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This prospective, multi-center study investigated the utility of pre-conditioning test pharmacokinetics (PK) of intravenous busulfan (IV Bu) to optimize dosing in 204 subjects with Hodgkin (n=64) and B-cell non-Hodgkin lymphoma (n=140) at 32 centers in the US and Canada. PK studies were conducted twice during the study: test PK on Day -14 to -11 and confirmatory PK on the first day of conditioning, Day -8. The test PK used a 2-hour infusion of a single IV Bu dose (0.8 mg/kg) in order to determine the area under the concentration-time curve (AUC). The test PK dosing was based on adjusted ideal body weight (AIBW) for all patients except for the subjects whose actual BW was less than or equal to the ideal BW, where actual BW was used. AIBW was calculated by adding 25% of the difference between ideal BW and actual BW to ideal BW. The conditioning dose of daily IV Bu was then calculated to achieve 20,000 mM*min as a total AUC. The same individualized Bu dose was administered over 3 hours once daily from Day -8 to Day -5. If needed, dose was further adjusted on Days -6 and -5 based on confirmatory PK results. VP-16 (1.4 g/m2) was administered on Day -4, followed by 2.5 g/m2/day of cyclophosphamide on Days -3 and -2.
Test PK from 204 subjects showed that 6 subjects (2.9%) had higher AUC than expected (>1,500 μM*min) and 68 subjects (33.3%) had lower AUC (<1,000 μM*min). Therefore, total AUC would have fallen outside the target range in 74 subjects (36.3%) if PK-directed dose adjustment had not been performed. The discrepancy between expected and observed exposure was not predicted by subject height, actual body weight, body mass index (BMI) or body surface area. For example, although a greater proportion of patients with high BMI were underexposed compared with those with normal BMI, the difference was not significant [Table 1]. In addition, all patients who had AUC>1,500 μM*min had normal or high BMI. Thus, it is not possible to prospectively identify the subpopulation which has a risk of suboptimal Bu exposure and would gain the most benefit from PK-directed dose optimization. Hence, PK-directed dose optimization should be considered for all subjects when tight regulation of Bu exposure is critical, and should not be limited to subpopulations.
Out of 200 patients whose confirmatory PK results were evaluable, 190 subjects (95.0 %) fell within the target range (AUC: 20,000 μM*min ± 20%). Eight (4.0%) and two (1.0%) patients required dose reductions and increases, respectively, for the last two days of Bu dosing. Again, no predictive factor was identified for these patients.
In conclusion, a pre-conditioning small dose of IV Bu estimated individual PK parameters and predicted Day-8 PK in 95% of the subjects. This relatively large PK study identified no factor that could predict outliers linked to Bu metabolism. Therefore, when Bu exposure has to be tightly controlled, PK-directed dose optimization should be conducted for all patients.
