Publication de Nicole Delepine : Interest of Pharmacological studies in the use of Ifosfamide in children

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Publié sur : Publication Powerpoint Nicole Delépine - 2002
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Interest of Pharmacological studies in the use of Ifosfamide in children
Gérard Delépine, V. Subovici, S. Alkallaf, P. Arnaud, F. Brion, JC. Desbois, Nicole Delépine

INTEREST OF PHARMACOLOGICAL STUDIES IN THE USE OF IFOSFAMIDE IN CHILDREN



Studies in the International littérature

Rational for the Study



Controversies about effectiveness of Ifosfamide in children are not yet resolved.

-Furthermore, the combination of VAIA is an effective therapy in childhood rhabdomyosarcoma.
-A high IFX dosage of 10 gr/sqm per cycle achieved a better response rate (83 %) than a lower dose 6 gr/sqm (68 %) (ASCO 1991).

The German PaediatricOncology Group found :



-improved response rate in children with Ewing's sarcome following substitution of IFX for CPX (Jurgens 1989).

Rational for the Study



-In contrast, the SFOP IFX based Ewing's sarcoma protocol found:
-no improvement in 3 year survival rate and an increased toxicity. (SFOP - Oberlin and al 1990)

Results of S.F.O.P protocols vaca and IVA-IVAd



Résults


Rational for the Study



Backgrounds of discordiant results could be age and pharmacokinetics of IFX un children

Material and methods



-48 patients aged 1,5 to 25 years with various solid tumors, received 137 courses of IPA (IFX, CDDP, THP ADR) with seric pharmacokinetic study.
-IFX was infused thermo-ionic detection.
-1850 dosages were computerized for statistical analysis.

Patients



-48 patients
-1,5y to 25y
-Various solid tumors.

IFX Infusion



-Continuous infusion by pomp 120 hours.
-Dosage of IFX by gaz chromatography with thermo-ionic detection.

Methods



Methods


1850 seric dosages with gazous chromatography and thermo ionic detection.

Method



Method


1850 dosage were computerized for statistical analysis.

Results



-Seric IFX reaches the steady state after 10-12 hours infusion.
-Half life increase is 4 hours (min 2 h 30 - max 7 h).
-A significant difference of mean seric level was found from day 1 to day 5.

For the daily infusion of 1,2 g/sqm:

-average D1 seric level is 12,63.10-3 g/l
-and average D5 seric level 9,81.10-3 g/l

Evolution of seric concentration of IFX



Evolution of seric concentration


Results



For a daily infusion of 1,2 g/m²
-The average seric level is 12,15.10-3 g/l (min 6,5 - max 20)
-The average seric IFX clearance is 72 ml/min (min 50, max 120)

-The seric clearance is significantly correlated (p < 0,001) with age.
-Young patients show a higher clearance and a lower seric concentration for a fixed dosage than older patients.

Correlation entre l'age et la concentration sérique a l'équilibre



Correlation age-concentration


Correlation age-concentration 2


Correlation age-concentration 3


Correlation age-concentration 4


Conclusions



-Significant correlation of IFX clearance with age could explain lower apparent effectiveness in young children at fixed dosage.
-Further studies are needed to find the best C plateau concentration or best AUC effective in different pathologies.
-Ability of IFX to produce response in patients with pediatric solid tumors refractory to CPX has been clearly demonstrated.
-Response rate as single agent in patients previously exposed to CPX, 24 to 32 %.

Highest level of response in tumors previously treated by CPX:
-Ewing
-Wilms
-Osteosarcoma
-Rhabdomyosarcoma

Magrath 1986 - Pinkerton 1989
Pratt 1989 - Schwartzmann 1989



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