Intravenous busulfan in adults prior to haematopoi

Authors: L Nguyen F Leger S Lennon C Puozzo

Publish Date: 2005/08/25

Volume: 57, Issue: 2, Pages: 191-198

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Abstract

An IV form of busulfan IV Bu has recently become available for high dose conditioning regimen before haematopoietic stem cell transplantation HSCT This IV form is expected to reduce the high pharmacokinetic variability exhibited with oral busulfan and as a result to better target the plasma area under the curve AUC Pharmacokinetics PK of IV Bu was investigated on 127 adult patients 333 PK administrations who received 08 mg·kg−1 of Bu as a 2h infusion every 6 h over 4 days followed by cyclophosphamide 60 mg·kg−1 day−1×2 A retrospective population PK analysis was carried out to search for important predictive factors of IV Bu PK and to develop a limited sampling strategy LSS through Bayesian methodology The analysis was conducted using the Non Linear Mixed Effect methodology and included a validation process on an independent data set Adjusted Ideal Body Weight AIBW and Body Surface Area BSA were the best covariates to explain the interpatient variability The final interpatient variability CV=16 in IV Bu clearance Cltot was estimated close to the intrapatient variability CV=13 There was neither agedependency nor gender effect IV Bu Cltot was not affected by elevated hepatic enzymes or by coadministration of either fluconazole or acetaminophen and was not altered in heavily pretreated or pretransplanted patients Normalised Cltot based on either AIBW or BSA was comparable between normal and obese patients BMI=18–269 kg·m−2 269 kg·m−2 respectively whereas significant differences existed when based on either actual ABW or ideal body weight IBW As a consequence no dose adjustment is required in obese patients when using a AIBW or BSAbased dose calculation A fixed dose of 080 mg·kg−1 of AIBW or 29 mg·m−2 of BSA yielded an average AUC of 1200 μM·min with 80 of patients within the “therapeutic” AUC range of 900–1500 μM·min Alternatively 080 mg·kg−1 based on either ABW or IBW for normal patients and on AIBW for obese patients would achieve the same performance A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset AUCs obtained from one to two samplings were demonstrated to be reliably estimated

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