Melphalan pharmacokinetics in children with malignant disease: influence of body weight, renal function, carboplatin therapy and total body irradiation

Nath, Christa E.; Shaw, Peter J.; Montgomery, Kay; Earl, John

doi:10.1111/j.1365-2125.2004.02319.x

Cited by 24 publications

(38 citation statements)

References 28 publications

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“…Our pharmacokinetic results (Table V) of melphalan given with concurrent BSO are similar to those reported in children for melphalan alone or given with other agents excluding carboplatin, which is known to decrease melphalan clearance and volume of distribution. [38,39] This suggests that BSO does not affect melphalan PK. Other studies of high-dose melphalan (140-180 mg/m 2 ) showed similar systemic clearance results ranging from 15.4 to 29.9 l/hr/m 2 .…”

Section: Discussionmentioning

confidence: 95%

A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma

Villablanca

Volchenboum

Cho

et al. 2016

Pediatr Blood Cancer

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Section: Discussionmentioning

confidence: 95%

A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma

Villablanca

Volchenboum

Cho

et al. 2016

Pediatr Blood Cancer

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“…In children, melphalan is currently dosed on a mg m −2 basis, and there are no guidelines for varying the dose in patients who are very heavy or who have impaired renal function. Many studies have noted wide variability in exposure in patients receiving the same surface area‐based dose [9, 10]. Children with high melphalan exposure have been previously shown to have increased toxicity [11], demonstrating a relationship between melphalan pharmacokinetics and melphalan toxicity.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

Nath

Shaw

Montgomery

et al. 2007

Brit J Clinical Pharma

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What is already known about this subject • In one of the largest studies in children to date, we have already published a paper that has described the pharmacokinetics of melphalan using a two‐stage approach. What this study adds • The current paper is a follow‐up study in which a population pharmacokinetic model for melphalan is developed and validated in children. • There have been no other population pharmacokinetic analyses published on melphalan given as a short infusion. • Additionally, a nomogram is produced to guide melphalan dosing. Aim To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. Methods Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. Results A two‐compartment model was fitted to the concentration‐vs.‐time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h−1) = 0.34.WT − 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min−1 1.73 m−2); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model‐predicted melphalan concentrations in the validation dataset. A three‐sample limited sampling model was developed which adequately predicted the area under the concentration–time curve (AUC) in the development and validation datasets. Conclusions A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.

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“…There are two studies that have reported no pharmacokinetic interaction between carboplatin and etoposide , and one study has reported an interaction between melphalan and carboplatin . As these drugs were coadministered in all patients in the present study, potential drug–drug interactions could not be investigated directly.…”

Section: Discussionmentioning

confidence: 81%

Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re‐evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function

Duong

Veal

Nath

et al. 2018

Brit J Clinical Pharma

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Aims Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration–time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high‐risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. Methods Data on children receiving high‐dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml–1·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight‐based dosing. Results Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min–1 1.73 m–2 but not for those with a GFR ≥100 ml min–1 1.73 m–2. A weight‐based dosing regimen of 50 mg kg–1 achieved the target AUC more consistently than the other formulas, regardless of renal function. Conclusions GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model‐based approach validates the use of weight‐based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

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Melphalan pharmacokinetics in children with malignant disease: influence of body weight, renal function, carboplatin therapy and total body irradiation

Cited by 24 publications

References 28 publications

A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma

A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re‐evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function

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