mL in the obese cohort and 779.3 ng/mL in the non-obese cohort (P < .001). When the obese cohort was compared to the non-obese cohort, a larger proportion of concentrations were subtherapeutic (41.3% vs 9.8%, P < .001), a smaller proportion were therapeutic (50.8% vs 74.4%, P = .003), and there was no difference in the proportion of supratherapeutic concentrations (7.9% vs 15.8%, P = .14). There was no difference in overall survival between the two groups (P = .18). The Day +100 progression-free survival was 81.4% vs 89.0% (P = .14) and the Day +365 progressionfree survival was 54.2% vs 71.2% (P = .04) in the obese compared to non-obese cohorts, respectively. Alternative dosing weights are presented in Table 1. Adjusted body weights with a 25% (ABW25) and 40% (ABW40) correction factor are appropriate to dose BU in obese patients while IBW, ABW25, and ABW40 are appropriate in non-obese patients. Actual body weight (ABW) was not appropriate in either group. Conclusion: The use of IBW to dose BU resulted in lower steady-state concentrations and a larger proportion of subtherapeutic concentrations in obese patients. While there was no difference in overall survival, there was a decrease in progression-free survival in the obese cohort suggesting that IBW should not be used to dose BU in these patients. This retrospective study is the largest to evaluate the dosing of BU in obese patients; however, prospective, multicenter studies are needed to validate these findings. (Figure 1)
Figure 1. Overall survival curve.
564 Tacrolimus Dosing in Pediatric Patients: An Age-Based Evaluation Kavleen Kaur 1, Katelin A. Kimler 2,3. 1 Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ; 2 Department of Pharmacy, Hackensack University Medical Center, Hackensack, NJ; 3 Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ Tacrolimus is a commonly used drug for graft versus host disease prevention and treatment. It has a narrow therapeutic index, requiring monitoring through serum levels with therapeutic goals from 10-20 ng/mL. Tacrolimus is dosed based on weight due to the proportional relationship between volume of distribution and clearance. Consensus dosing for hematopoietic stem cell transplantation is established in the adult population and based on a dose of .03 mg/kg/day. In the pediatric population, however, we have observed lower starting doses with daily monitoring and dose adjustments in order to reach therapeutic levels. Pediatric patients are known to have a higher tacrolimus clearance, therefore requiring higher doses for adequate therapy. In this singlecenter, restrospective evaluation, age, tacrolimus goals, serum levels of tacrolimus, monitoring frequencies, and other related factors were evaluated to determine differences in therapeutic doses as well as incidence of supratherapeutic and subtherapeutic levels among patients of different age groups. 32 patients were included in this review. Results did not show significant differences in supratherapeutic or subtherapeutic levels of tacrolimus concentrations by monitoring frequency. However, the pediatric population <6 years of age did require higher dosing than the older populations (.03 mg/kg/day versus .023 mg/kg/day for 6-12 years of age and .015 mg/kg/day for ≥12 years, P = .32). Additional
Table 1 Alternative Dosing Weights Cohort
Average Final Dose, IBW (mg/kg, SD)
Average Final Dose, ABW (mg/kg, SD)
Average Final Dose, ABW25 (mg/kg, SD)
Average Final Dose, ABW40 (mg/kg, SD)
P value
≥130% IBW (n = 63) 100 to <130% IBW (n = 82)
.91 (.17) .79 (.12)
.58 (.12) .69 (.10)
.79 (.14) .76 (.11)
.74 (.14) .75 (.11)
<.001 <.001
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
563 Pharmacokinetic and Clinical Outcomes When Ideal Body Weight is Used to Dose Busulfan in Obese Hematopoietic Stem Cell Transplant Recipients Shawn Griffin 1,2, Ashley Richards 3, Sarah Wheeler 3, Laura Wiggins 3. 1 Indiana University Health, Indianapolis, IN; 2 Indiana University Simon Cancer Center, Indianapolis, IN; 3 UF Health Shands Hospital, Gainesville, FL Background: Intravenous busulfan (BU) is widely used in conditioning chemotherapy prior to stem cell transplantation at an initial dose of .8 mg/kg and is then adjusted to achieve a pre-defined goal drug exposure. A variety of dosing weights have been described in the literature. The primary objective of this study was to determine the impact on steadystate concentrations when ideal body weight (IBW) was used to dose BU in obese transplant recipients compared to nonobese patients. The secondary objectives were to determine the impact on survival and to describe the use of alternative dosing weights. Methods: This was a retrospective, IRB-approved, singlecenter analysis of all adult stem cell transplant recipients who received BU between August 1, 2007 and October 31, 2014. The obese and non-obese cohorts were based on a cutoff of 130% IBW. P values <.05 were considered statistically significant. Results: There were 63 patients included in the obese cohort and 82 patients included in the non-obese cohort. The mean steady-state concentration after the first dose of BU was 673.7 ng/mL in the obese cohort and 779.3 ng/mL in the non-obese cohort (P < .001). When the obese cohort was compared to the non-obese cohort, a larger proportion of concentrations were subtherapeutic (41.3% vs 9.8%, P < .001), a smaller proportion were therapeutic (50.8% vs 74.4%, P = .003), and there was no difference in the proportion of supratherapeutic concentrations (7.9% vs 15.8%, P = .14). There was no difference in overall survival between the two groups (P = .18). The Day +100 progression-free survival was 81.4% vs 89.0% (P = .14) and the Day +365 progressionfree survival was 54.2% vs 71.2% (P = .04) in the obese compared to non-obese cohorts, respectively. Alternative dosing weights are presented in Table 1. Adjusted body weights with a 25% (ABW25) and 40% (ABW40) correction factor are appropriate to dose BU in obese patients while IBW, ABW25, and ABW40 are appropriate in non-obese patients. Actual body weight (ABW) was not appropriate in either group. Conclusion: The use of IBW to dose BU resulted in lower steady-state concentrations and a larger proportion of subtherapeutic concentrations in obese patients. While there was no difference in overall survival, there was a decrease in progression-free survival in the obese cohort suggesting that IBW should not be used to dose BU in these patients. This retrospective study is the largest to evaluate the dosing of BU in obese patients; however, prospective, multicenter studies are needed to validate these findings. (Figure 1)
Figure 1. Overall survival curve.
564 Tacrolimus Dosing in Pediatric Patients: An Age-Based Evaluation Kavleen Kaur 1, Katelin A. Kimler 2,3. 1 Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ; 2 Department of Pharmacy, Hackensack University Medical Center, Hackensack, NJ; 3 Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ Tacrolimus is a commonly used drug for graft versus host disease prevention and treatment. It has a narrow therapeutic index, requiring monitoring through serum levels with therapeutic goals from 10-20 ng/mL. Tacrolimus is dosed based on weight due to the proportional relationship between volume of distribution and clearance. Consensus dosing for hematopoietic stem cell transplantation is established in the adult population and based on a dose of .03 mg/kg/day. In the pediatric population, however, we have observed lower starting doses with daily monitoring and dose adjustments in order to reach therapeutic levels. Pediatric patients are known to have a higher tacrolimus clearance, therefore requiring higher doses for adequate therapy. In this singlecenter, restrospective evaluation, age, tacrolimus goals, serum levels of tacrolimus, monitoring frequencies, and other related factors were evaluated to determine differences in therapeutic doses as well as incidence of supratherapeutic and subtherapeutic levels among patients of different age groups. 32 patients were included in this review. Results did not show significant differences in supratherapeutic or subtherapeutic levels of tacrolimus concentrations by monitoring frequency. However, the pediatric population <6 years of age did require higher dosing than the older populations (.03 mg/kg/day versus .023 mg/kg/day for 6-12 years of age and .015 mg/kg/day for ≥12 years, P = .32). Additional
Table 1 Alternative Dosing Weights Cohort
Average Final Dose, IBW (mg/kg, SD)
Average Final Dose, ABW (mg/kg, SD)
Average Final Dose, ABW25 (mg/kg, SD)
Average Final Dose, ABW40 (mg/kg, SD)
P value
≥130% IBW (n = 63) 100 to <130% IBW (n = 82)
.91 (.17) .79 (.12)
.58 (.12) .69 (.10)
.79 (.14) .76 (.11)
.74 (.14) .75 (.11)
<.001 <.001