Background: The VNR-PLD association proved to be an effective therapy in the treatment of metastatic ovarian carcinoma. The advantages of VNR oral formulation are the ease of administration and the reduced need for hospitalization. Previous results obtained by our group showed that the pre-administration of PLD before iv VNR raises its plasmatic levels, due to VNR reduced elimination rate. The aim of this work is to study the influence of PLD on the absorption and elimination phases of oral VNR and viceversa. Methods: 12 patients (21 cycles), affected by metastatic ovarian carcinoma, were randomized to receive oral VNR 60 mg/m2 and PLD 20 mg/m2 every 14d in one of the following schedules: VNR d1 and PLD d2 (arm A), VNR d1 and PLD d1 2 hours after VNR (arm B), PLD d1 and VNR d1 immediately after PLD (arm C). Pk parameters were evaluated by non-compartmental analysis, while statistical analysis was performed by Kruskal Wallis test. Results: VNR median Cltot was reduced by PLD pre-administration (arm A vs. C: 513 vs. 274 l/h, p=0.066), while VNR AUCtot was increased (arm A vs. C: 161 vs. 430 ng*h/ml, p=0.113). It was also observed a VNR delayed Tmax (arm A vs. C: 1 vs. 2, p=0.202). On the other hand, PLD median t/2 was decreased by VNR preadministration (arm A vs. C: 90 vs. 68 h, p=0.046). All the other pk parameters were unmodified. The trend for arm B is very similar to that found in arm A, both for VNR and PLD. Conclusions: Our data demonstrate that PLD pre-administration (arm C) can increase VNR bioavailability, as a consequence of its reduced clearance. Comparing to our previous VNR iv-PLD study, results are apparently similar but substantially different. In that case, the VNR reduced clearance was depending only on elimination rate constant reduction; in this case indeed, was not depending neither on elimination rate constant nor volume of distribution reduction.
Study of sequence-dependent pharmacokinetic interactions between oral vinorelbine (VNR) and pegylated liposomal doxorubicin (PLD) in metastatic ovarian carcinoma
CATTEL, Luigi;MILLA, Paola;
2008-01-01
Abstract
Background: The VNR-PLD association proved to be an effective therapy in the treatment of metastatic ovarian carcinoma. The advantages of VNR oral formulation are the ease of administration and the reduced need for hospitalization. Previous results obtained by our group showed that the pre-administration of PLD before iv VNR raises its plasmatic levels, due to VNR reduced elimination rate. The aim of this work is to study the influence of PLD on the absorption and elimination phases of oral VNR and viceversa. Methods: 12 patients (21 cycles), affected by metastatic ovarian carcinoma, were randomized to receive oral VNR 60 mg/m2 and PLD 20 mg/m2 every 14d in one of the following schedules: VNR d1 and PLD d2 (arm A), VNR d1 and PLD d1 2 hours after VNR (arm B), PLD d1 and VNR d1 immediately after PLD (arm C). Pk parameters were evaluated by non-compartmental analysis, while statistical analysis was performed by Kruskal Wallis test. Results: VNR median Cltot was reduced by PLD pre-administration (arm A vs. C: 513 vs. 274 l/h, p=0.066), while VNR AUCtot was increased (arm A vs. C: 161 vs. 430 ng*h/ml, p=0.113). It was also observed a VNR delayed Tmax (arm A vs. C: 1 vs. 2, p=0.202). On the other hand, PLD median t/2 was decreased by VNR preadministration (arm A vs. C: 90 vs. 68 h, p=0.046). All the other pk parameters were unmodified. The trend for arm B is very similar to that found in arm A, both for VNR and PLD. Conclusions: Our data demonstrate that PLD pre-administration (arm C) can increase VNR bioavailability, as a consequence of its reduced clearance. Comparing to our previous VNR iv-PLD study, results are apparently similar but substantially different. In that case, the VNR reduced clearance was depending only on elimination rate constant reduction; in this case indeed, was not depending neither on elimination rate constant nor volume of distribution reduction.
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