Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer (original) (raw)
Related papers
Cancer Chemotherapy and Pharmacology, 2011
Purpose The interindividual variability of vincristine pharmacokinetics is quite large, but the origins of this variability are not properly understood. The aim of this study was to develop a population pharmacokinetic model of vincristine in a paediatric population treated for solid tumour disease and evaluate the impact of diVerent ABCB1, CYP3A4 and CYP3A5 polymorphisms on the diVerent pharmacokinetic parameters. Methods We assessed vincristine pharmacokinetics in 26 children treated for various solid tumour diseases. Genotypes were determined by real-time PCR with a Light-Cycler™ and ABCB1 haplotypes calculated using the software program Phase 2.1. Vincristine plasma concentrations were determined by LC-MS/MS, and a population approach was performed on 184 samples by the NONMEM computer program. Demographic, therapeutic and genotypic covariables were evaluated on vincristine pharmacokinetic parameters. Results The frequency of CYP3A4*1A/*1A and *1A/*1B genotypes were 87.5 and 12.5%, respectively. CYP3A5*1/*3 and *3/*3 were observed in 20.8 and 79.2% of the patients, respectively. The three major haplotypes were (allelic frequencies) CGC (50%), CGT (14.6%) and TTT (23.2%). Vincristine pharmacokinetics was well described by a two-compartment model. Large interindividual and interoccasion variability were observed. The diVerent polymorphisms studied did not improve the model prediction. Conclusions CYP3A4, CYP3A5 and ABCB1 polymorphisms did not signiWcantly aVect in vivo vincristine pharmacokinetics. Our results demonstrate that vincristine pharmacokinetic variability cannot be explained by these genetic polymorphisms.
Cancer Chemotherapy and Pharmacology, 2011
Purpose The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients. Methods Women with HER2 ? locally advanced or metastatic breast cancer progressing after B2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous K. Rezai and S. Urien contributed equally to this work and are considered as first author.
Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer
European Journal of Cancer, 1997
25 patients older than 65 years with metastatic breast cancer were treated with vinorelbine 30 mglm' i.v. days 1 and 8 every 3 weeks; the pharmacokinetics were studied in 10 of them. Vinorelbine showed a large apparent volume of distribution (mean 23.4 l/kg), a long terminal half-life (mean 26.2 h) and a large systemic clearance rate (mean 1.2 l/kg). These results are similar to those reported in younger patients. No correlation has been found between toxicity, age and drug exposure. We observed 6 partial responses out of 20 evaluable patients despite a relatively low mean dose intensity (67%). Severe neutropenia occurred in 37% of the patients; other side-effects were acceptable. This study does not provide a pharmacokinetic rationale for reducing the dosage of vinorelbine in selected elderly patients.
Clinical Lung Cancer, 2007
Cisplatin-based chemotherapy is the standard treatment for advanced-stage non-small-cell lung cancer (NSCLC) in different schedules including vinorelbine, gemcitabine, paclitaxel, or docetaxel, with equivalent efficacy in terms of response and survival. 1 Intravenous (I.V.) vinorelbine has demonstrated its efficacy and tolerability as first-line chemotherapy in advanced NSCLC, whether used alone or in combination with other drugs 2-4 ; other phase II studies demonstrated its efficacy even in the second-line setting when combined with gemcitabine or docetaxel. 5,6 However, the use of I.V. vinorelbine alone in the second line is debatable. Fossella et al documented a response rate (RR) of only 0.8% at the dose of 30 mg/m 2 , with high myelosuppression that required reduction or omission of the 15-day dose. 7 Disappointing results were observed by Pronzato et al, Rinaldi et al, 9 and Furuse et al. 10 In the Pronzato et al trial, no patients (n = 15) obtained an objective response with vinorelbine 25 mg/m 2 weekly for 2 months (1 treatment-related death caused by leukopenia was reported). 8 Analogue results were reported by Rinaldi et al with vinorelbine 20 mg/m 2 on days 1 and 8 administered every 21 days. In the Furuse et al study, 10 a RR of 18.6% was obtained in 70 patients treated with vinorelbine 20-25 mg/m 2 weekly, but all the responses Abstract PURPOSE: Intravenous vinorelbine has demonstrated its efficacy and tolerability in advanced non-small-cell lung cancer (NSCLC). An oral formulation of vinorelbine has been developed, and a number of phase II studies have shown its activity in chemotherapy-naive NSCLC, even in elderly patients, but no study has been performed to test activity and toxicity of oral vinorelbine in pretreated patients. The aims of our study were to investigate the activity and toxicity of oral vinorelbine in patients with NSCLC as salvage treatment. PATIENTS AND METHODS: Twenty pretreated patients with locally advanced (n = 6) and metastatic (n = 14) NSCLC entered the study. The schedule was oral vinorelbine 60 mg/m 2 once a week until progression or development of unacceptable toxicity. Median age was 70 years (range, 49-84 years). RESULTS: Seventeen patients were evaluable for response and all for toxicity. A median of 9 cycles were administered (range, 2-21 cycles). No objective responses were reported, 5 patients experienced stable disease, and 12 patients had progressive disease. Median time to progression was 2 months (range, 1-6 months), and median survival was 4 months (range, 1-13 months). Treatment was well tolerated, with grade 4 neutropenia in 1 patient (heavily pretreated); grade 2 diarrhea in 2 patients; asthenia in 2 patients; and abdominal pain in 1 patient. CONCLUSION: Oral vinorelbine 60 mg/m 2 once a week is a very safe schedule in heavily pretreated locally advanced and metastatic NSCLC; however, at this dose, the drug is inactive. Other phase II studies with oral vinorelbine 80 mg/m 2 weekly are warranted.
Annals of Oncology, 2005
A phase I study was performed to determine the maximal tolerated dose, recommended doses (RDs), safety and efficacy of oral vinorelbine when combined with capecitabine in an all-oral chemotherapy regimen in patients with metastatic breast cancer (MBC), with pharmacokinetic blood sampling to investigate potential drug-drug interactions. Patients and methods: Forty-four patients with MBC received as first-or second-line chemotherapy, oral vinorelbine at a dose of 60 or 80 mg/m 2 on days 1 and 8 (and 15) with escalating doses of capecitabine from 1650 to 2500 mg/m 2 /day days 1-14 every 3 or 4 weeks. Three schedules were tested: day 1, day 8 and weekly regimens of oral vinorelbine with a 14-day course of capecitabine every 3 weeks; and a days 1 and 8 regimen of oral vinorelbine with a 14-day course of capecitabine every 4 weeks. Results: With oral vinorelbine at 60 mg/m 2 , the RDs were established as oral vinorelbine 60 mg/m 2 on days 1 and 8 plus capecitabine 2250 mg/m 2 /day days 1-14 and oral vinorelbine 60 mg/m 2 /week plus capecitabine 2000 mg/m 2 / day days 1-14. With oral vinorelbine at 80 mg/m 2 , the RD was oral vinorelbine 80 mg/m 2 on days 1 and 8 plus capecitabine 2000 mg/m 2 /day days 1-14. Neutropenia was the main dose-limiting toxicity of the combination; it was reported in 40 patients (90.9%), with grade 3 in 14 patients (31.8%) and 6.2% of cycles, and grade 4 in 12 patients (27.3%) and 4.3% of cycles. Complications were rare with only three patients experiencing febrile neutropenia (one episode each). The most frequent non-haematological toxicity was gastrointestinal; however, the incidence of grade 3 was low, with no episode of grade 4. Hand-foot syndrome was reported in 14 patients (31.8%) and 22.6% of cycles, with grade 2 in two patients (4.5%) and 1.2% of cycles (two episodes each). No episode of grade 3 was observed. Objective responses were reported in 18 patients (three complete responses and 15 partial responses), yielding a response rate of 40.9% in the intention-to-treat population according to the investigator assessment. Results from the pharmacokinetic study demonstrated the absence of mutual pharmacokinetic interactions when both drugs were co-administered. Conclusions: The combination of oral vinorelbine and capecitabine is safe and easy to administer in an outpatient setting. This all-oral combination chemotherapy may offer a good alternative to the intravenous route for patients with MBC. Based on these promising results, a phase II study has started using oral vinorelbine 60 mg/m 2 /week with capecitabine 2000 mg/m 2 /day days 1-14 every 3 weeks as first-line chemotherapy in patients with MBC.
Cancer, 1999
BACKGROUND. Vinorelbine given by weekly bolus injection is active and less toxic than bolus vinblastine in the treatment of patients with metastatic breast carcinoma. Vinblastine given by 5-day continuous infusion showed a steep doseresponse curve. Pharmacokinetic studies of vinorelbine showed that it is possible to achieve a comparable antitumor effect with a smaller amount of the drug if it is given by continuous infusion. The purpose of this study was to determine the efficacy of vinorelbine given by 96-hour continuous infusion to patients with refractory metastatic breast carcinoma patients.
The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine
Drug Metabolism and Disposition, 2013
Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b 5 (CYP3A4+b 5) and CYP3A5 +b 5 , the Michaelis-Menten constants for vinorelbine were 2.6 and 3.6 mM, respectively, but the V max of 1.4 pmol/min/pmol was common to both enzymes. In HLMs, the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity, and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b 5 and CYP3A5+b 5 as determined by NMR and mass spectrometry analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b 5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.
Oral vinorelbine: feasibility and safety profile
Annals of Oncology
Patient preference as well as concerns and difficulties with intravenous access and pharmaco-economic issues have driven the development of oral vinorelbine. Four phase II studies were conducted in chemotherapy-naive non-small-cell lung cancer (NSCLC) and as first-line chemotherapy of advanced breast cancer (ABC). As recommended in the phase I dose-finding study, the first step used a weekly dose of 80 mg/m2. This regimen was associated with an excessive rate of early deaths (10%) due to complicated neutropenia and led to discontinuation of the first two studies. In a second step, the dose of 60 mg/m2/week was given for the first three courses and subsequently increased to 80 mg/m2/week, in the absence of severe neutropenia. One hundred and thirty eight patients (76 with NSCLC and 62 with ABC) received this regimen, of whom only five were unable to undergo dose escalation. The incidence of febrile neutropenia and neutropenic sepsis were low (2.9 and 3.6%, respectively). Although sev...
Pharmacokinetics of vindesine and vincristine in humans
Cancer research, 1977
Vindesine, a new Phase 1 Vinca alkaloid congener, exhibited serum pharmacokinetic behavior in humans compatible with a three-compartment, open mammilary model. The kinetic parameters included: t1/2 alpha=3.24+/-1.14 min, t1/2beta=99.0+/-44.5 min, t1/2gamma=1213+/-493 min, Vc (Valpha)=4.81+/-2.12 liters, Vbeta=58.2+/-50.5 liters, Vgamma=598+/-294 liters. Vincristine, studied only for the first 4 hr, behaved like a two-compartment system, with values of t1/2 alpha=3.37+/-0.72 min, t1/2beta=155+/-18 min, Valpha=4.53+/-0.49 liters, and Vbeta=57.3+/-21.1 liters. Urine excretion data demonstrated that most drug elimination occurred within the first 24 hr and amounted to 13.2+/-5.9% for vindesine and 9.5+/-5.1% for vincristine.
A phase I and pharmacokinetic study of liposomal vinorelbine in patients with advanced solid tumor
Investigational New Drugs, 2012
Purpose This phase I study was performed to determine the maximum tolerated dose (MTD) and doselimiting toxicity (DLT) of an untargeted liposomal formulation of vinorelbine (NanoVNB®) and to characterize its plasma pharmacokinetics in patients with advanced solid tumors which were refractory to conventional treatment or without an effective treatment. Patients & methods The study incorporated an accelerated titration design. Twentytwo patients with various solid tumors were enrolled. NanoVNB ® was administered intravenously at doses of 2.2-23 mg/m 2 once every 14 days. Pharmacokinetic endpoints were evaluated in the first cycle. The safety profiles and anti-tumor effects of NanoVNB® were also determined. Results Skin rash was the DLT and the most common non-hematological toxicity. The MTD was 18.5 mg/m 2 . Drug-related grade 3-4 hematological toxicities were infrequent. Compared with intravenous free vinorelbine, NanoVNB® showed a high C max and low plasma clearance. Of the 11 patients completing at least 1 post-treatment tumor assessment, 5 had stable disease. No responders were noted. Conclusion NanoVNB® was well tolerated and exhibited more favorable pharmacokinetic profiles than free vinorelbine. Based on dose-limiting skin toxicity, further evaluation of NanoVNB® starting from 18.5 mg/m 2 as a single agent or in combination with other chemotherapeutic agents for vinorelbine-active malignancies is warranted.