A Multicentre Study Investigating the Pharmacokinetics and Pharmacodynamics of Busulphan When Combined with Melphalan As Conditioning in Adult Autologous Transplant Recipients

Busulfan (Bu) is an alkylating agent commonly used in conditioning regimens prior to allogeneic stem cell transplantation (SCT). Whilst systemic drug exposure is thought to be critical for efficacy and safety of this agent (Kletzel et al. 2006; Bartelink et al. 2009; Andersson et al. 2002), there is a paucity of pharmacokinetic (PK) and pharmacodynamic (PD) evidence-based guidelines outlining how best to balance these potentially competing outcomes. In this study Bu PK was investigated in the setting of IV Bu-melphalan (mel) autologous SCT, with the primary intention of establishing factors influencing Bu exposure and how effectively PK assessment can be used to achieve desirable drug exposure. PD analysis was also performed to establish the effect of drug exposure on transplant-related toxicity.

Sixty-four adult patients with haematological malignancies were prospectively enrolled prior to IV Bu-mel autologous SCT. PK analysis was performed in all patients on a "test" dose of Bu (1.6mg/kg, ie. 50% of a therapeutic dose) on day-7 based on actual body weight (ABW) (n=38) or adjusted ideal body weight (AIBW; n=24) where AIBW (kg) = Ideal body weight + [0.25 x (ABW- IBW)]). All patients subsequently received a second 1.6mg/kg dose on day-6. Thereafter, 27 patients received a further three 'therapeutic' daily doses of 3.2mg/kg on days -5 to -3 irrespective of PK results whist the remaining 37 patients received a modified dose, guided by the results of the initial PK results, targeting a subsequent Bu exposure, expressed as the area-under-the-concentration-versus- time curve (AUC), between 4000-5000umol.min/day (4000 in 2, 4500 in 14, 4800 in 4 and 5000 umol.min/day in 17) the lower ranges targeted in older patients with less aggressive disease. All patients had repeat PK analysis on day-5. Pre−transplant factors including age, weight, body mass index (BMI) and renal function were evaluated for their effect on the relationship between Bu dose and AUC; a multivariate analysis was performed on all covariates that were significant (p<0.05) in a univariate analysis.

The mean Bu dose for patients receiving PK-guided dosing was 3.4mg/kg (range 2.6-4.8 mg/kg) with the mean AUCs in the target groups of 4000-4500 and 4800-5000 umol.min/day being 4821 (3639-5457) and 5142 (4138-6157) umol.min/day respectively; the mean AUC for the non-adjusted-dose cohort was 4785umol.min/day (3251-6305umol.min/day); (p=0.16). All but one patient in the PK-guided group (36/37) vs 22/27 (81%) in the non-adjusted group (p=0.03) achieved AUCs within the 3500-6000umol.min/day range, which has been found to be safe and effective in previous studies (Clemmons et al. 2015). Of the five patients who did not achieve this target, 3 achieved AUCs below 3500umol.min/day and 2 greater than 6000umol.min/day.

Day -5 dose adjustments (from 3.2mg/kg) were suggested for 92% (34/37) of eligible patients and implemented in 87% (32/37) patients. These consisted of a Bu dose less than 3.2mg/kg (2.6-3.1mg/kg) in 8 patients which resulted in a mean AUC 5182umol.min/day (3904-6157umol.min/day); 38% of these patients achieved their target AUC (+/-10%). Five patients received an unchanged Bu dose of 3.2mg/kg achieving a mean AUC of 4906umol.min/day (4302- 5717umol.min/day) of which two were within 10% of their target AUC. Twenty-four patients received an increase dose (3.3-4.8mg/kg) and achieved a mean 4954umol.min/day (3639-5890umol.min/day) 45% achieved their target AUC (+/-10%). The mean variance from the target was 11% (0-30%). Using ABW or AIBW did not impact on this variance (mean 10% vs 12% respectively). Doses were frequently reduced (51% in the dose-adjusted cohort, mean of 15%) from the suggested dose based on day-7 AUC as it was observed early that the mean day-5 AUCs, in both cohorts, were higher than anticipated for the dose prescribed (mean 11%, -22 - 31%).

Multivariate analysis demonstrated actual weight as the only independent variable impacting the relationship between Bu dose and AUC; higher body weight was associated with lower AUCs (p=0.02) relative to Bu dose. No correlation between AUC and the occurrence of grade 3 or greater transplant related toxicities such as mucositis (based on number of days requiring total parental nutrition) or hepatotoxicity was observed.

PK-directed Bu dosing may be of benefit in achieving a target level of drug exposure, but larger studies are needed to determine the clinical significance of this strategy.