Population Pharmacokinetic Model of Intravenous Busulfan in Hematopoietic Cell Transplantation: Systematic Review and Comparative Simulations

Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience

“…Figure 6 provides a schematic summary of our findings. Not surprisingly, our data confirmed the dependency of busulfan CL on body size metrics [ 18 , 25 , 30 , 52 ]. This dependency resulted mainly from the correlation and near proportionality between V of busulfan and the TBW, calculated from W , H , age, and sex.…”

“…In our study, BSA performed similar to TBW as a covariate for V. Considering the near agreement between V and TBW and its (potential) physiological meaning (namely that busulfan distributes in total body water), we preferred keeping TBW as a covariate rather than the more commonly used parameter BSA or W. In addition to the effect of TBW on V, we identified several covariates for k, as summarized in Figure 6. Most previous population PK studies used CL and V as fit parameters [30], while we based our model on the elimination constant k and V. As CL is the product of V and k, covariates for both parameters also affect CL. Takahashi et al recently published a comprehensive review on busulfan population PK studies [30].…”

“…Most previous population PK studies used CL and V as fit parameters [30], while we based our model on the elimination constant k and V. As CL is the product of V and k, covariates for both parameters also affect CL. Takahashi et al recently published a comprehensive review on busulfan population PK studies [30]. Covariates for busulfan CL included W, BSA, FFM, normal-fat mass, ideal body weight, age, GSTA1 variants, and co-medication with fludarabine or fludarabine together with clofarabine, aspartate transaminase, and the time after first busulfan administration [30].…”

“…In addition to the effect of TBW on V , we identified several covariates for k, as summarized in Figure 6 . Most previous population PK studies used CL and V as fit parameters [ 30 ], while we based our model on the elimination constant k and V . As CL is the product of V and k , covariates for both parameters also affect CL.…”

“…Nevertheless, a substantial fraction of patients elude accurate prediction of the AUC of the first and subsequent doses, which is evidence of substantial between-subject and -occasion variability. The large inter-patient variability of busulfan PK, especially in pediatric patients, is influenced by various factors including age, body weight, disease, drug interactions, and hepatic metabolism [ 18 , 25 , 26 , 27 , 28 , 29 , 30 ]. In addition, as a large fraction of busulfan irreversibly binds to leukocytes, erythrocytes, and plasma proteins (mainly albumin) [ 31 , 32 ], these patient-intrinsic factors should be considered, as they may contribute to busulfan elimination.…”