Selection of a dosing regimen with WST11 by Monte Carlo simulations, using PK data collected after single IV administration in healthy subjects and population PK modelling.
M.A. Fabre (2), E. Fuseau (2), P. Cohen, H. Ficheux (1).
(1) NEGMA - Avenue de l’Europe-TOUSSUS LE NOBLE - 78771 Magny Les Hameaux Cedex - FRANCE; (2) EMF Consulting, BP 2, 13545 Aix en Provence, France
Introduction: WST11 is a new compound to be used for Vascular Targeted Phototherapy (VTP) and it is expected to enable selective destruction of neovasculature with minimal side effects or skin photo toxicity.
Objectives: To describe pharmacokinetic of WST11 and perform simulations to optimise the IV infusion dosing regimen in combination with illumination, in this example, the target PK profile is being a plateau concentrations during approximately 30 minutes for ophthalmologic procedure.
Methods: The study included 42 healthy male subjects, administered 1.25, 2.5, 5, 7.5, 10 or 15 mg/kg as a 10-minute IV infusion. A population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM). Monte Carlo simulations of the population PK dataset (NONMEM) were performed to select series of dosing regimen which would result in a plateau of concentration lasting at least 30 minutes and allow laser illumination.
Results/Conclusion: A two compartment model with non-linear elimination best described the data. The clearance was shown to decreases when the dose administered increase, ranging from 6 L/h (dose of 79 mg) to 2 L/h (dose of 1110 mg). The duration of the infusion was estimated at 12 min. The volume of distribution of the central compartment was 3 L and the volume of the peripheral compartment was 1.15 L. The apparent inter-compartmental clearance was 0.137 L/h. The between subjects variability on clearance and on volume was low. Residual variability was moderate with a CV of 21%.
Due to the dose effect on clearance and the rapid elimination, simulations showed that sequential infusion with different input rate are necessary. For doses of 5 mg/kg and 10 mg/kg BW, the sequence 80% of the dose over 5 minutes, 15% over 10 minutes and the remaining 5% over 10 minutes is the best scenario. For lower doses, the sequence 70% in 5 min/ 20% in 10 min/ 10% in 10 min is preferable.
The only factor that determines the drug input profile is the dose level, since the elimination half-life decreases when the dose administered increases. The use of the population PK model for simulations has shown that, at dose level of 5 mg/kg or more, a loading dose of 80% dose given over 5 minutes followed by 15% of dose during 10 minutes and remained dose to give over 10 minutes would result in a favourable PK profile, of course different other PK regimen may be adapted according to clinical needs.
References:
[1] EMF Consulting. Selection of dosing regimen with WST11 by Monte Carlo simulations, using PK data collected after single IV administration in healthy subjects and population PK modelling. Journal of Pharmaceutical Sciences; 2007- Accepted on 27 February 2007.