BSA-based Dosing Research Articles

Developing a New Framework for Dose Calculation

Developing a New Framework for Dose Calculation

Constancy in Integrated Cisplatin Plasma Concentrations Among Pediatric Patients

The authors report on the variability in the integrated quantity of free (unbound) plasma cisplatin (area under curve of plasma concentration versus time, AUC). The AUC was measured in 19 patients receiving cisplatin doses proportional to body surface areas (BSA), 30 mg/m2 over 1 hour. The relative standard deviation (RSD, population standard deviation divided by mean value) for the maximum free plasma cisplatin concentration (Cmax, microM) was 0.338; for the half-life (t1/2, minute), 0.210; and for the AUC (microM minute), 0.320. Thus, BSA-based dosing gave significant variability in the AUC. We attempted to use (weight)a(height)b, seeking values of a and b that gave the smallest RSD in AUC, but only minimal improvement could be obtained by deviating from the BSA formula (a=b=0.5). However, dosing proportional to (weight)d(Cmax)f (with d approximately 3/4 and f approximately -1) reduced the RSD in AUC from approximately 1/3 to approximately 1/10. Dosing proportional to (weight)m (Cmax)n(t1/2)p (with m approximately 0.7, n approximately -1, and p approximately -1/2) reduced it further, to approximately 1/32. In contrast, using (weight)d(Cmax)f(age)g gave no improvement over (weight)d(Cmax)f. The authors conclude that the inconsistency in AUC can be reduced 10-fold with dosing proportional to the weight and the drug pharmacokinetic parameters [(weight0.7)/(Cmaxxt1/2(0.5))].

Evaluation of an Alternate Dosing Strategy for Cisplatin in Patients With Extreme Body Surface Area Values

The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average +/- 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population. In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value < or = 1.65 m2 was 16% slower (P < .001), while an 18% faster clearance (P < .001) was observed in patients with a BSA value > or = 2.05 m2. CONCLUSION Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (< or = 1.65 m2; 1.66 m2 to 2.04 m2; > or = 2.05 m2) are recommended.

Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer

To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo. Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m2). Accumulation of [G-3H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (+/- SD) apparent oral clearance of MS-275 was 38.5 +/- 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance. The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.

Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study

An IV form of busulfan (IV Bu) has recently become available for high dose conditioning regimen before haematopoietic stem cell transplantation (HSCT). This IV form is expected to reduce the high pharmacokinetic variability exhibited with oral busulfan and as a result, to better target the plasma area under the curve (AUC). Pharmacokinetics (PK) of IV Bu was investigated on 127 adult patients (333 PK administrations) who received 0.8 mg.kg-1 of Bu as a 2-h infusion every 6 h over 4 days, followed by cyclophosphamide (60 mg.kg-1 day-1x2). A retrospective population PK analysis was carried out to search for important predictive factors of IV Bu PK and to develop a limited sampling strategy (LSS) through Bayesian methodology. The analysis was conducted using the Non Linear Mixed Effect methodology and included a validation process on an independent data set. Adjusted Ideal Body Weight (AIBW) and Body Surface Area (BSA) were the best covariates to explain the inter-patient variability. The final inter-patient variability (CV=16%) in IV Bu clearance (Cltot) was estimated close to the intra-patient variability (CV=13%). There was neither age-dependency nor gender effect. IV Bu Cltot was not affected by elevated hepatic enzymes or by co-administration of either fluconazole or acetaminophen, and was not altered in heavily pre-treated or pre-transplanted patients. Normalised Cltot based on either AIBW or BSA was comparable between normal and obese patients (BMI=18-26.9 kg.m-2, >26.9 kg.m-2, respectively) whereas significant differences existed when based on either actual (ABW) or ideal body weight (IBW). As a consequence, no dose adjustment is required in obese patients when using a AIBW- or BSA-based dose calculation. A fixed dose of 0.80 mg.kg-1 of AIBW or 29 mg.m-2 of BSA yielded an average AUC of 1,200 microM.min, with 80% of patients within the "therapeutic" AUC range of 900-1,500 microM.min. Alternatively, 0.80 mg.kg-1 based on either ABW or IBW for normal patients and on AIBW for obese patients would achieve the same performance. A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset: AUCs obtained from one to two samplings were demonstrated to be reliably estimated.

Evaluation of body-surface area based dosing of cisplatin in patients with extreme BSA values

Background In view of their small therapeutic window, cytotoxic drugs for adults are dosed based on body-surface area (BSA), aiming to reduce interpatient variability in drug exposure. In a retrospective analysis no rationale was found for continuing of BSA-based dosing for cisplatin (CDDP) in the average patient[JCO 19 (2001), 3733]. Here, we studied the usefulness of this dosing strategy in patients at lower and upper extremes of BSA values. Methods Patients were randomized to receive a fixed dose of CDDP (based on an average BSA of 1.86m2) in course 1 and a BSA-adjusted dose in course 2 or vice versa. Plasma concentrations of unbound platinum (Pt) were determined and analyzed by noncompartmental analysis. Results 18 Patients are evaluable so far; 10 large patients (9 M> 2.05m2, 1 F >1.90m2) and 8 small patients (5 M 0.37), however with a large variability in CL. The average CL in large patients was approximately 30% faster than the average CL in small patients. Correction of CL for the BSA in both populations, resulted in a reduction of only 10–13% in the variability. Conclusion Unless better predictors for CL are identified, fixed dose regimens per BSA-cluster are recommended. Clinical Pharmacology & Therapeutics (2005) 77, P37–P37; doi: 10.1016/j.clpt.2004.12.033

Role of Cytochrome P450 Phenotyping in Cancer Treatment

It is remarkable that cancer chemotherapies, with generally narrow therapeutic windows and possibilities for life-threatening toxicities, are usually dosed according to body-surface area (BSA). The appropriateness of BSAbaseddosinghasbeenchallenged, 1 butitremainsingrained in clinical oncology practice. The continued use of BSA dosing is understandable, as it applies a precise calculation toanintuitivelyobviousnotionthattooptimizetreatment, larger patients should receive more drug than smaller patients. Moreover, there is no validated substitute for BSAbased dosing for most chemotherapy regimens. However, theemergingfieldofpharmacogeneticspromisestochange this situation. Interindividual variability in toxicity and therapeutic responseisfrequentlyobserved,leadingtopotentiallylethal consequences of cancer treatment. Variability in response may be due to a combination of tumor- and host-related factors. Variability in chemotherapy-associated toxicity is a host-related phenomenon that is largely a consequence of variability in absorption and distribution, and particularly of metabolism and clearance. There is a high degree of interindividualvariabilityinthesystemicclearanceofmany chemotherapeutic agents, primarily reflecting differences in rates of hepatic drug metabolism. The cytochrome P450 (CYP) system catalyzes the rate-limiting step in the overall metabolism and subsequent elimination of many drugs and is known to be involved in the metabolism of many anticancer drugs including ifosfamide, cyclophosphamide, etoposide, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine,andtamoxifen. 2,3 Thesearchforfunctionalpolymorphisms in the CYP genes, with the goal of using an

A dose-escalation study of the quinoxaline antitumor agent R(+)XK469 (XK) in patients with refractory solid tumors

2021 Background: XK is a member of the quinoxaline family of antitumor agents. COMPARE analysis of cytotoxicity data from the NCI-60 cell line screen showed that its mechanism of action is not comparable to that of any marketed cytotoxic agent. In vitro studies suggest that the antitumor activity of XK may be due to inhibition of topoisomerase IIβ, induction of G2-M cell cycle arrest by p53-dependent and mitogen-activated protein (MAP) kinase pathways, and/or pro-apoptotic interactions with the peripheral benzodiazepine receptor. Methods: XK was administered as a 30-minute intravenous infusion for 5 days at 15, 30, 60, 120, and 240 mg/d and every other day for 3 doses at 360, 540, 675, 850, 1100, and 1400 mg/d, repeated every 21 days. The dosing schedule was changed when pharmacokinetic (PK) analysis revealed a long half-life. Results: To date 42 pts (21 male/21 female, median age 60, median Karnofsky performance status 90%) have been treated at 11 dose levels. The principle site of toxicity has been bone marrow. Grade 3 anemia and thrombocytopenia have been observed at 1100 and 1400 mg. Grade 4 neutropenia on the scheduled day 1 of cycle 2 and fever in the setting of grade 4 neutropenia have been the only dose-limiting toxicities (DLT). Non-hematologic toxicities include grade 1–2 alopecia, anorexia, diarrhea, fever, headache, nausea, peripheral neuropathy, rash, stomatitis, and vomiting and grade 3 fatigue. Plasma concentrations of XK decline in a biphasic manner with a long mean terminal phase half-life of 60 h (CV 63%). Steady-state volume of distribution is 13 L (CV 23%); and mean total body clearance (CL) is 0.20 L/h (CV 50%), which is not correlated with dose (p=0.69) or BSA (p=0.93). All pts who experienced DLT had CL < 1 standard deviation (SD) below the mean. Conclusions: XK can be safely administered on a d 1, 3, 5 schedule without BSA-based dosing. As AUC increases with dose and 15% of our pts had CL ≤ 1 SD below the mean, safety concerns preclude further dose escalation > 1100 mg/d on this schedule. Cohort expansion continues at the phase II recommended dose of 1100 mg/d. Pharmacogenomic studies are ongoing to investigate the basis for the large PK variability. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Standardization of the body surface area (BSA) formula to calculate the dose of anticancer agents in Japan.

The importance of deciding the appropriate dose of anticancer agents cannot be overemphasized. Body surface area (BSA) has been used to calculate the dose in anticancer therapy since the 1950s. Japanese oncologists, often use their own Japanese BSA formula instead of western BSA formulae. However, it is not widely known that some discrepancies exist between the BSA products of the Japanese and western styles. On the other hand, recently dose-calculations according to BSA were criticized from the standpoint of pharmacokinetics (PK). Lately, we have had many opportunities for international collaborations, which make it necessary to review these BSA formulae, and the BSA-based dosing method. A unified BSA formula in cancer therapy is needed in Japan. We searched and compiled frequently used BSA formulae across the world using the MEDLINE search, oncology text, a web search on cancer clinical trial groups, and personally communicated with medical oncologists from western countries. Using these formulae, we calculated BSA for a typical Japanese individual, and compared their products. We calculated BSA using these formulae for individuals of widely varying physique, from 140 to 185 cm in height, and from 30 to 96 kg in weight, and estimated the amount of discrepancies among them. Among the various BSA formulae used in western countries, the DuBois formula is the standard. In Japan, the Fujimoto formula has been used frequently. The Fujimoto formula was based on a study of 201 Japanese subjects in 1949. For the average Japanese individual, the BSA calculated using the Fujimoto formula was about 3% lower than that which was calculated by western formulae. The BSA calculated for all heights and body weights using the Fujimoto formula, ranged between 0.7 and 4.8% less than those calculated by using the DuBois formula. The other western formulae showed larger discrepancies than the Fujimoto and DuBois formulae. BSA-based dosing has failed to standardize the variation in PK for most anticancer agents, and individual dosing techniques are currently being investigated. However, until their clinical utilities are confirmed, it is necessary to depend on the BSA-based calculation for determining the dose of most anticancer agents. The DuBois formula, which is the western standard formula, is validated to a greater extent and its accuracy has been confirmed more than others, including the Fujimoto formula. We recommend the use of the DuBois formula instead of the Fujimoto formula in cancer chemotherapy and propose the standardization of this formula in Japan.

Cautious Arguments in Favor of Body Surface Area–Based Dosing

Cautious Arguments in Favor of Body Surface Area–Based Dosing

Impact of body-size measures on irinotecan clearance: alternative dosing recommendations.

To evaluate relationships between various body-size measures and irinotecan (CPT-11) clearance and metabolism in cancer patients, and to provide future dosing recommendations for this agent. Pharmacokinetic data were obtained from 82 adult patients (50 men, 32 women; median age, 54 years) receiving CPT-11 as a 90-minute intravenous infusion (dose range, 175 to 350 mg/m(2)). In each patient, plasma samples were collected at timed intervals in the first administration of a 3-week schedule, and CPT-11 and its metabolite, SN-38, were measured by a liquid chromatographic assay. The mean (+/- SD) CPT-11 clearance was 33.6 +/- 10.8 L/h, with an interindividual variability (IIV) of 32.1%. When clearance was adjusted for body-surface area (BSA), the IIV was similar (34.0%). In addition, in a multiple linear regression analysis, none of the studied measures (BSA, lean body mass, [adjusted] ideal body weight, and body mass index) was a significant covariate (P >.13; r(2) <.014) in our population. Similarly, BSA did not significantly contribute to variability in the relative extent of conversion to SN-38 (P =.26). BSA is not a predictor of CPT-11 clearance or SN-38 pharmacokinetics and does not contribute to reducing kinetic variability. These findings provide a rationale for the conduct of a comparative phase III study between BSA-based dosing and flat or fixed dosing of CPT-11.

Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure.

Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m(2) (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non-protein-bound cisplatin in plasma by atomic absorption spectrometry. No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL(free)) was 57.1 +/- 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m(2) (mean, 1.86 +/- 0.19 m(2)), with an interpatient variability of 10.4%. When CL(free) was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL(free) and BSA (r = 0.42). Intrapatient variability in CL(free), calculated from 90 patients was 12.1% +/- 7.8% (range, 0.30% to 32.7%). In view of the high interpatient variability in CL(free) relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

Application of the area under the curve of carboplatin in predicting toxicity and efficacy

Current cytotoxic chemotherapy dosing is largely empirical and guided by the concept of improved therapeutic outcome with greater total dose delivered over a fixed period of time, i.e., dose intensity (1,2). Consequently, chemotherapy is clinical1 given as the maximum dose tolerated by the patient (3). In contrast to antibiotics, the intrinsic sensitivity of tumour or host cells to a cytotoxic drug is unclear, such that the likelihood of response or toxicity is not usually predictable prior to treatment. Additionally, most cytotoxic agents have a narrow therapeutic index but no clear surrogate markers to monitor for efficacy or toxicity Since the pharmacokinetics of chemotherapy drugs is highly variable between patients, one attempt in overcoming this problem is the traditional dosing in milligrams per square metre (mg/m2) of body surface area (BSA) (4). This BSA-based dosing is derived from the fact that the lethal dose in 10% of the population (LD,,) in animals is better correlated to the maximum tolerated dose (MTD) in humans when expressed in mg/m2 than in mg/kg (5). Nevertheless, inherent interpatient variability means that standardized dosing in mg/m2 can still lead to variable plasma concentrations (6). As a result, patients may be exposed to too much or too little drug, leading to potential toxicity or therapeutic failure. Moreover, since the MTD is established clinically on the dose producing significant toxicity in 50% of patients, extrapolating this dosing to all patients may lead to underdosing in half of the patients. The total area under the concentration-time curve (AUC) for a particular drug is the product

Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative.

To review the current dose-calculation practice and propose a non-body-surface area (BSA)-based dose-calculation method. Data that supported the introduction of BSA-based dose calculation in the late 1950s were reviewed. Data on 18 drugs that correlated pharmacokinetic (PK) variables for cytotoxic drugs with BSA were examined. Other methods of dose calculation, such as therapeutic drug monitoring (TDM) and adaptive control, were also examined. The BSA-based method of dose calculation was adopted without adequate investigation of its accuracy. BSA fails to standardize the marked interpatient variation in PK for most cytotoxic drugs. A definite correlation was found between PK variables and BSA for only one drug (docetaxel). PK parameters correlate with toxicity, as well as response in some tumors, but do not completely explain the variation in drug effect between individuals. The complexities of TDM may make its universal use impractical. A non-BSA-based dose calculation method is proposed that defines three mandatory steps: prime dose, modified dose, and toxicity-adjusted dose (PMT dosing). Prime dose is the fixed dose of a drug used alone or in combination and is derived from the reanalysis of phase I/II studies and from clinical practice. Modified dose is an adjustment of the prime dose before administration, based on dose-adjustment guidelines that predict the drug-handling ability of an individual. Population pharmacodynamic studies may be used for the development of these guidelines. Subsequent doses are adjusted in each patient according to a target toxicity, such as nadir neutrophil count or other objective toxicity, that serves as a surrogate marker for potential antitumor effect (toxicity-adjusted dose). Patients who are predicted to have very abnormal drug handling should be excluded from such a dosing scheme and TDM may be more suitable. The routine use of BSA for dose calculation should be reevaluated. Other methods of dose calculation should be investigated. TDM may be impractical in all patients and remains unvalidated. PMT dosing ensures that the condition of each individual is considered, to predict drug effects better. Clinical dose-calculation systems such as PMT dosing should be evaluated prospectively.

Pharmacokinetic variability in the adolescent: Implications of body size and organ function for dosage regimen design

Although there are convincing clinical studies demonstrating important pharmacokinetic differences between the adult and Pediatric patient, guidelines for adjusting the dosages of specific drugs are often based on empirical and limited data. Adult doses often provide the reference point for therapy in children with adjustment for body size. Both body weight and body surface area (BSA) are commonly used to adjust adult doses for pediatric patients but yield substantially different absolute doses. For the child age five years, the BSA-based dose will be more than 50 percent greater than the dose adjusted for body weight. The choice of weight or BSA is often arbitrary and may be an important confounding variable when evaluating drugs over wide ranges of age in pediatric patients or comparing two drugs for which doses are not adjusted in a similar manner. For example, comparative trials for HIV-infected pediatric patients are evaluating zidovudine dosed by BSA with zalcitabine dosed by body weight. Organ function changes with age in pediatric patients yet little information is available on the effects of maturation on hepatic or renal function and the consequences for drug disposition. The use of model substrates for organ function offers potential for elucidating organ function relative to maturation and, in particular, to those functional capacities associated with the onset of puberty and gender differentiation.

Optimization of Busulfan Dosage in Children Undergoing Bone Marrow Transplantation: A Pharmacokinetic Study of Dose Escalation

Abstract Busulfan (BU) is a widely used myeloablative and antineoplastic agent in clinical bone marrow transplantation (BMT). The lower incidence of BU-associated toxicities and lower therapeutic effectiveness in young children given BU doses based on body weight (ie, 16 mg/kg) is associated with altered pharmacokinetics of BU; the area under the curve (AUC) of BU concentration versus time is significantly less in these patients than those observed in older children and adults. To optimize BU dosage in young BMT recipients, we developed a dosage regimen based on body surface area (BSA) and determined BU pharmacokinetics and BU-associated toxicities. Seven children (median age, 3.9 years, range, 1.1 to 5.7) undergoing allogeneic or autologous BMT for leukemia received 40 mg/m2/dose BU every 6 hours for 16 doses; BU concentrations were measured in the plasma, and AUCs were determined for each patient after the first and 13th doses. Expressed as a function of body weight, the median BU dosage was 26.4 mg/kg (range, 24.3 to 28.2), a 60% increase over the BU dosage based on body weight. Four patients developed mucositis, and one of them also developed nonfatal hepatic veno-occlusive disease (VOD). No patients receiving 40 mg/m2 BU developed neurotoxicity (eg, seizures) or interstitial pneumonitis. Prompt and sustained engraftment was observed in the allogeneic BMT recipients, and late graft failure was not seen. The mean BU AUCs were 1,105 mumol/L.min (range, 790 to 2,080) after the first dose and 1,022 mumol/L.min (range, 632 to 1,860) after the 13th dose of BU, comparable to the AUCs in adults given 16 mg/kg of BU. These studies suggest that, in young children, BSA-based dosing of BU (40 mg/m2) provides drug exposures (AUCs) closer to adult values with acceptable toxicities and may improve therapeutic effects.

Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation

Busulfan (BU) is a widely used myeloablative and antineoplastic agent in clinical bone marrow transplantation (BMT). The lower incidence of BU-associated toxicities and lower therapeutic effectiveness in young children given BU doses based on body weight (ie, 16 mg/kg) is associated with altered pharmacokinetics of BU; the area under the curve (AUC) of BU concentration versus time is significantly less in these patients than those observed in older children and adults. To optimize BU dosage in young BMT recipients, we developed a dosage regimen based on body surface area (BSA) and determined BU pharmacokinetics and BU-associated toxicities. Seven children (median age, 3.9 years, range, 1.1 to 5.7) undergoing allogeneic or autologous BMT for leukemia received 40 mg/m2/dose BU every 6 hours for 16 doses; BU concentrations were measured in the plasma, and AUCs were determined for each patient after the first and 13th doses. Expressed as a function of body weight, the median BU dosage was 26.4 mg/kg (range, 24.3 to 28.2), a 60% increase over the BU dosage based on body weight. Four patients developed mucositis, and one of them also developed nonfatal hepatic veno-occlusive disease (VOD). No patients receiving 40 mg/m2 BU developed neurotoxicity (eg, seizures) or interstitial pneumonitis. Prompt and sustained engraftment was observed in the allogeneic BMT recipients, and late graft failure was not seen. The mean BU AUCs were 1,105 mumol/L.min (range, 790 to 2,080) after the first dose and 1,022 mumol/L.min (range, 632 to 1,860) after the 13th dose of BU, comparable to the AUCs in adults given 16 mg/kg of BU. These studies suggest that, in young children, BSA-based dosing of BU (40 mg/m2) provides drug exposures (AUCs) closer to adult values with acceptable toxicities and may improve therapeutic effects.