Enantioselectivity on the kinetic disposition and metabolism of cyclophosphamide and busulfan dose adjustment in patients who underwent stem cell marrow transplantation.

Author(s)

Francine Attié de Castro

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2013-08-21

Examining board members

Vera Lucia Lanchote; Gilberto de Nucci; Belinda Pinto Simoes

• Advisor: Vera Lucia Lanchote

Abstract

Busulfan (BU) and cyclophosphamide (CY) are drugs used during conditioning treatment for hematopoietic stem cell transplantation (HSCT). BU presents narrow therapeutic window, high interindividual variability in the pharmacokinetics and serious adverse effects. The present study evaluated the administration of a BU test dose for dose individualization, set the best sparse sampling scheme for BU therapeutic monitoring and validated an algorithm based on compartmental and population pharmacokinetics model in HSCT patients. Thirty patients received BU individualized treatment based on an oral test dose of 0.25 mg/kg. Doses were based on apparent clearance calculated with BU test dose. Plasma concentrations were confirmed after the fifth treatment dose. Coefficients of variation obtained between the clearance values evaluated in the test dose and fifth dose were <= 30%, except for 5 patients. No association between BU pharmacokinetic parameters and clinical outcome was observed. To estimate the ideal sampling scheme for BU therapeutic drug monitoring, a population pharmacokinetic model was used. Sparse sampling scheme with no more than five samples per patient (t = 0.5, 2.25, 3, 4 and 5 hours after dosing) was shown to be sufficient to characterize the BU pharmacokinetics. This study also evaluated the pharmacokinetics of the cyclophosphamide enantiomers and its metabolites (4-hydroxycyclophosphamide and carboxicyclophosphamide) in HSCT patients. We investigated patients with systemic sclerosis (SS) (n = 10) and multiple sclerosis (MS) (n = 10) in the conditioning regimen with CY 50 mg/kg/day for 4 days. Two specific tests based on LC-MS/MS analysis were developed and validated to analyze the CY enantiomers and its metabolite 4-hydroxycyclophosphamide (HCY) and carboxicyclophosphamide (CEPM) in human plasma. Pharmacokinetics of CY enantiomers and its metabolites were calculated using WinNonlin software and showed plasma accumulation of (S)-(-)-CY (AUC 215.0 vs 186.2 ?g.h/mL for the MS patient and 219.1 vs. 179.2 ?g.h/mL for the SS patient) and HCY (1), probably the (R)-(+)-HCY (AUC 5.6 vs 3.7 ?g.h /mL for MS patients and 6.3 vs 5.6 ?g.h/ mL for the SS patients) enantiomers in both groups of investigated patients. CEPM kinetics disposition showed lack of enantioselectivity. The pharmacokinetics of CY and its metabolites (HCY and CEPM) did not differ between patients with MS or SS. There was no correlation between the metabolism of CY, CYP2B6 and CYP2C9 genotypes. It was not possible to correlate the AUC0-? of CY enantiomers and/or its metabolites (HCY and CEPM) with CY toxicity due to the small number of patients investigated. (AU)

• FAPESP's process: 09/17545-4 - Enantioselectivity on the kinetic disposition and metabolism of cyclophosphamide and dose ajustment of busulfan in patients undergoing stem cell transplantation
• Grantee: Francine Attié de Castro
• Support Opportunities: Scholarships in Brazil - Doctorate