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CLINICAL PHARMACOKINETICS OF CARBOPLATIN IN CHILDREN
The present study was undertaken to evaluate in children the plasma
pharmacokinetics of free carboplatin given at different doses and
schedules and to evaluate the inter- and intrapatient variability and
the possible influence of schedule on drug exposure. A total of 35
children (age range, 1-17 years) with malignant tumors were studied. All
patients had normal renal function (creatinine clearance corrected for
surface body area, above 70 ml min(-1) m(-2); range, 71-151 ml min(-1)
m(-2)) and none had renal involvement by malignancy. Carboplatin was
given at the following doses and schedules: 175, 400, 500, and 600 mg/
m(2) given as a l-h infusion; 1,200 mg/m(2) divided into equal doses and
infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m(2) given
as a 5-day continuous infusion. A total of 57 courses were studied.
Carboplatin levels in plasma ultrafiltrate (UF) samples were measured
both by high-performance liquid chromatography and by atomic absorption
spectrophotometry. Following a 1-h infusion, carboplatin free plasma
levels decayed biphasically; the disappearance half-lives, total body
clearance, and apparent volume of distribution were similar for
different doses. In children with normal renal function as defined by
creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we
found at each dose studied a limited interpatient variability of the
peak plasma concentration (C-max) and the area under the
concentration-time curve (AUC) and a linear correlation between the dose
and both C-max (r = 0.95) and AUC (r = 0.97). The mean value +/- SD for
the dose-normalized AUC was 13+/-2 min m(2) 1(-1) (n = 57). The
administration schedule does not seem to influence drug exposure, since
prolonged i.v. infusion or bolus administration of 1,200 mg/m(2)
achieved a similar AUC (13.78+/-2.90 and 15.05+/-1.44 mg ml(-1) min,
respectively). In the nine children studied during subsequent courses a
limited interpatient variability was observed and no correlation (r =
0.035) was found between AUC and subsequent courses by a multivariate
analysis of dose, AUC, and course number. The pharmacokinetic parameters
were similar to those previously reported in adults; however, a weak
correlation (r = 0.52, P = 0.03) between carboplatin total body
clearance and creatinine clearance varying within the normal range was
observed. A dosing formula appears unnecessary in children with normal
renal function since a generally well-predictable free carboplatin AUC
is achieved following a given dose