Melphalan pharmacokinetics in children with malignant disease: influence of body weight, renal function, carboplatin therapy and total body irradiation.
OBJECTIVE
To analyse the pharmacokinetics of melphalan in 52 children (0.3-18 years) and determine whether any clinical factors affect the pharmacokinetic parameters Additionally, to examine whether a test melphalan dose can predict the pharmacokinetics of a full dose, when there are 5 intervening days of carboplatin therapy.


METHODS
Melphalan concentrations were measured in 14 blood samples collected from each child following doses ranging from 30 to 180 mg m(-2). The pharmacokinetics were analysed with Kinetica 4.0.


RESULTS
Children who did not have carboplatin (n = 27) had median melphalan clearance (CL) of 15.5 l h(-1) m(-2) (interquartile range: 12.4-19.9 l h(-1) m(-2)) and steady state volume of distribution (Vss) of 14.9 l m(-2) (interquartile range: 12.7-18.3 l m(-2)). Children who had carboplatin (n = 25) had 34% lower median CL (10.2 l h(-1) m(-2)) and 18% lower median Vss (12.2 l m(-2)) (P < 0.001). Melphalan elimination was impaired in a separate group of three children given concomitant carboplatin and etoposide. Stepwise multiple linear regression indicated that weight, carboplatin, glomerular filtration rate (GFR) and total body irradiation (TBI) significantly affected CL, while weight and carboplatin influenced Vss. A test dose (10 mg m(-2)) tended to underpredict the area-under-the-concentration-vs.-time-curve for a full (180 mg m(-2)) dose in 19 individuals given carboplatin.


CONCLUSIONS
In children, melphalan CL is influenced by weight, carboplatin, TBI and GFR. Vss is influenced by weight and carboplatin.
Nath
Christa E
CE
Department of Biochemistry and Oncology, The Children's Hospital at Westmead, NSW, Australia. christan@chw.edu.au
Shaw
Peter J
PJ
Montgomery
Kay
K
Earl
John W
JW
D000293:Adolescent; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001835:Body Weight / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000379:methods; D016190:Carboplatin / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D007223:Infant; D007674:Kidney Diseases / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008558:Melphalan / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D016190:Carboplatin; D008558:Melphalan