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. 2007 Aug;64(2):151-64.
doi: 10.1111/j.1365-2125.2007.02862.x. Epub 2007 Feb 23.

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

Christa E Nath  1 , Peter J Shaw, Kay Montgomery, John W Earl
Affiliations

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

Christa E Nath et al. Br J Clin Pharmacol. 2007 Aug.

Abstract

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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Figures

Figure 1
Figure 1
Diagnostic plots of the covariate population pharmacokinetic model for melphalan in the model development dataset (39 children, 571 observations). (A) Scatterplot of observed and population-predicted melphalan concentrations. (B) Plot of weighted residual vs. population-predicted melphalan concentrations
Figure 2
Figure 2
Melphalan concentration–time profile in a child who received 180 mg m−2 melphalan. •, Individual observed concentrations; —, population-predicted concentrations using the covariate population pharmacokinetic model
Figure 3
Figure 3
Post hoc assessment of predictive performance of the covariate population pharmacokinetic model in the validation dataset (20 children, 277 concentration observations). (A) Scatterplot of observed vs. population-predicted melphalan concentrations. (B) Superimposed histogram and fitted normal curve plots of frequency of occurrence vs. residual (predicted − observed concentration)
Figure 4
Figure 4
Histograms showing the distribution of expected AUC values in our population of 59 children using (A) a dose determined with the nomogram and (B) a 140 mg m−2 dose
Figure 5
Figure 5
Correlation between NONMEM-determined AUC and LSM-estimated AUC in the (A) development and (B) validation datasets
See this image and copyright information in PMC

References

    1. Shaw PJ, Pinkerton CR, Yaniv I. Melphalan combined with carboplatin dose based on glomerular filtration rate followed by autologous stem cell rescue for children with solid tumours. Bone Marrow Transplant. 1996;16:401–5. - PubMed
    1. Michel G, Maraninchi D, Demeocq F, Perrimond H, Blaise D, Gaspard MH, Stoppa AM, Gastaut JA, Lepeu G, Novakovitch G, Marguerite G, Carcassonne Y. Repeated courses of high dose melphalan and unpurged autologous bone marrow transplantation in children with acute non-lymphoblastic leukemia in first complete remission. Bone Marrow Transplant. 1998;3:105–11. - PubMed
    1. Cornwell GG, III, Pajak TF, McIntyre OR, Kochwa S, Dosik H. Influence of renal failure on myelosuppressive effects of melphalan: cancer and leukemia group B experience. Cancer Treat Rep. 1982;66:475–81. - PubMed
    1. Moreau P, Kergueris M-F, Milpied N, Le Tortorec SL, Mahe B, Bulabois C-E, Rapp M-J, Larousse C, Bataille R, Harousseau J-L. A pilot study of 220 mg/m2 melphalan followed by autologous stem cell transplantation in patients with advanced haematological malignancies: pharmacokinetics and toxicity. Br J Haematol. 1996;95:527–30. - PubMed
    1. Sarosy G, Leyland-Jones B, Soochan P, Cheson BD. The systemic administration of intravenous melphalan. J Clin Oncol. 1988;6:1768–82. - PubMed

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