Pharmacokinetics Of a Generic Formulation Of Intravenous Busulfan (BUCELON 60™) In Patients Undergoing Hematopoietic Stem Cell Transplantation

High-dose Busulfan (Bu) in combination with cyclophosphamide or fludarabine is widely used conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) for various hematological malignant and non-malignant disorders. Intravenous (i.v) formulation of Bu, along with targeted dose adjustment has resulted in reliable systemic exposure (due to its predictable pharmacokinetics (PK)) while minimizing toxicity and treatment failure. We have previously demonstrated the population pharmacokinetics of oral Bu in thalassemia patients undergoing HSCT (Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 3349) and factors predicting or influencing the outcomes. Since 2010, a generic form of i.v Bu (BUCELON 60™, Celon Labs, India) with targeted dose adjustment has been used at our center, for HSCT with all Bu based conditioning regimen. There is no report on the PK of Bucelon in patients undergoing HSCT. The objectives of the present study were to evaluate the PK of Bucelon in patients undergoing HSCT, compare the systemic exposure to i.v Bucelon vs. previous reports in patients with various hematological diseases and report the toxicity and outcome after i.vBucelon in our patient cohort.

Ninety five patients diagnosed with various haematological disorders receiving high dose i.v Bu as combination chemotherapy between June 2010 and July 2013 was included. Seventy three patients received single daily (Q24H-130mg/m²/day) while 22 had 6 hourly doses (Q6H-0.8mg/kg/dose) of Bu. Patient demographics are shown in Table. Peripheral blood samples were collected at different time points (0, 3, 4, 5 & 7hr in Q24H and 0,2,3,4 & 6hr in Q6H) on day 1 and day 3 and plasma Bu concentration were analyzed using an LC-ESI MS/MS method ^{(Salamun DE et al.2013)}. An AUC of 5000-5500µmoles (cumulative AUC target: 20000 to 22000µmoles) in Q24H or 900-1350µmoles in Q6H was targeted. The effect of pharmacogenetic factors on the PK/systemic exposure of i.v Bucelon were evaluated. The PK parameters estimated were: AUC, Clearance (CL) and volume of distribution (V) after the 1^st dose of Bucelon and after dose adjustment. The median day 1 AUC was 4180µmoles*min (1713-10456) and 599.5µmoles*min (307-1456) in Q24H and Q6H respectively. The median CL and V are 4.19L/h (0.81-21.55) 17.5589L/h (2.51-243.90) in Q6H and 41.83L/h (2.47-144.84) and 156.3L/h (6.5-454.51) in Q24H respectively. We analyzed the effect of polymorphisms in the drug metabolizing genes (GST, CYP) on the first dose AUC of Bu in these patients. Out of the eight polymorphisms in GSTA1, GSTM1, GSTT1, GSTP1, CYP2B6*6, CYP2C19*2, CYP2C19*3, CYP3A4*1B analyzed, GSTM1 positive patients in Q6H showed a significantly lower median Bucelon AUC, 589µmoles*min (307-1456) than when compared to GSTM1 null patients (median AUC, 963µmoles*min (670-1240) (P=0.0122) Figure). None of the other polymorphisms were found to influence the 1^st dose Bucelon AUC in patients receiving once daily or Q6H dose. However, the median day 1 AUC is found to be much less compared to previous report on patients with thalassemia major receiving Q6H i.v Bu: 599.5µmoles*min (307-1456) vs. 971µmoles*min (630-1621) as well as in malignant conditions receiving Q24H dose of i.vBu: 4180µmoles*min (1713-10456) vs. 5113μmoles*min (2796 - 9355).

Patient Characteristics

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GSTM1 polymorphism on Bu AUC

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GSTM1 polymorphism on Bu AUC

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When we analyzed the regimen related toxicity in these patients, 10 of the 95 (10.5%) developed sinusoidal obstruction syndrome (SOS) of which 3 was severe. Eight patients (8.4%) had not engrafted or rejected and 5 (5.2%) relapsed, 13 patients (13.7%) developed Grade III-IV GVHD and 3 had Hemorrhagic Cystitis. There was no significant difference in the cumulative AUC between those who develop toxicities and those who did not.

We report the PK of i.v Bucelon, a generic formulation of i.v Bu for the first time in patients undergoing HSCT. Since the systemic exposure to Bucelon seems to be lower in similar age, disease matched cohort, this may mean that targeted adjustment of Bu is necessary when we use i.vBucelon as conditioning regimen for HSCT. The lower systemic exposure could be due to population difference in PK or due to the drug formulation, or a combination of both, which needs to be validated further.