Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients.
Invest Ophthalmol Vis Sci
; 53(7): 4205-12, 2012 Jun 28.
Article
in En
| MEDLINE
| ID: mdl-22628208
ABSTRACT
PURPOSE:
To characterize melphalan pharmacokinetics after superselective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma.METHODS:
Vitreous and plasma samples of five Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan cytotoxicity was evaluated in retinoblastoma cell lines with and without topotecan. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage, and systemic toxicity was studied in patients.RESULTS:
In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, a large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (P<0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (P<0.05). These children had 50% probability of grades 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (P<0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines.CONCLUSIONS:
Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Retinoblastoma
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Retinal Neoplasms
/
Melphalan
Type of study:
Prognostic_studies
Limits:
Animals
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Child
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Child, preschool
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Female
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Humans
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Infant
/
Male
Language:
En
Journal:
Invest Ophthalmol Vis Sci
Year:
2012
Document type:
Article
Affiliation country:
Argentina