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PERSONALIZED BUSULFAN THERAPY: IMPLEMENTATION OF A THERAPEUTIC DRUG MONITORING PROGRAM (TDM)

European Statement

Clinical Pharmacy Services

Author(s)

VERA DOMINGOS, VERA PIRES, SÍLVIA SANTOS, PATRÍCIA TRINDADE, ANA INÁCIO, ELZA CANDEIAS, SUSANA SIMÕES, PAULO PAIXÃO, NUNO MIRANDA, ANTÓNIO GOUVEIA

Why was it done?

Personalized BU dosing is considered because BU has a narrow therapeutic index and exposure have been associated with important clinical outcomes. High exposures have been associated with an increased risk of toxicities (acute graft-versus-host disease and veno-occlusive disease) and low exposures with graft rejection and relapse.
For this reason, in a multidisciplinary working group, we identified an opportunity to improve the treatment of your patients.

What was done?

Implementation of a TDM procedure for Busulfan (BU) in conditioning therapy for hematopoietic stem cell transplantation (HSCT). Study variability in PK parameters and evaluate TDM efficacy. From this initial period, we perform TDM on all patients under Bu conditioning.

How was it done?

The steps followed were:
1. Pre-implementation: bibliographic research, identify reference centers to perform BU plasma assay. Development and validation of a LC-MS / MS method by the National Institute of Forensic Medicine. PK analysis using ADAPT-5 software.
2. Pilot: Trial and assess the feasibility of the procedure. Cross-validation of the results with UMC Utrecht.
3. Implementation: clinical practice, doing the necessary dose adjustments. Prospective collection of clinical and PK data.

The main obstacle is the lack of analytical methodology in our center and the turnaround time.

What has been achieved?

We performed a preliminary analysis with 21 patients. Mean clearance (CL) was 0,19L/h*kg±0,05L/h*kg and volume of distribution 0,65L*kg±0,22L*kg. Body weight was the most predictive covariance.
CL was significantly different between patients 10 years old (p = 0,024) and over treatment (p=0,0191). The type of conditioning regimen didn’t show relation with the BU CL (p=0,0514).
TDM increased the number of patients with an optimal exposure (target AUC ±10%) from 42% to 83%.Dose was reduced in 10 patients (max 37%) and increased in 3 (max 19%). 1 patient maintained the prescribed dose.

What next?

TDM increased significantly the number of patients with optimal exposure to BU.
This procedure is pioneer at a national level and it relies on a strict protocol which includes collaboration with several hospital departments and other highly-specialized external centers. This can be used as a tool for other drugs and to empower the pharmacist as an active agent in the clinical setting.

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