P82 Is busulfan clearance different in patients with sickle cell disease (SCD) compared to patients without sickle cell disease?
Authors: Remy A , Théorêt Y , Ansari M , Bittencourt H , Ducruet T , Krajinovic M , Nava T , Pastore Y , Rezgui MA , Kleiber N 
Published: May 2019

Background

Haematopoietic stem cell transplantation (HSCT) is the only current curative treatment for Sickle Cell Disease (SCD), with potential life-threatening consequences. Busulfan is an alkylating agent used in HSCT conditioning regimen. Because of its narrow therapeutic window, determining the optimal first dose a priori remains a challenge.

Busulfan is metabolized in the liver by conjugation with glutathione, which is catalyzed by Glutathione-S-Transferases (GSTs). GSTA1 is a known determinant of Busulfan clearance1 2 (just like age and weight) suggesting that those characteristics should be known a priori to adjust the first dose of Busulfan.

Haemoglobinopathies (SCD and thalassemia) are not associated with changes in Busulfan clearance in a recent study.3 However, SCD is known to alter pharmacokinetics of other drugs.4 5 As it leads namely to liver dysfunction6 it may affect busulfan pharmacokinetics independently from genetic or anthropometric factors.

Our aim is to compare the clearance of the first dose of Bu between patients with and without SCD, considering other constitutional factors.

Methods

Patients with SCD were paired to patients without SCD on known Busulfan clearance’s covariates including GSTA1 group, age and frequency of administration.

Data were collected retrospectively from the HSCT Unit database at Sainte-Justine Hospital and also used in previous studies.1 2 Weight adjusted clearance was compared between the two paired groups using a mixed procedure on SAS software.

Results

Among the 129 patients included, 16 had SCD. Each patient was matched with up to 4 controls (total of 50 controls). Mean weight adjusted clearance was 3.04 ml/min/kg [SD:0,18] in patients with SCD versus 3.11 ml/min/kg [SD:0,14] in controls (difference 0.07 ml/min/kg F=0,14 p>F=0.714).

Conclusions

The diagnosis of SCD did not reveal to influence independently the clearance of the first dose of Bu. Consequently, no dose tailoring is needed in those patients only by the fact of being affected by SCD.

References

Ansari M, Curtis PH-D, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget 2017 Oct 31;8(53).

Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Curtis PH-D, Duval M, et al. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. British Journal of Clinical Pharmacology. 84(7):1494–504.

McCune JS, Baker KS, Blough DK, Gamis A, Bemer MJ, Kelton-Rehkopf MC, et al. Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. Journal of Clinical Pharmacology. 2013 Mar;53(3):264–75.

Maksoud E, Koehl B, Kaguelidou F, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother 2018 Apr;62(4).

Dampier CD, Setty BN, Logan J, Ioli JG, Dean R. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995 Mar;126(3):461–7.

Gremse DA, Fillingim E, Hoff CJ, Wells DJ, Boerth RC. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998 Jun;132(6):989–93.

Disclosure(s)

Nothing to disclose