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PEDIATRICS |
From the US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology (Dr Booth, Dr Rahman, Dr Sahajwalla, Dr Mehta, Dr Gobburu); US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Oncology Drug Products, Division of Drug Oncology Products (Dr Dagher); National Institutes of Health, National Cancer Institute, Division of Cancer Prevention, Gastrointestinal and Other Cancers Research Group (Dr Griebel); independent consultant, oncology and transplant, Minnesota (Dr Lennon); and Genzyme Europe Research, Cambridge, United Kingdom (Dr Fuller).
Address for reprints: Brian P. Booth, Food and Drug Administration, Office of Clinical Pharmacology, Division of Clinical Pharmacology 5, 10903 New Hampshire Avenue, Building 21, Room 3668, Silver Spring, MD 20993-0002.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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4 years or >4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients 12 kg should be dosed at 1.1 mg/kg and those >12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.
Key Words: Busulfan • pharmacokinetics • dosing • modeling • pediatrics
Busulfan/cyclophosphamide regimens have also been used as preparative regimens for hematopoietic stem cell transplantation in children, and a pediatric trial was proposed using the intravenous formulation of busulfan. A key issue for this trial was the appropriate therapeutic window for pediatric patients. The available data suggested that the therapeutic window was similar to that of adults,8,9 but this issue was confounded by the increased variability in the pharmacokinetics of orally administered busulfan in pediatric patients compared to adults.10 Based on the available data, the target busulfan therapeutic window used in this study was similar to adults, except that a lower, more conservative threshold for toxicity was used (1350 instead of 1500 µm•min). The purpose of this study was to establish an intravenous busulfan dosing regimen that achieved the target exposure midway between 900 and 1350 µm•min (3.7 to 5.5 µg•h•mL-1) in pediatric patients. Twenty-four pediatric patients were administered intravenous busulfan as a part of a myeloablative regimen. Population pharmacokinetic (PPK) modeling and simulations were used to optimize the intravenous busulfan dosing regimen. Nguyen et al have reported an analysis of these data that was used for labeling intravenous busulfan in Europe.11 The present study was the basis for labeling intravenous busulfan in the United States.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Dosing Regimen
Intravenous busulfan (IV Busulfex [busulfan] injection; ESP Pharma, Edison, NJ) was infused over 2 hours at 1.0 mg/kg in patients 4 years of age or younger and at 0.8 mg/kg in patients older than 4 years, every 6 hours for 16 doses. Intravenous busulfan dosages were adjusted in some patients, depending on their AUCs following the first dose. Following completion of intravenous busulfan, patients were treated with 50 mg/kg cyclophosphamide daily for 4 days. After a 1-day rest period, hematopoietic stem cells were infused. All patients were pretreated with phenytoin as seizure prophylaxis as prescribed in the product labeling.
Sampling Design
Dense blood sampling (6-8 samples) was performed following doses 1 and 9, and sparse sampling was performed (2-3 samples) following dose 13. Dense sampling included blood collection at predose and at approximately 30, 45, 60, 120, 150, 180, 240, 300, and 360 minutes after the start of the infusion from a contralateral vein. Samples were analyzed at a single site. Plasma concentrations of total busulfan were determined using a gas chromatographic method with mass spectrometric detection.12 The internal standard used was 1,5 pentanediol dimethylsulfonate, and selected ion monitoring was used at an m/z of 183 and 197. The assay was linear from 62 to 2000 ng/mL, and the lower limit of quantification was 50 ng/mL. Accuracy and precision were within 10% of nominal values for all standards.
PPK Analysis
Structural Model
The base PPK model was a 1-compartment open model with intravenous infusion and first-order elimination. A 1-compartment model has been used previously to describe the pharmacokinetics of busulfan.10 The disposition parameters were clearance (CL) and volume of distribution (Vd), as follows:
 | (1) |
Random Effects
The between-subject variability was described by a proportional error models, where
 | (2) |
 | (3) |
CLbsv is the difference between individual (CLi) and population mean (TVCL), CLbov is the difference in CL between occasions. Vdbsv is the difference between individual (Vdi) and population mean (TVVd), and Vdbov is the difference in Vd between occasions.
Residual Error
The difference between the predicted concentration and the observed concentration reflects the measurement error and the model misspecification error. It was modeled using a combined proportional and additive error model:
 | (4) |
where F is the model predicted concentration, CVCP is the coefficient of variation for the proportional error, and SDCP is the standard deviation of the additive error.
Software and Estimation Methods
Nonlinear mixed-effects modeling was conducted for estimations and simulations using NONMEM, version V, release 1.1.13 The compiler used was Compaq Visual Fortran version 6.1A. First-order conditional estimation with interaction was used in all cases.13
Criteria for Model Selection
Visual inspection of the model predictions and mechanistic reasoning were used to evaluate the model. The effect of covariates on the pharmacokinetic parameters was determined by sequentially adding covariates to CL and Vd. Weight (actual body weight [ABW]), body surface area (BSA), and age were the demographic covariates tested. Biological reasoning, statistically significant changes in minimum objective function (MOF) of 3.841 (which indicates a change that is significant,14 P < .05), goodness-of-fit of the predicted versus observed concentration plots, and variability on the parameter estimates were used to judge the influence of each covariate. The 90% confidence intervals of the parameter estimates were derived by estimating the final model parameters for 1000 bootstrap data sets.
Simulations
Using the final PPK model for intravenous busulfan, different dosing regimens were tested with NON-MEM to find a dosing regimen that maximized the proportion of patients who achieved the target AUC of (1125 µm•min) with the first dose of busulfan. The target AUC chosen was the midpoint in the 900 to 1350 µm•min (3.7 to 5.5 µg•h•mL-1) therapeutic window. For each dosing scenario, 1000 replications were performed. Regimens were tested that employed from 1 to 7 dosing steps, and each dosing step was defined by a specific dosage for a specific range of patient weights. The patient weight cutoffs (12-50 kg) used spanned the range of weights observed in the patients from the pharmacokinetic study (7.1 to 
63 kg). The dosage for each step was empirically chosen and ranged from 0.7 to 1.2 mg/kg. For example, in 1 of the 2-step dosing regimens that was evaluated, the weight cutoff chosen was 1 mg/kg busulfan for patients <12 kg and 1.2 mg/kg for patients 
12 kg.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Ninety-six percent of the patients were successfully engrafted following bone marrow ablation with the busulfan/cyclophosphamide regimen. Twenty-one percent of the patients in this study suffered VOD (5 of 23 patients), which is within the range of VOD that has been reported in children receiving preparative regimens (including busulfan-containing regimens) for hematopoietic stem cell transplantation.15 Four of these 5 patients had plasma busulfan AUCs that were greater than 1350 µm•min at least once during 1 of the 3 periods when plasma concentrations were assessed. Three of these 4 patients received busulfan dose adjustments, which returned busulfan concentrations to the target window, and 1 patient did not receive a dose adjustment. The remaining patient had an AUC that was within the target window but had been highly pretreated with chemotherapy before starting the busulfan/cyclophosphamide regimen.
Table I presents the effect that the inclusion of various demographic covariates had on the base PPK model for busulfan, as reflected by the MOF. Each covariate was added sequentially until there was no further significant decrease in the MOF. The inclusion of interoccasion variability on the CL and Vd parameters reduced the MOF significantly to 4698 and yielded the best overall fit of the model. The effect of BSA was comparable to the inclusion of body weight on CL and V estimation. The final structural model for intravenous busulfan included ABW as the covariate according to the allometric equations as follows16:
 | (5) |
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where WTCL is the exponent of the allometric equation for CL.
 | (6) |
where WTVd is the exponent of the allometric equation for Vd.
Figure 1 depicts the population and individually predicted busulfan concentrations for the pediatric patients versus the observed concentrations. The solid line of identity indicates the relationship that would result if the observed concentrations were predicted perfectly by the model. The predictions are scattered closely and uniformly around the line of identity, which indicates the model fits the data well.
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Table III lists the outcome for the most successful simulations for each dosing regimen with 1 to 7 dosing steps. The 6-step dosing regimen yielded the highest success of achieving the target AUC with the first dose (59.4%). However, the range in success rates was between 56% and 59% for the regimens containing between 2 and 7 steps. The 2-step dosing nomogram was nearly as successful as the 6-step nomogram, with 56% of the patients within the desired range of AUCs with the first dose, and it is simpler to implement. The percentage of patients who were below (% missed lower limit) or above (% missed upper limit) the target therapeutic window are also listed for each dosing regimen. Although the percentage of patients in whom the concentrations were too low or too high varies somewhat among the different regimens tested, the total percentage of patients who miss the target window is approximately 40% in all cases. Therefore, the simplest regimen that achieves a high degree of success is the 2-step dosing nomogram (1.1 mg/kg for patients 12 kg, 0.8 mg/kg for patients >12 kg).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Clinical evidence from several studies indicates that the therapeutic window for busulfan in adults is between 900 and 1500 µm•min (3.7-6.2 µg •h•mL-1). However, the therapeutic window for busulfan use in pediatric patients was not well established at the time that this study was commenced. Some early studies provided some limited evidence that suggested the adult 900 to 1500 µm•min (3.7-6.2 µg•h•mL-1) window may be appropriate for pediatric patients as well.8,9 However, in this study, the 900 to 1350 µm•min (3.7-5.5 µg•h•mL-1) window was used, in which the upper limit of 1350 µm•min (5.5 µg•h•mL-1) represents a more conservative safety threshold. Later studies subsequently suggested that the 900 to 1500 µm•min (3.7-6.2 µg•h•mL-1) window may be appropriate for pediatric patients.18,19 One of the purposes of this study was to develop a pharmacokinetic model that mathematically and predictably describes the pharmacokinetics of intravenous busulfan to rationally choose an effective dosing regimen. Generally, accounting for all of the influences on the pharmacokinetics and pharmacodynamics of a drug can be quite daunting. With respect to busulfan, especially in pediatric patients, a number of significant physiological aspects can have an impact on the pharmacokinetics. Busulfan is metabolized predominantly by glutathione-S-transferase (GSTA1-1),20-22 and this enzyme is polymorphically expressed. The variability in the expression of this enzyme could be expected to cause significantly different metabolism and plasma concentrations among individuals, which might lead to an overshoot of the upper limit of the therapeutic window, resulting in toxicity. Furthermore, as GST polymorphisms occur at different rates in different populations,23 race might be expected to play a role in busulfan pharmacokinetics as well. Modeling the pharmacokinetics of busulfan in patients over such a wide age range may also be problematic because of age-related changes that occur in many biological and enzymatic processes. Often these changes do not occur in a temporally linear fashion. In the case of busulfan, it has been demonstrated that the extent of metabolism by GST is different between young and adult patients because of differences in the activity and/or expression of GST with age.4 These relationships may be further confounded by pathophysiologies induced by disease, which could affect drug clearance, as has been demonstrated for busulfan by Vassal et al.24
In the current study, we were unable to account for all of these potential influences. For instance, the GSTA1-1 status of each patient was not determined, and the impact of this parameter could not be assessed. Of the previously described factors that might affect the pharmacokinetics of busulfan (termed covariates), only the potential influence of age and/or weight could be practically assessed. Both of these covariates—age and body size—have been reported to be important for busulfan disposition.25,26 Although the patients studied were not demographically homogenous, there were too few differences among patients to assess disease or race as covariates that might affect busulfan pharmacokinetics.
In consideration of these limitations, an allometric scaling approach was used to develop the PPK model.16 The basic pharmacokinetic model was a 1-compartment open-model with first-order elimination, which generally describes the disposition of busulfan. Covariates were added sequentially to assess the impact of each on the performance of the model, beginning with weight. The addition of weight (ABW) on CL and Vd reduced the MOF significantly, which supports the conclusion that CL and Vd are a function of weight. Inclusion of age as a covariate on CL did not result in any improvement of the fit (MOF was not significantly altered). This finding contrasts with literature reports concerning busulfan clearance in pediatric patients,25 in which age was found to exert a significant influence on busulfan pharmacokinetics. However, as weight generally increases with age, the impact of age may already have been captured by the inclusion of weight in the current model. Furthermore, as Gibbs et al4 have shown, there is considerable variability in liver weight for a given age (which is likely true of body weight as well); therefore, it is perhaps not surprising that weight contributed more to the pharmacokinetic fit of busulfan than age did. Estimating interoccasion variability on CL and Vd also significantly reduced MOF.
The suitability of the final model is demonstrated by how well the busulfan plasma concentration data are fit and how well it compares to previously described models. As seen in Figure 1, the data are equally and tightly scattered on either side of the line of identity, which indicates that the actual concentrations are well predicted by the model and that there is no bias to overestimate or underestimate concentration. Post hoc fits of data from individual patients also indicate that the model works well (see Figure 2). Figures 3 and 4 indicate how well the CL and the Vd estimates relate to weight. In both cases, the observed data are closely scattered around the line of identity. The relationship for CL is slightly curvilinear, which might be expected, given the potential differences in metabolism that might occur as a function of growth. Nevertheless, CL appears to be well predicted by the model, suggesting that any age-related changes in metabolism or pharmacokinetics are well handled by the model.
The CL of busulfan determined in this study (3.53 mL/min/kg; 4.04 L/h/20 kg) compares well with other reported estimates of busulfan. The clearance of busulfan following oral or intravenous dosing from previous studies ranged from 1.86 to 4.84 mL/min/kg.27-30 In the present study, the between-subject variability for CL was 23%, and for Vd, it was less than 11%, based on the final model. Furthermore, the 90% confidence intervals on the CL and Vd estimates in these studies were both within 10% of the mean population estimates. The variability of CL following oral dosing of busulfan in pediatric studies has been reported as 28% by Sandstrom et al27 and 26% by Schiltmeyer et al.28 The interpatient variability for CL following intravenous administration of busulfan in pediatric patients is reported to be 19% by Nguyen et al11 and 28% by Oechtering et al.30 Therefore, the PPK model developed in this study predicts the pharmacokinetics of busulfan well.
Simulations were then conducted to find a dosing regimen that achieved a busulfan exposure that was within the target therapeutic window of 900 and 1350 µm•min (3.7-5.5 µg•h•mL-1). This therapeutic window should minimize the failure to engraft and the incidence of VOD and other serious toxicities. For each dosing regimen tested, 1000 simulations were conducted, and the rate of successfully achieving the target therapeutic window was observed. Regimens with 1 to 7 dosing steps were tested. For regimens with 2 to 7 dosing steps, multiple combinations of weights and doses were tested. The results, which are listed in Table III, are the best outcomes for each regimen with 1 to 7 dosing steps. These data indicate that the greatest success was achieved with a 4-step dosing regimen (59.6%). The single dosing step yielded the poorest success (49%). However, the dosing regimens of 2 to 7 steps provide reasonably similar success rates. None of these dosing regimens achieved better than 60% success with the first dose of busulfan. This appears to occur because the therapeutic target window is too narrow, given the between-subject variability for busulfan. Consequently, a relatively large proportion of patients fail to achieve the target window with the first dose of busulfan. This finding indicates the need for therapeutic drug monitoring (TDM) in these patients, as previously suggested.31,32
Each of the 2- to 7-step dosing regimens should provide similar busulfan AUCs with the first dose. From a practical perspective, however, the fewest dosing steps would be the best solution, as it will reduce potential confusion regarding dosing in pediatric patients. Therefore, a 2-step dosing regimen was proposed: 1.1 mg/kg in children weighing less than or equal to 12 kg and 0.8 mg/kg in children weighing greater than 12 kg. The second dosing step, 0.8 mg/kg, is the same dosage recommended for adults in the intravenous busulfan labeling.33 The 1.1-mg/kg dosage was slightly higher than the starting dose in this study (1.0 mg/kg), but these doses were subsequently altered (higher and lower) as deemed necessary based on the measured busulfan exposure.
The results of the simulation also underscore another important point, which is that no better than 60% of the patients can achieve the therapeutic target window for busulfan with the first dose. Therefore, approximately 40% of the patients are theoretically at risk of either a failure to engraft or VOD with the first dose of busulfan. This result indicates that TDM will be useful for busulfan to allow for dosage adjustment of subsequent doses. The between-occasion variability for CL and Vd were both less than 10%, which makes intravenous busulfan a good candidate for TDM. It is worth contrasting these results and conclusions with those of Nguyen et al,11 who subsequently analyzed the same study results in an alternative manner. Nguyen et al11 reported that their simulations indicated a higher rate of achieving the busulfan AUC in the target therapeutic window with the first dose, albeit with a 33% wider therapeutic window (900-1500 µm•min [3.7-6.2 µg•h•mL-1] instead of the 900 to 1350 µm•min [3.7-5.5 µg•h•mL-1] window used in this study). These authors proposed a more complex, 5-step dosing nomogram in an effort to achieve the target busulfan AUC without TDM. Uncertainty regarding the patient's exposure will remain without appropriate monitoring.
A number of approaches to TDM have been described for busulfan.18,34,35 These studies generally describe suitable methods to establish busulfan AUC and subsequent dose adjustment. In the present study, TDM based on 3 samples following the first dose was chosen as 1 approach to determine busulfan AUC quickly and accurately, so that dose adjustments could be implemented as quickly as possible. This approach is based on samples obtained at 2, 4, and 6 hours following the first dose of busulfan and the determination of the AUC using commercial pharmacokinetic software. The instructions for these determinations are described in the product labeling, which allows the user to decide on the appropriate dose adjustment as early as possible.
In summary, the Food and Drug Administration (FDA) approved the addition of limited safety and dosing information to the special populations section (pediatrics) of the label for Busulfex in 2002. The 2-step dosing regimen (1.1 mg/kg in children 12 kg and 0.8 mg/kg to children >12 kg) provides virtually the highest proportion of patients within the target therapeutic window with the first dose of busulfan, with the fewest number of steps. This reduces the possibility of confusion, which might occur with the use of more complex nomograms. Dosing based on body weight is consistent both with the dosage proposed for adults and current pediatric practice. Finally, the recommendation for TDM should ensure that for those patients who fall outside the therapeutic window, subsequent dose adjustment can be made to improve clinical outcome by reducing the risk of either toxicity and/or lack of effectiveness.
Performing numerous clinical trials to investigate different dosing strategies is prohibitively resource intensive. Modeling data from this trial allowed exploration of various dosing strategies and resulted in an alternative algorithm to that used in the trial and identification of the need for TDM. As a general note, drug development should include the collection of valuable data, such as concentrations, especially in the dose-ranging and pivotal trials. Exposureresponse relationships should be explored to gain better insights into using drugs more efficiently. Several FDA initiatives encourage drug developers to consider such practices, some of which are described in the FDA Guidances for Industry: Population Pharmacokinetics36 and the Guidance for Industry: Exposure-Response Relationships—Study Design, Data Analysis, and Regulatory Applications.37
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: None declared.
The views expressed in this article are those of the authors and do not reflect official policy of the Food and Drug Administration (FDA). No official endorsement by the FDA is intended or should be inferred.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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