Body Weight-Dependent Pharmacokinetics of Busulfan in Paediatric Haematopoietic Stem Cell Transplantation Patients

Bartelink, Imke H.; Boelens, Jaap Jan; Bredius, Robbert G. M.; Egberts, Toine C. G.; Wang, Chenguang; Bierings, Marc; Shaw, Peter J.; Nath, Christa E.; Hempel, G.; Zwaveling, J.; Danhof, Meindert; Knibbe, Catherijne A. J.

doi:10.2165/11598180-000000000-00000

Cited by 125 publications

(184 citation statements)

References 52 publications

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“…Both these models have been proposed for the prediction of drug clearances in pediatrics (4,(8)(9)(10)(11). Although the BDE model was developed based on inulin clearance, the model's predictive power was comparable for GFR based on inulin and creatinine clearance.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies by many investigators have shown that the concept of quarter-power law or so-called theoretical allometry (fixed exponents of 0.25, 0.75, or 1.0) is incorrect (43)(44)(45)(46)(47)(48)(49)(50)(51). The exponents of allometry for drug clearance in preterm and term neonates are generally >1 (4,(8)(9)(10)(11)39). Therefore, it is not surprising that even for GFR the exponent 0.75 (model 3) provided a very poor prediction (systematic over-prediction by hundreds of percent) of GFR in preterm, term, and children ≤1 year of age as compared to exponent 1.15, 1.0, or 0.9, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The maturation model has been applied to predict clearance of several drugs such as morphine (5), propofol (6), and midazolam (7). The BDE model has been applied to predict clearance of morphine (8), propofol (9,10), and busulfan (11). Besides BDE model, another empirical model called age-dependent exponent (ADE) model has been developed for the prediction of drug clearance from preterm neonates to adults (4).…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Mahmood

Staschen

2016

AAPS J

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Abstract. The objective of this study was to evaluate the predictive performance of several allometric empirical models (body weight dependent, age dependent, fixed exponent 0.75, a data-dependent single exponent, and maturation models) to predict glomerular filtration rate (GFR) in preterm and term neonates, infants, children, and adults without any renal disease. In this analysis, the models were developed from GFR data obtained from inulin clearance (preterm neonates to adults; n = 93) and the predictive performance of these models were evaluated in 335 subjects (preterm neonates to adults). The primary end point was the prediction of GFR from the empirical allometric models and the comparison of the predicted GFR with measured GFR. A prediction error within ±30% was considered acceptable. Overall, the predictive performance of the four models (BDE, ADE, and two maturation models) for the prediction of mean GFR was good across all age groups but the prediction of GFR in individual healthy subjects especially in neonates and infants was erratic and may be clinically unacceptable.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Mahmood

Staschen

2016

AAPS J

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“…This is similar to studies conducted in adults that have reported that GSTA1 polymorphisms could account for 15-18% of the variability in first-dose BU CL, and in line with the unexplained variability of BU CL among pediatric patients reported in a recent meta-analysis. 16,30,39 Homozygous GSTA1*A2 individuals had an augmentation of BU dose, owing to increased CL of BU. Although reaching the target level, *A2 carriers had still lower Css after the eighth dose as compared with non-carriers, which may suggest the need to reduce the BU dose in patient without *A2 haplotype.…”

Section: Discussionmentioning

confidence: 99%

“…2,[12][13][14] Body weight and body surface area have been also shown to contribute to PK variability. [15][16][17][18][19] Nevertheless, a large proportion of BU variability remains unexplained 20 and could be due to GST polymorphisms influencing GST activity [21][22][23][24][25] (Table 1). Although some studies have shown that GSTA1 genotypes influence the PK of oral and i.v.…”

Section: Introductionmentioning

confidence: 99%

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

Ansari

Rezgui

Théôret

et al. 2013

Bone Marrow Transplant

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on behalf of the Pediatric Disease Working Parties of the European Blood and Marrow Transplant Group BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (Pp0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (Pp0.03). Gene-dosage effect was also observed (Pp0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P ¼ 0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P ¼ 0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P ¼ 0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.

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Inherited metabolic disorders

Boelens

Wynn

2017

Clinical Manual of Blood and Bone Marrow Transplantation

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Body Weight-Dependent Pharmacokinetics of Busulfan in Paediatric Haematopoietic Stem Cell Transplantation Patients

Cited by 125 publications

References 52 publications

Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

Inherited metabolic disorders

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