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Purpose: This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment., Methods: Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m(2) weekly., Results: Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m(2)) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m(2) and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m(2) allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug-drug interactions., Conclusions: Afatinib 40 mg QD plus vinorelbine 25 mg/m(2) weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients.

Background: Vinflunine (VFL) is a bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with epirubicin (EPR) to establish the recommended dose (RD), to evaluate the safety and efficacy profiles and to investigate potential pharmacokinetic (PK) drug-drug interaction (DDI)., Patients and Methods: Two schedules (day 1 every 3 weeks; days 1 and 8 every 3 weeks) were investigated as first-line chemotherapy of metastatic breast cancer patient. PK DDI was evaluated through population PK approaches., Results: Thirty-nine patients received a total of 197 cycles of the VFL-EPR combination (median 6). The RDs were VFL 250 mg/m(2) + EPR 75 mg/m(2) every 3 weeks for schedule 1 and VFL 170 mg/m(2) + EPR 35 mg/m(2) every 3 weeks for schedule 2. The PK analysis demonstrated no clinically relevant mutual DDI between VFL and EPR. The main dose-limiting toxicity was neutropenia. The most frequent non-haematological adverse events were nausea, fatigue, constipation, vomiting, anorexia and stomatitis. Objective response rate was achieved in 45.9 % of the patients., Conclusion: VFL-EPR combination is feasible with manageable toxicity. The antitumour activity was promising and supports further evaluation.

Background: Erlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug-drug interaction was also investigated., Patients and Methods: Patients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg., Results: Thirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease., Conclusion: The recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.

Objective: To determine the recommended dose (RD) of vinflunine in combination with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and to investigate potential pharmacokinetic (PK) interactions., Patients and Methods: In the first part of the study, two dose levels of vinflunine given every 3 weeks were explored (280 and 320 mg/m(2)) combined with trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly). For each level of dose, six patients were enrolled to determine the RD for phase 2 studies (RP2S). In the second part of the study, 18 additional patients at RP2S have been evaluated to confirm safety and investigate preliminary antitumor activity., Results: The RD was 320 mg/m(2) according to the dose escalation plan. Eleven of 15 additional patients who received this dose experienced dose-limiting toxicities, leading to a reduction in the RD to 280 mg/m(2). When compared to prior trials when vinflunine was used as a single agent, neither vinflunine total blood clearance nor trastuzumab serum concentrations were modified when the drugs were combined. All patients were evaluable, and the overall response rate was 73.3 % (95 % CI 54.1-87.7). The median progression-free survival was 11.3 months (95 % CI 9.4-21.0). At the dose of 280 mg/m(2), grade 3-4 neutropenia were seen in 4 patients (44.4 %) without febrile neutropenia. Non-hematologic grade 4 toxicities were not reported while grade 3 peripheral sensory neuropathy concerned 2 patients (22.2 %)., Conclusion: The RD of vinflunine in combination with the standard regimen of trastuzumab is 280 mg/m(2) every 3 weeks. No mutual PK drug-drug interaction was seen. This regimen appears to be active with a favorable safety profile. Its role in HER2-positive MBC treatment needs to be defined in prospective comparative clinical trials.

Background: Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe., Methods: In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations., Results: Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%., Conclusion: Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.

Purpose: A phase I study was performed to determine the maximal tolerated dose (MTD), recommended dose (RD), safety and efficacy of vinflunine when combined with capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes, with pharmacokinetic blood sampling to test potential drug-drug interactions., Patients and Methods: Sixteen patients with MBC who had received anthracyclines and taxanes in the neo/adjuvant setting, if progression occurred during or within 12 months of chemotherapy completion, and/or as first-line chemotherapy of MBC were enrolled. Vinflunine (VFL) was given on day 1 with capecitabine (CAPE) twice daily from days 1 to 14, every 3 weeks. Three dose levels (DL) were investigated (DL1: VFL 280 mg/m² and CAPE 1,650 mg/m²/day, DL2: VFL 320 mg/m² and CAPE 1,650 mg/m²/day and DL3: VFL 280 mg/m² and CAPE 2,000 mg/m²/day)., Results: The RD was established as vinflunine 280 mg/m² on day 1 plus capecitabine 1,650 mg/m²/day on days 1 to 14 given every 3 weeks. Dose-limiting toxicities were grade 4 neutropenia lasting at least 7 days for 2 patients, anorexia with fatigue for 1 patient and diarrhoea with fatigue, anorexia and febrile neutropenia for 1 patient. Neutropenia was the main toxicity of the combination, it was reported in 15 patients (93.8%) with grade 3 in 7 patients (43.8%) and 22.6% of cycles and grade 4 in 7 patients (43.8%) and 19.8% of cycles. Complications were rare with only one patient experiencing febrile neutropenia at DL exceeding the RD. The most frequent non-haematological toxicities were fatigue and gastrointestinal disorders; however, no grade 3 or 4 episode was observed at the RD. Hand-foot syndrome was reported in 5 patients (31.3%) and 22.6% of cycles, no episode of grade 3 was seen. Concerning pharmacokinetics, no modifications were detected for VFL, while slight accumulation between days 1 and 14 was observed for 5-FU formed from CAPE. The risk of clinical significant drug-drug interaction was considered weak. Objective partial responses were reported in 7 patients, yielding a response rate of 43.8% in the all-treated population according to the investigator assessment., Conclusions: The combination of vinflunine and capecitabine is safe and showed promising antitumour activity in MBC patients who have failed prior anthracyclines and taxanes. Further clinical development of this combination is warranted.

Purpose: This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin(®)) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination., Methods: Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m(2) on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m(2) weekly. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2-4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods., Results: Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents., Conclusions: Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

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 ≤ 2 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 schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m(2))] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib + vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a non-linear mixed effect model program (Monolix version 3.1 s)., Results: A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote inter-compartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h(-1). The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib., Conclusions: The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m(2) D1 & D8.

Purpose: Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo., Methods: The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo., Results: Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t (1/2) = 9.7 h) relative to vincristine (t (1/2) = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine., Conclusions: These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized.

Patient's preference is for oral chemotherapy when both oral and i.v. are available, provided that efficacy is equivalent. Reliable switch from oral to i.v. is possible if correspondence between respective doses has been established. Vinorelbine oral was developed as a line extension of VRL i.v. on the basis that similar AUCs result in similar activities. From a first crossover study on 24 patients receiving VRL 25 mg/m2 i.v. and 80 mg/m2 oral data extrapolation concluded on AUCs bioequivalence between Vinorelbine 30 mg/m2 i.v. and 80 mg/m2 oral. A new trial was performed to support this calculation. In a crossover design study on patients (PS 0-1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 i.v., 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Forty-eight patients were evaluable for PK: median age 58 years (25-71), PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1,230 +/- 290 and 1,216 +/- 521 ng/ml for i.v. and oral, respectively. The confidence interval of the AUC ratio (0.83-1.03) was within the required regulatory range (0.8-1.25) and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 +/- 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3-4). This new study, conducted on a larger population, confirmed the reliable dose correspondence previously established between vinorelbine 80 mg/m2 oral and 30 mg/m2 i.v.

Purpose: Aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist approved for the treatment and prevention of emesis caused by moderately and highly emetogenic chemotherapy, is an inhibitor, inducer, and substrate of the cytochrome P450 3194 pathway. The CYP3A4 pathway is the major pathway of the metabolism of vinorelbine, a vinca alkaloid frequently used in combination with cisplatin. Therefore, we studied the potential interaction of the aprepitant 3-day antiemetic regimen on the pharmacokinetics of vinorelbine., Patients and Methods: Fourteen patients with metastatic solid tumors were included in this open-label, balanced, 2-period crossover study. In treatment arm A, vinorelbine (25 mg/m2 weekly) was administered alone, while in treatment arm B the same dose of vinorelbine was administered following the administration of the aprepitant antiemetic regimen on day 1 and alone on day 8. The antiemetic regimen of aprepitant was comprised of the following; on day 1: 125 mg aprepitant, 12 mg dexamethasone, and 32 mg ondansetron; on days 2 and 3: 80 mg aprepitant and 8 mg dexamethasone and on day 4: 8 mg dexamethasone. Blood samples for vinorelbine pharmacokinetic analysis were collected over 96 h., Results: Two patients discontinued the study due to adverse events that were judged not to be drug-related. Complete pharmacokinetic data of vinorelbine administered alone and with the aprepitant antiemetic regimen were obtained in 12 patients. The mean plasma concentration profile of vinorelbine administered with aprepitant was identical to that following vinorelbine administered alone, with geometric mean vinorelbine plasma AUC ratios of treatment B day 1/treatment A day 1 and of treatment B day 8/treatment A day of 1.01 (0.93, 1.10) and 1.00 (0.92, 1.08), respectively., Conclusion: As the aprepitant antiemetic regimen has no detectable inhibitory or inductive effect on the pharmacokinetics of vinorelbine, aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone can be safely combined with vinorelbine at clinically recommended doses.

The purpose of the study is a presentation of a fatal case involving an 83-year-old woman, who died due to an overdose of vinblastine-a cytostatic agent of a vinca alkaloid employed in cancer chemotherapy. The postmortem investigation included an autopsy and histological examination, as well as a toxicological analysis of post-mortem specimens collected in the course of autopsy. The authors performed a toxicological assessment of vinblastine employing liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (LC-MS-MS-APCI). The determined vinblastine concentration levels amounting to 29 ng/g in blood and 52.5 ng/g in liver were in a considerable excess of values encountered in patients on chemotherapy using the drug. The fatality was investigated in the context of medical error. In the described case, the erroneous and medically unjustified administration of vinblastine was identified by a series of unfortunate events involving as many as three acting consecutively individuals: a physician, a pharmacist and a nurse. The report may thus document the clinical course of vinblastine poisoning along with postmortem changes resulting from the drug action.

Purpose: This study sought to determine the maximum tolerated dose of flat-dosed vinorelbine in combination with capecitabine in patients with metastatic breast cancer. At the time of study initiation, it was anticipated that vinorelbine would be developed as an oral capsule. A flat dosing scheme of both drugs was used to facilitate development of the oral regimen, and because neither drug's clearance is associated with body surface area (BSA), pharmacokinetic and pharmacogenetic endpoints were explored., Experimental Design: Capecitabine was administered orally at 3,000 mg/day on days 1-14. The starting dose of vinorelbine was 20 mg intravenously on days 1 and 8 of a 21-day cycle. The vinorelbine dose was escalated until dose limiting toxicity (DLT). Vinorelbine pharmacokinetics were measured after the first dose. Patients underwent genotype analysis for polymorphisms in the CYP3A5 gene, and the erythromycin breath test (ERMBT), a phenotypic test of CYP3A enzyme activity., Results: Twenty five eligible patients were enrolled. Hematologic DLT was seen at the 50 and 45 mg vinorelbine doses; thus the recommended dose is 40 mg on days 1 and 8. Response rate was 30%, and disease stabilization rate was 64% (all dose levels included). Vinorelbine clearance was not associated with ERMBT, BSA, or age. CYP3A5 genotype in this small sample did not have an obvious relationship to clearance or toxicity., Conclusions: A non-BSA based dosing scheme of capecitabine and vinorelbine is safe and efficacious. BSA did not affect vinorelbine clearance. We recommend future studies with capecitabine and/or vinorelbine to compare the safety and efficacy of flat dosed versus BSA-dosed treatment.

Purpose: This study was designed to determine the effects of P-glycoprotein (P-gp) and cytochrome P450 3a metabolism on the oral bioavailability of the vinca alkaloid Vinorelbine (Navelbine; VRL)., Methods: Pharmacokinetics of VRL were determined in FVB wild-type and mdr1a/1b (-/-) mice after oral and intravenous administration of 10 mg/kg VRL with or without oral ritonavir (5 mg/kg) prior to VRL. Serial blood samples were drawn for a period of up to 48 hours using mice with a cannulated jugular vein. Feces was collected for a period of 96 hours. VRL was determined by ion-exchange HPLC in combination with fluorescence detection., Results: The oral bioavailability in wild-type was 16.0+/-1.4% (mean+/-SE) and was not significantly higher in mdr1a/1b (-/-) mice (17.9+/-0.7%). Both after intravenous and oral administration, the AUC was not significantly different between wild-type and mdr1a/1b(-/-) mice. When RTV was co-administered the AUC of intravenous VRL increased significantly by 30% (p = 0.012). Because RTV increased the AUC of oral VRL by 83% the oral bioavailability was increased to 22.5+/-2.3% (p = 0.016). The fecal recovery of unchanged VRL was about 34 and 6% of the dose in wild-type and mdr1a/1b(-/-) mice, respectively, and was not altered by RTV., Conclusion: This study shows that P-gp has little effect on the disposition and oral bioavailability of VRL. A substantial fraction of an oral dose of VRL is absorbed from the gut of wild-type mice. Consequently, first-pass metabolism is the most important factor for explaining the modest oral bioavailability, but the results with RTV suggest that cyp3a plays only a modest role in metabolic breakdown in mice. Apparently, other routes of metabolic elimination are more important. These results suggest that also in patients the oral bioavailability may not gain substantially from the co-administration of a potent P-gp and/or Cyp3a inhibitor.

Unlabelled: Due to advances in the methods used to quantitate vinorelbine, this study was conducted to characterize fully the bioavailability of an oral dosage form of vinorelbine. Twenty-seven eligible patients with solid tumors were enrolled onto this study and were treated in a randomized crossover design to receive either 70 mg/m2 orally or 30 mg/m2 intravenously followed by the alternative treatment one week later. Vinorelbine was administered orally as a soft-gelatin capsule. Pharmacokinetic sampling was carried out for 7 days following each dose. Whole blood vinorelbine concentrations were measured using a sensitive LC/MS/MS method. The data from patients were excluded if they vomited within 3 h after the oral dose., Results: Three subjects were removed from study following the first dose due to safety reasons. Of the remaining 24 subjects, five experienced vomiting within 3 h of oral dosing. Total body clearance calculated from the intravenous dose was 43.65 L/h (+/-10.9) and the terminal half-life was estimated to be 49 h. Using complete data from the remaining 19 subjects, the mean absolute bioavailability of the oral dosage formulation of vinorelbine was calculated to be 33% (+/-18%). In conclusion we have characterized the pharmacokinetics of both orally administered and intravenous vinorelbine over 7 days after administration and have determined the mean oral bioavailability of this oral formulation to be 33%.

As pharmacokinetics represents a bridge between pharmacological concentrations and clinical regimens, the pharmacokinetic exploration of the therapeutic dose range is a major outcome. This study was aimed at assessing pharmacokinetic linearity of i.v. vinorelbine through an open design with intra-patient dose escalation (3 doses/group). Three groups of six patients received either 20-25-30 mg/m2; or 25-30-35 mg/m2; or 30-35-40 mg/m2. The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25-75 years, WHO PS < or =2, normal haematology and biochemistry, life expectancy > or =3 months. The pharmacokinetics was evaluated in both whole blood and plasma over 120 h. Twenty-six patients were recruited and 18 were evaluable for pharmacokinetics. The toxicity consisted in grade < or =3 leucopenia and neutropenia (<20% of courses) and two grade 4 constipation with rapid recovery (2/54 courses). Compared to blood, plasma was demonstrated to underestimate the pharmacokinetic parameters. In blood, the drug total clearance was about 0.6 l/h/kg, with minor contribution of renal clearance, steady state volume of distribution close to 13 l/h/kg, and elimination half-life at about 40 h. A pharmacokinetic linearity was demonstrated up to 40 mg/m2, and even up to 45 mg/m2 when pooling data from another study. A pharmacokinetic-pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.

Purpose: To develop a population pharmacokinetic model of vinorelbine administered by short intravenous infusion in metastatic breast cancer patients., Methods: Vinorelbine was administered as infusions of 5-10 min at 15, 20 or 25 mg/m(2) to 30 patients. Blood samples were collected over 18 h. Plasma concentrations of vinorelbine were determined by HPLC. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method., Results: Vinorelbine concentration-time profiles were best described by a three-compartment open model. Plasma clearance (CL) was high and positively related to lean body weight (LBW) and body surface area (BSA) or to a combination of height and body weight (BW). Elevated serum alkaline phosphatases had a negative effect on CL. Typical population estimates of CL and central distribution volume (V(1)) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V(1) were 17.0% and 32.0%, respectively. The stability and predictive performance of the final population pharmacokinetic model were assessed using 200 bootstrap samples of the original data., Conclusion: This study identified combined effects of BSA and serum alkaline phosphatases on clearance. These results partly support the conventional dose adjustment of vinorelbine based on BSA, but suggest dose modification in cases of extreme values of serum alkaline phosphatases.

Purpose: Anhydrovinblastine (AVLB) is a novel semisynthetic vinca alkaloid. We conducted a phase I trial to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacokinetics of AVLB given as a 1-h intravenous infusion once every 3 weeks in patients with advanced refractory solid tumors., Patients and Methods: Entered into the study were 24 patients with normal bone marrow, hepatic and renal function, and of these 21 were evaluable. There were 12 males and 12 females with a median age of 60 years (range 27-75 years). Diagnoses were non-small-cell lung cancer (NSCLC) (11), colorectal cancer (5), soft tissue sarcoma (4), and miscellaneous (4). Patients had had a median of three prior chemotherapy regimens (range one to six). A total of 51 courses were administered at doses of 2.5, 5, 10, 16.5, 21, 25 and 30 mg/m(2) in one, three, one, three, six, six and one patient respectively., Results: Grade 2 infusional hypertension, anemia, and dizziness were noted at 16.5 mg/m(2). At 25 mg/m(2), two of six evaluable patients had DLT. DLT was grade 4 constipation, neutropenia and grade 3 nausea/vomiting. At 21 mg/m(2) one of six evaluable patients had DLT (grade 3 nausea/vomiting). This dose was the MTD. Stable disease was noted in one patient with metastatic sarcoma to the lungs and in three patients with metastatic NSCLC. The pharmacokinetics of AVLB were linear, and well characterized by a two-compartment model, with a mean clearance of 26.4 l/h per m(2) and median terminal half-life of 18 h., Conclusions: The recommended phase II dose is 21 mg/m(2). A phase II study in NSCLC is being initiated.

Purpose: Preclinical data indicate that progestational agents (progesterone, medroxyprogesterone acetate and megestrol acetate) interact with p-glycoprotein (P-gp) and reverse P-gp-associated resistance to vinca alkaloids and other natural products. Based on these data, we performed a phase I study of high-dose oral megestrol acetate and vinblastine to evaluate the safety of this regimen., Patients and Methods: Enrolled in the study were 61 patients with advanced solid tumors, refractory to standard therapy. Cohorts of patients received megestrol acetate according to the following escalation scheme (loading dose/maintenance dose, twice daily for 7 days): 750 mg/250 mg, 750 mg/375 mg, 1000 mg/500 mg, 1500 mg/1000 mg, 3000 mg/2000 mg, 4500 mg/3000 mg, 6000 mg/4000 mg, and 7500 mg/5000 mg. They also received 1.5 mg/m(2) per day of vinblastine by continuous infusion for 5 days (days 2 to 6)., Results: Of the 61 patients, 59 were evaluable for toxicity. A maximum tolerated dose (MTD) was not reached. The regimen was well tolerated. Of the 59 patients, 10 (17%) experienced grade 4 leukopenia. All of these cases were at dose levels 3 to 8. There was an increase in the steady-state concentration (Css) of megestrol acetate with increasing dose up to the sixth dose level. Further increases in the dose produced no change in the megestrol acetate Css. Only 2.4% of megestrol acetate was free in the plasma as compared to 65.6% in RPMI culture medium. Megestrol acetate administration was associated with profound suppression of ACTH and cortisol levels., Conclusions: The combination of vinblastine and megestrol acetate was well tolerated. An MTD for this combination was not achieved as a result of the saturable absorption of megestrol acetate. Although potentially therapeutic serum concentrations of megestrol acetate were achieved, it is unlikely that MDR was reversed given the high protein-binding of the drug. Profound suppression of the pituitary-adrenal axis was also observed during the administration of megestrol acetate.

Purpose: As vinorelbine is 78% bound to platelets, it seems interesting to investigate the pharmacokinetic profile of this drug from blood and to compare it to that determined from plasma. Thus, in this study, the comparative blood/plasma pharmacokinetics of vinorelbine were investigated in 15 elderly patients with advanced metastatic cancer., Methods: The drug was given as a short (10 min) peripheral intravenous infusion; the administered dose ranged from 20 to 30 mg/m2 depending on the patient. Chemotherapy was repeated weekly. During the first and the fifth courses, each patient underwent pharmacokinetic evaluation. Toxicity evaluation was performed after each course of chemotherapy; a total of 109 courses was studied. Plasma and blood vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorimetric detection. Individual pharmacokinetic parameters were estimated with an empirical Bayes methodology. An open three-compartment pharmacokinetic model was used to describe the kinetics of vinorelbine., Results: The half-lives of the terminal part of the curves, determined from blood and plasma data, were of the same order of magnitude: 31-35 h. Mean total clearances were about 0.71 l/h/kg from plasma and 0.45 l/h/kg from blood. Except during the first 15-20 min following the end of infusion, vinorelbine concentrations were 1.9 times higher in blood than in plasma. The ratio AUC(B)/AUC(P) (AUC(B) and AUC(P) are the area under the concentration-time curve from blood and plasma data, respectively) averaged 1.7; it was comparable to the blood/plasma ratio of 1.6 that remained constant over the 72 h of the study. There was substantial intra- and interpatient variability in vinorelbine pharmacokinetic parameters. This variability is similar within and between patients, and between pharmacokinetic parameters computed from blood and plasma. The elimination half-life is the parameter with the lowest intra- and interindividual variability (10-14%), while the AUC is the parameter presenting the highest variability (20-65%). The main haematological toxicity was anaemia (12 patients) and neutropenia (10 patients). Thrombocytopenia occurred in only one patient. At the first cycle, significant correlations were found between AUC(B) and AUC(P) and the decrease in neutrophil count (P < 0.05). The highest haematological toxicities encountered in this study occurred in patients presenting the lowest platelet count. AUC computed from plasma data decreased significantly with the increase of platelet count (P = 0.03)., Conclusion: From the results of this study, blood did not appear to be a better predictor of haematological toxicity than plasma, but the decrease of platelet count seems to be a good predictor of this toxicity. Indeed, changes in platelet count are likely to produce strong variations in the unbound fraction of vinorelbine; this exposes the patient to a high risk of toxicity.

Purpose: Vinflunine (20'-20'-difluoro-3',4'-dihydrovinorelbine), a novel derivative of vinorelbine characterized by marked antitumour activity in vivo in a series of experimental murine and human tumours is currently undergoing phase I evaluation. To investigate its potential for inclusion in combination chemotherapy regimens, this preclinical study was undertaken. The in vitro cytotoxicity of vinflunine incubated simultaneously with one of the following drugs was investigated: camptothecin, cisplatin, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, mitomycin C, paclitaxel or vinorelbine., Methods: The combinations were first evaluated in vitro against the A549 human non-small-cell lung cancer cell line using median-effect analyses., Results: The results revealed synergistic cytotoxicity when vinflunine was combined with cisplatin, mitomycin C, doxorubicin or 5-fluorouracil. Synergy was also observed when testing similar combinations against CCRF-CEM human leukaemia cells. Finally, these findings were comparable with those resulting from such combinations involving vinorelbine instead of vinflunine., Conclusion: Vinflunine appears a promising candidate for combining with other anticancer drugs.

The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22 +/- 28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3 +/- 1.6 h in the fasting state to 2.5 +/- 1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16 +/- 51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity.

We determined the kinetic parameters that describe the effect of 20 different modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells (P388/ADR), and on the reversal of cell killing for these cells. When measured by a direct comparison of the amplitude of the pertinent protocol (accumulation or cell killing), the Ki for reversal of accumulation was generally some four or five times larger than that for reduction of cytotoxicity. We showed that this was only an apparent discrepancy, since a full theoretical analysis of the two protocols allowed the intrinsic Ki to be obtained for the two procedures and these computed Ki values were then almost identical. We found that for six of the modulators studied (namely, cyclosporin A, quinidine, dipyridamole, propafenone, mefloquine, tamoxifen) the extent of pump reversal should be better than 90% at tolerated plasma levels culled from the literature.

Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m2) and vinblastine (4 mg/m2) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml-1 min.

We investigated the pharmacokinetics of the experimental semisynthetic vinca alkaloid vinleucinol (VileE; O4-deacetyl-3-de(methoxycarbonyl)-3-[[[1-ethoxycarbonyl-2- methylbutyl]amino]carbonyl]-vincaleukoblastine). The study was performed in male FVB mice receiving 10.5 mg/kg VileE i.v. or p.o. Plasma, urine, faeces and tissue samples were analysed by a selective method based on ion-exchange normal-phase high-performance liquid chromatography (HPLC) with fluorescence detection and liquid-liquid extraction for sample clean-up. Apart from the parent drug, two other metabolic compounds were detected. One of these metabolites is vinleucinol acid (VileA; O4-deacetyl-3-de(methoxycarbonyl)-3-[[[1-carboxyl-2- methylbutyl]amino]carbonyl]-vincaleukoblastine), which possesses no cytotoxic activity. The structure proposed for the second metabolite (VileX) was based on tandem mass spectrometry (MS-MS) and infrared (IR) spectroscopy data. Metabolization of VileE to VileX must occur in the amino acid moiety of the molecule, with a (beta- or gamma-) lactone ring being formed after oxidation of the (beta- or gamma) carbon of the amino acid. VileX is a major metabolite, which is excreted in faeces and urine after i.v. administration and accounting for up to 23% of the administered dose. The activity of VileX against cultured L1210 cells is four times that of the parent drug VileE and comparable with that of vinblastine (VBL). At 48 h after administration of VileE, the concentration of VileX exceeds that of the parent drug in many tissues. These findings indicate that the metabolite VileX may be at least largely responsible for the activity observed against xenografts in mice after administration of the parent drug, VileE.

The ability of the multidrug resistance modifiers R- and R,S-verapamil (VPL), cyclosporine A (CsA) and its non-immunosuppressive derivative SDZ PSC 833 (PSC 833) to inhibit P-glycoprotein (P-gp)-mediated transepithelial flux of tritiated vinblastine was investigated using tight and highly resistant (R > 1,400 omega cm2) monolayer cultures of intestinal adenocarcinoma-derived HCT-8 cells grown on permeable tissue-culture inserts. Apical addition of these chemosensitizers inhibited drug flux (137 pmol h-1 cm-2; range, 133-142 pmol h-1 cm-2) in the basal to apical secretory direction at clinically relevant concentrations, with PSC 833 showing the highest activity, exhibiting inhibition at concentrations as low as 10 ng/ml (9 nM). Acidification of the modulator-containing apical compartment to an extracellular pH (pHo) of 6.8 had no influence on MDR reversal by CsA at 1 microgram/ml (0.9 microM; flux inhibition, 52%) or by PSC 833 at 100 ng/ml (0.09 microM; flux inhibition, 60%), in contrast to R,S- and R-VPL, which showed decreased inhibition and caused less accumulation of vinblastine in HCT-8 cells under this condition (flux inhibition of 35% and 23%, respectively, at pHo 6.8 vs 50% and 43%, respectively, at pHo 7.5). P-gp-mediated rhodamine 123 efflux from dye-loaded single-cell suspensions of HCT-8 cells as measured by flow cytometry was not impeded at pHo 6.8 in comparison with pHo 7.5 in standard medium, but at low pHo the inhibitory activity of R-VPL (29% vs 60% rhodamine 123 efflux inhibition) was diminished significantly, again without a reduction in the effect of PSC 833 (rhodamine 123 flux inhibition, 75%). In conclusion, drug extrusion across polarised monolayers, which offer a relevant model for normal epithelia and tumour border areas, is inhibited by the apical presence of R,S- and R-VPL, CsA and PSC 833 at similar concentrations described for single-cell suspensions, resulting in increased (2.2- to 3.7-fold) intracellular drug accumulation. Functional apical P-gp expression, the absence of paracellular leakage and modulator-sensitive rhodamine 123 efflux in single HCT-8 cells indicate a P-gp-mediated transcellular efflux in HCT-8 monolayers. In addition to its high MDR-reversing capacity, the inhibitory activity of PSC 833 is not affected by acidic extracellular conditions, which reduce the VPL-induced drug retention significantly. As far as MDR contributes to the overall cellular drug resistance of solid tumours with hypoxic and acidic microenvironments, PSC 833 holds the greatest promise for clinical reversal of unresponsiveness to the respective group of chemotherapeutics.

Vinorelbine (Navelbine, NVB) is a new semi-synthetic vinca alkaloid that is currently used in the treatment of advanced breast cancer and advanced non-small-cell lung cancer (NSCLC). In this study we investigated the tumoral and healthy pulmonary tissue concentrations of NVB in previously untreated NSCLC patients undergoing surgery. A total of 13 patients (mean age, 60 years; range, 42-70 years) were included and received NVB (20 mg/m2) at 1 h (mean, 1.1 h; SD, 0.2 h; n = 6 patients) and 3 h (mean, 3.0 h; SD, 0.6 h; n = 7 patients) before tumor resection. A tumoral and adjacent healthy lung-tissue specimen as well as simultaneously sampled serum were analyzed for NVB by high-performance liquid chromatography (HPLC). NVB levels were much higher in tissue than in serum (up to 300-fold). The tissue/serum ratio increased between the 1-h sampling time (range, 0.1-100) and the 3-h time point (range, 10-300). In all patients but two, NVB concentrations were lower in tumors than in healthy lung tissue. The tumor/healthy tissue ratio ranged from 0.06 to 1.3 (median, 0.09) at 1 h and from 0.18 to 1.1 (median, 0.55) at 3 h. This ratio increased between the 1-h sampling time and the 3-h time point as a consequence of increasing tumor levels (median, 50.4 ng/g at 1 h and 278 ng/g at 3 h). In four patients, concentrations could be measured in necrotic and peripheral tumor zones, showing lower values in necrotic areas. Thus, these data indicate that NVB is highly distributed in lung tissue, with the disposition rate being slower in tumor tissue than in healthy parenchyma during the first 3 h.

The biliary elimination and pharmacokinetics of vinorelbine (NVB) were investigated in five conscious micropigs provided with a double-terminal choledocal fistula allowing the collection and reinstillation of bile. After the i.v. administration of NVB (0.5 mg/kg), serum and bile samples were collected over a 48-h period. The concentrations of NVB were measured by high-performance liquid chromatography. The serum concentrations decreased rapidly from a maximal value of 208.6 ng/ml (SD, 111.7 ng/ml). The mean half-life was 10.9 h (SD, 8.6 h) and the mean AUC0-48 h was 292.8 ng ml-1 h (SD, 79.4 ng ml-1 h). The bile concentrations were high, amounting to 16.0 micrograms/ml (range, 5.4-27.7 micrograms/ml). The 0- to 48-h biliary excretion of unchanged NVB accounted for 25.8% (SD, 5.7%) of the injected dose, with 21.5% (SD, 4.0%) being eliminated during the 0- to 8-h period. Desacetyl-NVB was found in an inconstant manner and in very low amounts in bile samples. In addition, no glucuronide of NVB could be detected. Thus, in the micropig, biliary excretion represents an important route of elimination for NVB.

We have developed and validated a selective analytical procedure, based on ion-exchange normal-phase liquid chromatography with fluorescence detection and liquid-liquid extraction, for the analysis of vinblastine (VBL) in biological matrices. The assay is suitable for the determination of the parent compound and its metabolites in plasma, tissue, faeces and urine specimens. Pharmacokinetics studies were performed in male FVB mice receiving VBL by intravenous (i.v.) bolus injection at a dose of 6 mg/kg. Plasma concentrations were monitored until 48 h after drug administration. Urine and faeces samples were collected in 24-h portions for up to 72 h and tissue samples were obtained at 4, 24, 72 and 168 h after drug administration. To facilitate a comparison between the findings we obtained by high-performance liquid chromatography (HPLC) and the results of previous studies using radiolabeled drug monitoring, some of the animals were also given radiolabeled drug. Large discrepancies were observed between the results obtained by the two methods. Excretion of the radiolabel in faeces and urine was 85% of the dose within 72 h. HPLC revealed that only 18% of the dose was excreted as unchanged drug and 19%, as measurable metabolites [O4-deacetylvinblastine (DVBL) and two unknown compounds]. In most of the tissues taken at 4 h after drug administration, virtually all of the radioactivity represented VBL or DVBL. In all tissues taken at 72 h after drug administration, however, only very little of the radioactivity remained in the form of these compounds. Following the administration, VBL and DVBL were distributed extensively to most tissues. Many tissues appeared to possess effective means of extruding the cytotoxic drug with decreasing plasma levels. However, in some organs, including those from the genital tract and lymphatic tissues, VBL and DVBL were retained for prolonged periods. Our studies confirm previous indications that selective retention may be the basis of the activity of VBL against malignant transformations derived from these tissues.

S12363, a new vinca alkaloid derivative, was considerably more cytotoxic to murine L1210 cells and five human tumor cell lines (HL60, HT-29, COLO 320DM, NCI-H460, and PANC-1) than was vincristine (VCR) or vinblastine (VLB). S 12,363 bound to tubulin in crude extracts from brain or L1210 cells with an affinity similar to that of VLB and VCR (apparent Kd value: 1.1-1.6, 1.2-1.7, and 0.6-0.8 microM, respectively). After 1 h exposure, the accumulation of 20 nM [3H]-S 12,363 by L1210 cells was 4- to 18-fold that of [3H]-VLB and [3H]-VCR, respectively. After the cells had been preloaded for 1 h with the labeled drugs and then incubated for 3 h in drug-free medium, 37%-55% of the [3H]-S 12,363 was retained by the cells vs 36%-47% of the [3H]-VCR and less than 6% of the [3H]-VLB. Similar results were obtained for the five human cell lines tested. The accumulation factors (intracellular vs extracellular concentrations) found for [3H]-S 12,363 (54- to 167-fold) were significantly higher than those observed for [3H]-VCR (5- to 14-fold) or [3H]-VLB (19- to 41-fold). Greater than 90% of the radioactivity extracted from L1210 cells that had been treated with [3H]-S 12,363 was recovered as unmodified drug, demonstrating that [3H]-S 12,363 was not metabolized by these cells. S 12,362, which differs from S 12,363 only in the absolute configuration of the asymmetric carbon atom of its alpha-aminophosphonic side chain, was 300 times less cytotoxic, bound to tubulin with a lower affinity (apparent Kd value, 4.9-9.6 microM), and was neither accumulated nor retained by the cells. Taken together, these results demonstrate that the potency of S 12,363 is due at least in part to its cellular accumulation and retention.

The pharmacokinetic behavior of navelbine was investigated in 19 patients presenting with advanced cancers (mainly women with breast cancer). Navelbine was given orally at seven dose levels of up to 200 mg/week. For a given dose, patients received four successive weekly treatments. Five subjects also received two different doses. After drug administration, plasma was collected for 48 or 72 h and monitored for navelbine concentration by radioimmunoassay. Absorption of navelbine was very rapid after oral administration: maximal drug concentrations were reached within the first 1 or 2 h (Tmax, 0.9-1.75 h; cmax, 70.9-832.6 ng/ml), with absorption constants ranging from 0.85 to 2.42 l/h. A comparison of dose-normalised plasma concentration profiles revealed significant time dependence in six evaluable patients (P less than 0.001). Only four subjects who received low doses (less than or equal to 100 mg/week) exhibited time-independent kinetics. All of the five patients who were treated at different doses displayed apparent dose dependence (P less than 0.001). No individual profile was characterised by both time- and dose-independent pharmacokinetics. In all, 18 patients presented biphasic plasma concentration-decay patterns, and only 1 subject exhibited monophasic decay kinetics. The navelbine pharmacokinetic parameters obtained following oral administration were similar to those observed after i.v. bolus injection and were characterised by high oral clearance (0.43-1.45 1 h-1 kg-1), a large apparent volume of distribution (27.4-45.9 1/kg), and a long terminal half-life (24.2-56.5 h). Large intra- and inter-individual variations in pharmacokinetic parameters were observed. Moreover, after a high dose of 200 mg, an enterohepatic cycle and/or a delay in navelbine's absorption at a distal intestinal site as evidenced by a marked plasma level rebound was observed.

Unidirectional blood-brain barrier transfer of the lipophilic anticancer agents vincristine and vinblastine was studied in anesthetized rats, using an isolated, in situ brain perfusion technique. Drug binding to plasma constituents was also measured. Despite the high lipophilicity of these agents (the log octanol/physiological saline partition coefficient equalled 2.14 and 1.68, respectively), the cerebrovascular permeability-surface area product, PA, of vincristine in plasma was only 0.49 x 10(-4) ml s-1 g-1 for parietal cerebral cortex, whereas that of vinblastine was too low for determination. These values are similar to those of water-soluble, poorly diffusible nonelectrolytes. The PAs were significantly higher in the absence of plasma protein, being 1.24 x 10(-4) and 5.36 x 10(-4) ml s-1 g-1, respectively. Even these values, determined by brain perfusion of protein-free buffer, were lower than would be expected from the lipophilicity of the agents. The results suggest that additional factors, such as steric hindrance and molecular charge distribution, related to the chemical and geometric structure and the large size of vincristine and vinblastine (molecular weight, 825 and 814 daltons, respectively) restrict their passage across the blood-brain barrier. As a consequence of their paradoxically low permeability at the blood-brain barrier and restrictive binding to plasma and blood constituents, doses of both agents that cause significant inhibition of extracerebral Walker 256 carcinosarcoma tumor implants in rat have no effect on tumor located in the brain.

A study was designed to investigate the fate of navelbine (NVB) and its excretion routes in two cancer patients treated with tritiated NVB (30 mg/m2) by i.v. bolus injection. Plasma and red blood cell concentrations and urine and stool elimination were monitored over long periods of time. NVB plasma and urine concentrations were measured by both radioimmunoassay (RIA) and direct radioactive (RA) determination. Samples were also analyzed by high-performance liquid chromatography to evaluate the importance of NVB metabolism. Whereas the major excretion route for NVB was the stool (from 34% to 58.4% of the total dose given over 21 days), urinary excretion was low (about 21% within the same time period), corresponding mainly to that of unchanged drug. Thus, a good correlation was found between RIA and RA determinations in urine. In contrast, plasma area under the curve (AUC) values obtained after RA and RIA analysis differed markedly (AUC RIA/AUC RA = 0.23-0.31), demonstrating that a significant proportion of the plasma-circulating drug was biotransformed, mainly during the last elimination phase. This could have important pharmacological and toxicologic implications in clinical practice.