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>Limited Sampling Strategies for Investigating Paclitaxel Pharmacokinetics in Patients Receiving 175 mgsol;m2as a 3-Hour Infusion
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Limited Sampling Strategies for Investigating Paclitaxel Pharmacokinetics in Patients Receiving 175 mgsol;m2as a 3-Hour Infusion
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机译：Limited Sampling Strategies for Investigating Paclitaxel Pharmacokinetics in Patients Receiving 175 mgsol;m2as a 3-Hour Infusion
Results from a randomised European-Canadian trial showed that paclitaxel 175 mgsol;m2infused as a 3-hour infusion is recommended in patients with platinum-refractory ovarian cancer. We assessed limited sampling models for relevant paclitaxel pharmacokinetic parameters using stepwise forward multiregression analysis for both area under the plasma concentration versus time curve from time 0 to 27 hours (AUC) and the time above a plasma threshold concentration of 0.1 mu;molsol;L (Tge;0.1 mu;molsol;L) for the 3-hour infusion of 175 mgsol;m2. These strategies will be incorporated into future studies investigating pharmacokineticsol;pharmacodynamic relationships of paclitaxel, using this dose and schedule. 24 pharmacokinetic curves were investigated from 24 patients with ovarian cancer treated with paclitaxel. 13 curves were selected by computer randomisation for the development of the model and the other 11 curves were used for the validation of the developed strategy. All patients received paclitaxel during a 3-hour infusion at a dosage of 175 mgsol;m2. Both pharmacokinetic parameters of interest, AUC and Tge;0.1 mu;molsol;L, could be predicted adequately with a 2-sample point model. This 2-point model, selected as optimal for the determination of the Tge;0.1 mu;molsol;L, was:Tge;0.1 mu;molsol;L (h) equals; minus;4.11 (h middot; mu;molsol;L) middot; C1h(mu;molsol;L) plus; 68.53 (h middot; mu;molsol;L) middot; C8h(mu;molsol;L) plus; 8.579 (h)Using the best 2-point model for Tge;0.1 mu;molsol;L, a 2-point model was developed for estimating the AUC:AUC (mu;molsol;L middot; h) equals; 5.49 (h) middot; C1h(mu;molsol;L) plus; 12.88 (h) middot; C8h(mu;molsol;L) plus; 6.312 (mu;molsol;L middot; h)where C1his the plasma concentration of paclitaxel at 1 hour after the end of a 3-hour infusion and C8his the paclitaxel concentration at 8 hours after the end of the infusion.Both models are predictive for Tge;0.1 mu;molsol;L (r2equals; 0.91) and AUC (r2equals; 0.92), and proved to be unbiased and precise for Tge;0.1 mu;molsol;L with a relative mean predictive error (MPEpercnt;) of minus;0.08 plusmn; 1.94percnt;, and a relative root mean square error (RMSEpercnt;) of 6.2percnt; and for the estimation of the AUC (MPEpercnt; equals; minus;0.94 plusmn; 2.49percnt;, RMSEpercnt; equals; 7.9percnt;).For patients treated with paclitaxel at a dose of 175 mgsol;m2given by a 3-hour infusion, the Tge;0.1 mu;molsol;L and the AUC of paclitaxel can be adequately estimated from two of the same timed plasma concentrations (C1hand C8h). These limited sampling strategies may greatly accelerate future studies on pharmacokineticsol;pharmacodynamic relationships of paclitaxel in patients treated with 175 mgsol;m2of the drug given as a 3-hour infusion.
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