DRUG DISPOSITION

Clin. Pha rma cokinet . 1996 Sept ; 3 t (3); 184-197 0312-5963/96/ 0009'()I84/ S07.00/ 0

© AdisInternational Umited. Allrightsreserved.

Clinical Pharmacokinetics of Vinorelbine Dominique Leveque and Francois Jehl Department of Pharmacokinetics, Institute of Bacteriology, Strasbourg, France

Contents Summary . 1. Chemistry . . . . . . . . . . . 2. Pharmacological Properties 2.1 Mechanism of Action . 2.2 Resistance . 2.3 Preclinical Antitumour Activity 3. Overview of Clinical Activity . . . . 3.1 Advanced Non-Small-Cell Lung Cancer 3.2 Advanced Breast Cancer . . .. 4. Drug Formulation and Administration 5. Analytical Methodology . 5.1 Radioactive Assays . . . . . . . . 5.2 High Performance Liquid Chromatography 6. Pharmacokinetic Properties 6.1 Absorption. 6.2 Distribution . 6.3 Metabolism 6.4 Excretion. . 6.5 Pharmacokinetic Parameters . 6.6 Infusional Pharmacokinetics . 6.7 Pharmacokinetics in Children . . 6.8 Effect of Diseases 6.9 Exploration of Pharmacokinetic Interactions 7. Pharmacodynamics .

Summary

184 186 186 186 187 187 187 188 188 188 188 188 189 189 189 190 191 191 192 193 193 194 194 194

Vinorelbine (5/-noranhydrovinblastine) is a recently developed semisynthetic anticancer drug which belong s to the Catharanthus alkaloid family. Its mechanism of action is only partially known but it is assumed that it acts, like vinblastine and vincristine, as an antimicrotubule agent arresting cell division in mitosis . Clinically, vinorelbine has mainly shown activity in the treatment of advanced non-small-cell lung cancer and the treatment of metastatic breast cancer. Early pharmacokinetic data were obtained with radioactive assays (radioimmunoassay or 3H-labelled vinorelbine), then with more selective high performance liquid chromatographic techniques. Vinorelbin e is usually administered intravenously but there has also been some experimentation with an oral formulation . The bioavailability of a liquid filled gelatin capsule ranges between 12 and

Vinorelbine

185

59% with a mean value of 27% [standard deviation (SO) 12%]. Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. In vitro, vinorelbine is mainly distributed into the blood cells, especially platelets (78%) and lymphocytes (4.8%). The unbound blood fraction is around 2%. In lung tissue vinorelbine concentrations are much higher than in serum, by up to 300-fold 3 hours after admini stration. Little is known about the biotransformation of vinorelbine . Oesacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25 % of the injected dose. Urinary excretion of vinorelbine is low, accounting for less than 20% of the dose. Faecal elimination has been demonstrated in 2 patients who were administered 3H-labelled vinorelbine: the amount of radioactivity recovered in the faeces was 33.9 and 58.4% for the 2 patients , respecti vely. The pharmacokinetic profile of vinorelbine is often described as a 3-compartment model characterised by a long terminal half-life (t'/2) that varies between 20 and 40 hours and a large apparent volume of distribution (Vd) of around 70 L/kg. Systemic clearance ranges between 72.54 and 89.46 Llh (\209 and 1491 ml/min) when determined by high performance liquid chromatography and is higher than that reported by radioimmunoassay [46.2 L/h (770 ml/min)]. This could be due to the greater specificity of the chromatographic method. Vinorelbine has been administered by continuous intravenou s infusion over 4 days. Steady-state was reached and the concentrations obtained were above the in vitro ICso (concentration of drug causing 50% inhibition) . The effect of liver disease on vinorelbine pharmacokinetics has been studied in patients with breast cancer. Patients with massive secondary liver disease had a lower systemic clearance than those who have no liver disease or a lesser invasion. In children, vinorelbine seems to display a shorter t'/2(\4.7 hours) than that found in adults . In addition , the systemic clearance is highly variable [from 12 to 93.96 Llh/m 2 (200 to 1566 ml/min/m 2)]. Vinore1bine is often co-administered with cisplatin in the treatment of advanced non-small-cell lung cancer. The disposition of the alkaloid is not altered by concurrent administration of cisplatin. Vinorelbine (5'-noranhydrovinblastine) is an anticancer agent belonging to the Catharanthus alkaloid family. Other marketed compounds of this group are vinblastine, vincristine and vindesine. The Catharanthus alkaloids represent a major class of cytotoxic drugs which are extensively used in curative and palliative polychemotherapy of numerous haematological and solid tumours. Vinblastine and vincristine are natural compounds that were extracted from the leaves of an ornamental periwinkle botanically classified as Catharanthus roseus G. Don (also erroneously referred to as © Adis International Limited, All rights reserved.

Vinca rosea) in the late 1950s.[I]The search for new active agents with an improved therapeutic index and a broader spectrum has led to the synthesis of vindesine.Pl an alkaloid derived from vinblastine which wa s later shown to be clinically less act ive . Vinorelbine was obtained by semi-synthesis by Professor Potier's team (Gif-sur-Yvette, France) in the late 1970s. 13J In general, the clinical pharmacokinetics of Catharanthus alkaloids have not been studied as extensively as tho se of other classes of anticancer drugs such as topoisomerase II inhibitors (anthrac jn, Pharmacokinet, 1996Sept: 31 (3)

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Catharanthine nucleus

Vindoline nucleus

Fig. 1. Chemical structure of vinorelbine.

cyclines, epipodophyllotoxins), antimetabolites or taxoids, although vinblastine and vincristine have been used in clinical setting for a long time (vinblastine since March 1959 and vincristine since June 1961). Thefirst papers dealing with their clinical pharmacokinetics were only published in 1975 for vinblastine!" and 1977 for vincristine.Pl Given the low dosages administered, pharmacokinetic investigations of Catharanthus alkaloids have been limited by the lack of suitable analytical methodology. Pharmacokinetic investigations only became possible when radiolabelled products became available. Kinetic data concerning vinorelbine are relatively limited but have benefited from the use of liquid chromatographic anal ytical techniques. Thi s paper updates what is known about the disposition of vinorelbine in humans. Data concerning the pharmacology, resistance to and clinical activity of vinorelbine are also presented.

1. Chemistry Vinorelbine is a dimeric molecule formed by the catharanthine unit indolic moiety and the vindoline unit (dihydroindolic moiety) joined by a carboncarbon bridge (fig. I ). The chemical structure ofvinorelbine is characterised by a modified catharanthine unit with the loss of a carbon atom and establishment of a double bond, in relation to vinblastine and vincristine. The molecular weight of vinorelbine is 779 for the basi s and 1079 for the salt (ditartrate ).l6 ] It is a very lipophilic molecule; hence, the © Adis Interna tio na l Umited. A ll rig hts reserve d .

partition coefficient octanol/buffer pH 7.2 which relates lipophilicity is 16 for vinorelbinelsl and is much higher than for vinblastine (3.6)[71 and vincristine (2.5).l 7J

2. Pharmacological Properties 2.1 Mechanism of Action The mechanism of action of vinorelbine is partially known but it is assumed that it act s as its congeners, i.e. as an antimicrotubule agent arre sting cell divi sion in mitosis. Microtubules are protein polymers mainl y composed of dimeric tubulin subunits (ex and ~ ).[S J They are involved in man y fundamental processes including nerve conduction , neurotransmi ssion, cell shape and the formation of the mitotic spindle.If At least 3 type s of drug binding sites exi st on tubulin (Catharanthus alkaloids, colchicine and paclitaxelj.If The antiproliferative activity of Catharanthus alkaloids is due to the inhibition of mitosis with accumulation of cells in metaphase.I'" For a long time this antiproliferative action was attributed to the depolymerisation of mitotic microtubules (a property that contrasts with polymerising action of paclitaxel). Leslie Wilson' team[IO,lll has revolutionised thi s approach, showing, in Hela cell s, that vinbla stine and vincristine (as well as paclitaxel) exhibit antiproliferative and antimitotic activity at very low doses « 6 nmol/L) in vitro by inhibiting the dynamics of spindle microtubules and without decreasing the microtubule polymer mass. In fact, as was earlier described, depolymerisation of the C lin. Pha rmacokine t. 1996 Sept: 3 1 (3)

Vinorelbine

mitotic spindle occurred at higher concentration but did not correlate with antiproliferative activity.U '" 111 vitro, vinorelbine ha s been shown to be as active as vincristine and vinblastine on mitotic microtubules.Uf Indeed, vinorelbine at a concentration s of 2 umol/L (roughly twice the human peak serum concentration) produced an arrest of mitotic cells in metaphase with depolymerisation of mitotic interpolar micro tubules.[IZ]At a higher concentration (25 umol/L), depol ymerisation of kinetochore microtubules (i.e. those carrying the chromosomes) occurred) IZJConversely, depolymeri sation ofaxonal microtubules was obtained with higher concentrations (40 umol/L) than with vinblastine (30 umol/L) and vincristine (5 umol/L). It ha s been suggested that this could explain the lower incidence of neurotoxicity ob served with vinorelbine. The mechanism of act ion at very low concentrations « 10 nmol/L) has not been studied as has been done with vinblastine and vincristine) 10, I I] It could be that vinorelbine exhibits an anti proliferative activity in the nmol/L range without altering the microtubule polymer ma ss. 2.2 Resistance Very little is known about resi stance to vinorelbine. At least 4 mechanisms of resistance to Catharanthus alkaloids ha ve been described. (i) The mo st documented is a phenotype of multidrug resistance associated with the overexpression of a transmembrane protein called Pvglycoprotein.Uf This cross resistance ha s been o)jserv~d ill vitro and ill vivo and involves, besides Catharanthus alkaloids, doxorubicin, daunorubicin, etoposide , mitox antrone, dactinomycin and paclitaxel. Pglycoprotein encoded in humans by the MDR-I gene, is though to act as a pump that expels the drug from the cell, lowering its concentration and hence its activity.U f (ii) Vinbla stine and vincristine are also implicated in another phenotype of multiresistance reported ill vitro and related to the overex pressi on of a gene coding for a protein called multidrug resistance associated protein (MRP»)14.IS] The mechanism of this resistance is partially known but could e Adis Inter national Umited. All rights reserved .

187

be linked to a decreased accumulation of the drug in the cell ) 16] (iii) A form of resistance has been ob serv ed ill vitro for vinblas tine and is related to mutations on tubulin subunits.Uf The mechanism is not very well known but does not seem to be associ ated with a defect in binding.Uf Thi s type of resistance ha s also been sugges ted for vincristine)1 9.z0] (iv) Finally, myeloperoxidase, an enzyme which, ill vitro, ca talyses the degradation of Catharanthus alkaloids, could be associated with the intrinsic resistance of acute myeloblastic leukaemia to vincristine.P'J Vinorelbine seems to also be involved in the phenotype of multi drug resi stance associated with the hyp erexpression of the membrane P-glycoprotein efflux pumpPZ] In addition, a phenotype of resistance to vinorelbine and paclitaxel has been reported ill vitro in a bladder carcinoma cell line.Ft' The mechanism could be linked to alteration s of microtubule dynamic s.F'l 2.3 Preclinical Antitumour Activity The cytotoxic ac tiv ity of vinorelbine ha s been tested ill vitro aga inst 24 human tumour cell line s (leukaemia, small cell and non-small-cell lun g cancer, breast cancer, colon cancer, melanoma, central ner vou s sys tem canc er )p 4] The IDso (the concentration that decreased the growth rate to 50 % of that of the control cell s) were low and ranged between I and 10 nmol/L following a prolonged expo sition of 48 hours. When compared with vinblastine and vincri stine, vinorelbine was less active against L 1210 leukaemia cells but was more cytotoxic against the non-small-cell lung cancer line NSCLC N6L2.[ Z4] Vinorelbine was shown to be at least as active as other Catharanthus alkaloids in vivo in murine tumour models.P" Furthermore, vinorelbine wa s acti ve against human tumours xenografted in nude mice and particularly the lung cancer L27 line whereas vinblastine and vindes ine were inactive. R''l

3. Overview of Clinical Activity Data from phase I studies of vinorelbine indi cate that neutropenia wa s the do se limiting toxicClin. Pharmac o kinet. 1996 Sept; 31 (3)

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ity)251 The maximum tolerated dosage ranged between 30 and 35 mg/m 2/week.[25] The recommended do sage for phase II studies was set at 30 mg/m 2/ week. Unlike vinblastine and vincristine, vinorelbine is only given with palliative intent. Vinorelbine has mainly been investigated in patients with advanced non-small-cell lung cancer and advanced breast cancer; hence, vinorelbine is marketed in France and some European countries for use in these 2 indications. Vinorelbine is approved in the US for the treatment of advanced non-smallcell lung cancer. Detailed reviews on the clinical activity of vinorelbine have been published else where.[26,27] The main clinical features are also presented in sections 3.1 and 3.2. 3.1 Advanced Non-Small-Cell Lung Cancer The preclinical activity of vinorelbine against non-small-cell lung cancer cell lines and the high lung tissue uptake observed in rodents (when compared with vinblastine and vincristine) lead to clinical research in patients with advanced non-smallcell lung cancer. In a phase II study,[28] vinorelbine as a single agent produced a 29.4% response rate in 78 previously untreated patients. Advanced non-small-cell lung cancer (unresectable and metastatic) is highly resistant to chemotherapy and very few drugs are active as a single therapy; compared with other agents, it was estimated that vinorelbine was one of the most active drugs . In a large randomised study including 612 patients.U?' vinorelbine combined with cisplatin procured a higher response rate (30 %) than the combination vindesine+cisplatin (19 %) and vinorelbine-only (14 %) therapy. In addition, the median duration of survival was significantly longer in the vinorelbine+cisplatin arm (40 weeks) than in the vindesine+cisplatin arm (32 weeks) and in the vinorelbine arm (31 weeks) of the study. The benefits of vinorelbine+cisplatin over vinorelbine-only therapy have not be observed in other comparative trials either in terms of response rate[30] or survival.U!' © Adis Intemational Limited. All rights reserved .

Leveque & Jehl

3.2 Advanced Breast Cancer Although vinorelbine has been little tested in breast cancer models, numerous clinical investigations have been conducted, demonstrating significant activity and leading to the publication of many papers.132-381 In previously treated patients, vinorelbine, as a single agent, procured an overall response rate ranging from 32 to 46 %,132-34] In the sole randomised study, 135] vinorelbine demonstrated activity superior to melphalan (an alternative therapy) in terms of survival (35 weeks versus 31 weeks) in patients with anthracycline-refractory breast cancer. Documented response rates in previously untreated patients (first-line therapy) where between 35 and 41%.[34,36, 371When combined with doxorubicin, objective responses have been observed in 74% of the patients.P'" Overall, vinorelbine is considered an active agent in the treatment of advanced breast cancer, although the clinical value of vinorelbine remains to be established in controlled trials with regard to reference treatments and in comparison with new active compounds such as paclitaxel and docetaxel. Besides these 2 indications, vinorelbine has produced promising results in the treatment of advanced ovarian cancer.P" Hodgkins disease.P'" head and neck cancer[26] and esophageal cancer.P?'

4. Drug Formulation and Administration Vinorelbine is currently available in a solution for intravenous use at a concentration of 10 mg/ml of water for injection . Vinorelbine is usually diluted in 5% dextrose or saline solution (0.9%) and administered by short intravenous infusion over 15 to 20 minutes; the recommended dosage is 30 mg/m 2/ week. An oral formulation is currently being investigated.

5. Analytical Methodology 5,1 Radioactive Assays Early pharmacokinetic data on vinorelbine were obtained in humans and animals with radioactive assays. One radioimmunoassay study has been reCtin. Pharma cokinet. 1996 Sept; 31 (3)

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Vinorelbine

ported using anti-vinorelbine antibodies generated from rabbits.[401 The limit of detection for this method is 0 .1 mg/L.l40]The major drawback of this assay is the lack of specificity between the parent drug and the eventual metabolites since the antibodies recognise the catharanthine moiety. Although little is known about Catharanthus alkaloids metabolism, biotransformation is likely to occur in the vindoline moiety as is the case for vinblastine. A radioactive assay has been described using vinorelbine labelled with triuum.H!' Drug concentration was estimated by counting the radioactivity of biological fluid samples after separation by high performance liquid chromatography (HPLC).

5.2 High Performance Liquid Chromatography Because there was evidence of the existence of biotransformation of vinorelbine,[42] there was a need for a specific methodology. This led to the development of HPLC techniques that permit a more selective analysis.l 43-48] The first published technique allowed the determination of vinorelbine and 2 eventual metabolites, desacetylvinorelbine and vinorelbine N-oxide, in biological fluids.l 43] The assay is based on ultraviolet detection at 268nm and used a cyanoanalytical column and a mobile phase mainly containing acetonitrile. The extraction involves 1ml of biological fluid and is performed with diethyl ether. The limit of detection for vinorelbine is 1 ug/L in serum.F" Other systems of detection have been used, such as amperometriclr'J or coulometric detectionl''U and fluorescence.F'l Most of the extraction procedures in biological fluids involve diethyl ether except for one paper that reported ion-pair extraction.l'vl A technique for the determination of vinorelbine in tumour cells has been described.t'vl as well as one regarding tissue extraction based on the crushing of frozen fragments in a freezer-mill under liquid nitrogen.F?' © Adis International Limited. All rights reserved.

6. Pharmacokinetic Properties 6.1 Absorption All Catharanthus alkaloids are administered intravenously except for vinorelbine which is also currently undergoing experimentation in an oral formulation. In the past, vinblastine[50-53] and vinzolidine (an abandoned semisynthetic compound)[54.55] have been tested orally, but their clinical development has being discontinued because of high, unpredictable and sometimes fatal toxicity. Oral administration is potentially preferred since it is easier and more convenient for the patient and allows ambulatory treatment. Thus, oral vinblastine was developed to avoid certain adverse effects due to intravenous administration (phlebitis, pain at the injection site) . From a pharmacological point of view, the oral route theoretically provides a continuous exposure to low concentrations consistent with the anti proliferative effects of vinorelbine observed in vitro. On the other hand, opinions have been expressed recommending the parenteral route because of the variability in drug absorption after oral administration.!56] The first pharmacokinetic study on vinorelbine oral administration was performed in 2 patients who received 3H-labelled vinorelbine in a capsule form at a dose of 30 mg/m 2.1 571The bioavailability was 40 .6 and 93% when estimated by radioimmunoassay and total radioactivity respectively. Total radioactivity theoretically accounts for both parent drug and metabolites or degradation products, and hence a first pass effect (hepatic and intestinal) was suspected. The study was extended to 19 patients who were given 7 dosage levels (from 50 to 200 mg/m 2/week).I58] Vinorelbine was rapidly absorbed, and the peak plasma concentration was reached between 0.9 and 1.75 hours. The maximum plasma concentration (C max) determined by radioimmunoassay ranged between 70 .9 ug/L (dose 50 rng/rn-) to 832 .6j.tg/L (dose 160 mg/m-), The terminal half-life (tI/2) ranged between 24.2 hours and 56 .3 hours; after considering the 7 dose levels it was judged that the concentrations were similar to Clin . Pharmacokinet. 1996Sept: 31 (3)

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those reported after intravenous administration using the same analytical methodology. Furthermore, it was shown that vinorelbine exhibits a better absorption when formulated in a liquid-filled capsule than in a powder-filled capsule.L59] Even with this positive pharmacokinetic data, the development of a powder-filled formulations was stopped because of the risk to workers inhaling the aerolised drug during the manufacture.t'Pl This has led to the development of a liquid-filled capsule. The bioavailability of a liquid-filled gelatin capsule after administration of 100 mg/rn? to 17 patients ranged between 12 and 59 % with a mean value of 27% (SD 12%) when determined by HPLC)61] Vinorelbine was rapidly absorbed and the peak serum concentration was reached within 2 hours [mean 1.49 hours (SD 0.99)] . The mean C max was 114.3 J-lglL (SD 42 .6). The intraindividual variability was 32 %)61] Orally administered vinorelbine has been studied in 162 patients with non-small-cell cancer recei ving dosage rangi ng from 50 to 100 mg/m-" week.[62] The pharmacokinetics were also investigated in 57 patients who had blood samples collected corresponding (theoretically) to peak concentration times (I and 2 hours after administration). The plasma concentration estimated by HPLC showed a wide interpatient variability with values ranging from nondetectable to 124 ug/L at 1 hour)62] The effect of food ingestion on the bioavailability of vinorelbine formulated in the liquid-filled capsule has been evaluated in 13 patients taking the capsule in the fasting state and after a standard meal)63] The preliminary kinetic data reported in an abstract form suggested that food has little impact on the bioavailability of this formulation since the median ratio between the 2 states (fed and fasting) was 90%)6 3] Overall, the bioavailability of this formulation is low ; this can be attributed to both incomplete absorption and to a first pass effect (intestinal and hepatic). The search for desacetylvinorelbine or additional chromatogram peaks potentially arising from a first pass effect has not been reported.l''!' In addition, it should be noted that vinorelbine appar© Adi s Intemational Limited . All rights reserved.

ently is a MDR I-related drug, of which absorption might be limited by P-glycoprotein expressed at the apical side of enterocytes as has been described in vitro with vinblastine)64.65] Clinically the value of oral vinorelbine is not yet clearly established. In patients with advanced non-small-cell lung cancer, the oral schedule appeared promising since it was shown to be as active as the intravenous modality in terms of median survival time)62] In patients with advanced breast cancer, the activity of oral vinorelbine seems moderate.l'vl With respect to tolerability, neutropenia represented the major toxicity as it is observed with the parenteral formulation . Nevertheless, gastrointestinal adverse effects (nausea, vomiting and diarrhoea) appeared to be more common[62,66] and could be partly due to a local effect. These adverse effects were also reported with oral vinblastine. L50,52] 6.2 Distribution The distribution of vinorelbine, in vitro, showed that it is 84 % bound to blood cells , mainly to platelets (78 %), 14% bound to serum protein and only 2% unbound. L67] In serum, vinorelbine, as with vin blastine, mainly binds to aI-acid glycoprotein and low density lipoproteins.F'l When determined in sera collected from cancer patients, the unbound fraction of vinorelbine ranged between 8.8 and 20.4% (mean 13.5%) .[67J The pulmonary disposition of vinorelbine has been investigated in patients with non-small-cell lung cancer undergoing thoracic surgery.[49] 13 patients were included and received vinorelbine 20 mg/m? by short intravenous infusion either 1 or 3 hours before tumour resection. Vinorelbine concentrations in lung tissue varied widely and were much higher than in serum, up to 300-fold 3 hours after injection. In all but 2 patients concentrations were lower in tumoural tissue than in healthy parenchyma, The tumour: healthy tissue concentration ratio increased between the I hour sampling time (median 0.09) and the 3 hour point (median 0.55) as a consequence of increasing concentrations in neoplastic tissue. The tumour concentrations ranged from 24 to 372 ng/g tissue at I hour Clin. Pharmacokinet. 1996 Sept; 31 (3)

Vinorelbine

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Table I. Elimination of vinorelbine in humansafter intravenous administration Study

No. of patients

Rahmani et al.[74]

Duration of the study (days)

Cumulativeexcretion Cumulativeexcretion in faeces" in urine" (SO)

Dose (mg/m2)

Assay

10

15

RIA

3

4.0 (2.0)

7

30

RIA

3

3.3 (1.4)

Bore et al.[41]

2

30

Radioactivity

Jehl et al.[71]

20

30

HPLC

21

33.9 - 58.4

2

15.8-21 10.9 (0.7)

a % of the injecteddose.

Abbreviations: HPLC = high performance liquidchromatography; RIA = radioimmunoassay.

(median 50.4 ng/g) and from 180 to 857 ng/g at 3 hours (median 278 ng/g))49 l Tissue distribution investigations with anticancer drugs are rare and to our knowledge only 1 study has been performed with Catharanthus alkaloids; that concerned vinblastine in brain tumours. For vinorelbine, the high concentrations observed in human lung[49l as well as those measured in murine lung (as compared with its analoguesjlv! could partly explain its activity in the treatment of non-small-cell lung cancer. 6.3 Metabolism

In general, little is known about the metabolism of Catharanthus alkaloids. Although numerous types of potential metabolic transformations appear possible.P'" to date only 2 metabolites (desacetylvinblastine and desacetylvinorelbine) have been detected in human biological fluids . In vitro, vinblastine.l'P' as well as vindesine.Pv' are biotransformed by human liver microsomes in one major unknown, and apparently less polar, metabolite. The cytochrome P450 (CYP) 3A subfamily accounted for the biotransformation. Vinorelbine competitively inhibited vinblastine and vindesine metabolisms and the authors suggested a possible implication of CYP3A in its metabolism)69,70l Nevertheless, the impact of CYP3A in the biotransformation of Catharanthus alkaloids in vivo is not yet established. Some preclinical data obtained in vivo and in vitro suggests the existence of 3 metabolites; these include desacetylvinorelbine and vinorelbine Noxide.[ 42l Desacetylvinorelbine is considered a potential metabolite of vinorelbine since it has been © Adis International Limited. All rights reserved.

found in urinary fractions of treated patients.'? I J Nevertheless, desacetylvinorelbine is a minor metabolite, representing only 0.25% of the administered dose.I"!' Furthermore, it has not been detected in human serum.U!' Although desacetylvinorelbine shows the same activity and toxicity as the parent drug,[42l it cannot account for the overall activity of vinorelbine. Vinorelbine N-oxide has never been detected in any biological fluid (serum or urine) of treated patients.F!' The search for the presence of a glucuronide of vinorelbine in human urine[72 l and bile samples obtained from fistulated micropigs'P' has been performed but none could be detected. 6.4 Excretion

As for its analogues, vinorelbine is poorly excreted in the urine, both in its unchanged form and as a metabolite (table I). The first study performed in 10 patients with a radioimmunoassay method revealed a 4% (SD 2.0) and a 3.3% (SD 1.4) urinary excretion following the injection of 15 and 30 mg/m", respectively.F'l When determined by HPLC, the urinary excretion of vinorelbine represents 10.9% of the administered dose.P!' After administration of 3H-labelled vinorelbine in 2 patients, urinary excretion accounted for 15.8 and 21% of the injected dose during a 3-week period.H!' The amounts of radioactivity recovered in the faeces were 33.9 and 58.4% for the 2 patients, respectively .U!' In a model of Yucatan micropigs provided with a double-terminal choledocal fistula, the 0- to 48-hour biliary excretion of unchanged vinorelbine accounted for 25.8% of the injected dose when determined by HPLC.[ 73l DesacetylClin , Pharmacokinet. 1996 Sept; 31 (3)

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192

vinorelbine was found in very low amount s and in an incon sistent manner.F'l Thus, the main vinorelbine pathw ay is hepat ic clearance as biliary excretion, but the definiti ve part of biotransform ation rema ining to be eva luated. Overall, as for the other Catharanthu s alkalo ids, recovery remains incomplete , indicatin g a sustained reten tion of drug in the tissue and/or the existence of polar metabolites that would not have been extracted by diethyl ether. ;::::

~~

6.5 Pharmacokinetic Parameters

'"' 'ui...."' ui ....

U?Ln ;::-~ ~ t:::. N m

m

M

:::..

~

~ ~ ~ ~

o .~ VI

., :l?-

c.'"

~~

ci. ci E E

ci. E

888

ci.. ci.. E E o 0 ci. ci. u u E E c: c:

8 8

oc: c: 0

© Adi s Inte rna tion al Limije d . All rights reserved .

Human kinetic parameters obtain ed after short infu sion are presented in table II. Vinorelbine kinetic s are best described as a 3-compartment model characterised by a large apparent Vd (75 Llkg ) and a long tY2(20 to 40 hour s). The first pharm acokinetic study was performed in 5 patients concomitantly with a phase I triaI.!751 Pharm acok inetic data were obtained by radioimmunoassay at various doses rangin g from 2 1 to 70m g. Th e t l/ 2 ranged from 27.9 to 39 .5 hours; total body clearan ce ranged from 46 .2 to 447 .6 L/h (770 to 1460 ml/min). The Vd varied between 37.2 and 101.9 Llkg.l751The study was extend ed to 11 patient s who were administered vinorelbine 15 and 30 mg/m 2 . [74 ] Overall , the phannacokinetic parameters were similar at the 2 dosages. The clini cal pharmacokinetics of vinorelbine were then investigated in 20 patient s receiving 30 mg/m/ , using a HPLC procedure.F' J The mean t 1/ 2 was 42.0 hour s (SD 20.8 )171] and was comparable to that obtained by radioimmunoassay [hal f-l ife (t Y2) 38.0 hour s (SD 12.7)] .[74] On the other hand , the mean systemic clearance was higher when determined by HPLC [88 .2 L/h (SD 27 .6) [1470 ml/min (SD 490 )][71 1 versus 46 .2 L/h (SD 20.28) [770 ml/m in (SD 338)]];[74] this could be attributable to the greater specificity of the HPLC methodolog y. Radioimmunoassay probably ove restimates the area under the concentration-time cur ve (AVC) in measurin g both parent drug and metabolites and henc e underestimates the value s of the systemic clearance. The app arent Vd was high [mean 75 Llk g (SD 41.0 )] reflectin g the inten se tissue uptake .P! ' Th is is not surprising given the lipoph ilicC lin. Phorma c o kinet. 1996 sept; 31 (3)

Vinorelbine

ity of vinorelbine and the fact that Catharanthus alkaloids concentrate in cells.f79-81] Other studies using HPLC have reported similar results, particularly the total clearance which ranges between 72.54 and 89.46 LJh(1209 and 1491 mllmin»)61,76- 781

Some discrepancies appear in the determination of the t1;2' Khayat et aIJ 78] and Rowinsky et al.161j found a shorter t1;2 (27 and 18 hours, respectively). Almost all the pharmacokinetic investigations have been performed at the recommended dose 30 mg/m- , although recently the maximal tolerated dose was reevaluated.Pf Indeed, it was estimated that grade IV neutropenia occurred only in 10% of patients treated at the maximal tolerated dose (34.5 mg/m-) . A new phase I trial has been conducted leading to a maximal tolerated dose of 45 mg/m 2,178 1 Besides this clinical investigation, the pharmacokinetic profile was explored at 3 dosages step, 35, 40 and 45 mg/m-. The data have been reported in abstract form and does not suggest a dose-dependent behaviour in the dosage ranges studied.Uf With regard to other Catharanthus alkaloids, direct pharmacokinetic comparisons are difficult because of the differing analytical methodologies and the high variability of the data reported. No pharmacokinetic data for vincristine, vinblastine and vindesine have been reported as a full paper in adult humans using HPLC. Overall, vinorelbine exhibits pharmacokinetic properties comparable with those of its congeners (i.e . long t l/ 2 and high systemic clearance). When compared with vinblastine and vindesine ,182J vinorelbine displays a longer t1;2 (20 to 40 hours vs 20 to 28 hours) and a higher systemic clearance [88.2 Llh versus 42 L/h (1470 ml/min versus 700 ml/min) for vinblastine'V' and 9 to 18 Llh (150 to 300 ml/min) for vindesinel .F" Comparisons with vincristine are much more difficult, because between the different papers t1;2 ranges from 22 to 85 hours and systemic clearance from 8.4 to 105 Llh (140 to 1750 ml/min»)8 2] The apparent Vd of vinorelbine is the highest among the Catharanthu s alkaloids (vinorelbine 75 L/kg; vinblastine 19 to 27 L'kg; vindesine 3 to 9 L/kg ; vin© Adis International Limited . All right s reserved .

193

cristine 2 to 10 L/kg), this can partly be attributed to its high lipophilicity. 6,6 Infusional Pharmacokinetics

Attempts to improve the efficacy and/or to reduce the toxicity of Catharanthus alkaloids have been made by using continuous intravenous infusion (for at least 24 hours).[831 The rationale for the prolonged exposure is based on the phase specificity of these agents. Indeed, Jackson and Benderl841 have shown that the cytotoxic effects of vincristine in vitro were both drug concentration- and time-dependent. The cytotoxic effects of Catharanthus alkaloids (including vinorelbine) occur at a very low concentrations (in the nmol/L range) in vitro when the exposure duration is 2 to 3 daysP4,80,84.851 In this light, a phase I and II trial of vinorelbine administered intravenously for 4 days continuously has been conducted in 64 patients with advanced breast cancer)86] The pharmacokinetic behaviour of vinorelbine has been studied in 7 patients who were given a 5-minute intravenous bolus injection (8 mg/m-) immediately followed by a continuous infusion over 4 days (5.5 or 8 mg/m? per day)J86] Steady-state was reached and the concentrations obtained by HPLC above the 10 50 determined in vitro)86J The mean concentrations at steady-state determined by HPLC were 12 and 8 ug/L in 5 patients who received 5.5 rng/m? per day and 2 who received 8 mg/m? per day, respectively.l'vl This schedule was judged feasible by the investigators who suggest a better neurological tolerance when vinorelbine is administered by continuous infusion. The limiting toxicity was neutropenia as for the 15-minute administration. 6.7 Pharmacokinetics in Children

Catharanthus alkaloids are extensively used in the treatment of paediatric malignancies. Preliminary pharmacokinetic data in paediatric cancer patients has only been reported in abstract form )87] Nine children received oral vinorelbine 90 mg/m '' on week 1 and 30 mg/m? by intravenous infusion on week 2. The median bioavailability estimated Clin . Phormacokinet. 1996 sept; 31 (3)

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by HPLC was 40% (range 6 to 130%).[87] The systemic parameters obtained after the 30 mg/m'' intravenous injection were as follows: the mean t Y2 was 14.7 hours (coefficient of variation 57%) and the mean Vd at steady-state was 544 Llm 2.[87] The total clearance was highly variable [12 to 93.96 Lzh/m? (200 to 1566 ml/min/m-)] with a mean value of 50.7 Llh/m 2 (845 ml/min/m 2).l87] The authors reported that this value is substantially higher than that observed in adults at 30 mg/m-. In fact, it is very close to the systemic clearance found in adults and reported in 4 studies.l 61,71 ,76.77] On the other hand, the tl/2 of vinorelbine seems shorter in children than in adults . The pharmacokinetics of Catharanthus alkaloids are poorly documented in children. Crom et al.[88] have studied the pharmacokinetic profile of vincristine in 52 children using HPLC . The systemic clearance was higher than that reported for adults using radioimmunoassay. Crom et al. suggested that this difference could be attributed to age, although the analytical methodologies were different. [88] 6.8 Effect of Diseases

Vinorelbine pharmacokinetics have been studied in breast cancer patients with liver metastases.l81] Patients with massive secondary liver diseases (> 75% of liver volume replaced by tumour; bilirubin 6.7 mg/dl) have been shown to have a lower systemic clearance than those who have no liver disease or a lesser liver invasion « 75 %; bilirubin 0.6 mg/dl) [0.499 versus 1.2 L/h/kg].[81 ] No pharmacodynamic data were reported. Dosage reduction is already recommended by the manufacturer for patients with liver dysfunction, but no administration guidelines are available. 6.9 Exploration of Pharmacokinetic Interactions

Until now, no pharmacokinetic interaction has been reported with vinorelbine. Vinorelbine combined with cisplatin has been shown to produce an objective response rate greater than that for vinorelbine alone . To assess whether this increased ac© Ad is International Limited . All rights reserved .

tivity was related to a kinetic interaction, the disposition of vinorelbine was investigated in patients with advanced non-small-cell lung cancer who had received either the alkaloid or the combination therapy. Five patients were injected with vinorelbine 30 mg/m- and 4 patients received cisplatin 80 mg/rn? I hour after the vinorelbine infusion. Blood was sampled over a 3 day penod.P?' In both groups the pharmacokinetic profile of vinorelbine was similar in term s of AUC and total clearance, and it was concluded that cisplatin did not alter vinorelbine dispo sition.

7. Pharmacodynamics Pharmacodynamic data relative to vinorelbine (i.e. linking pharmacokinetics to clinical response) are scarce and have only been published in abstract formJ80J A relationship between AUC and haematological toxicity (neutropenia) has been suggested in 15 patients who received 3 dosage levels, 35, 40 and 45 mg/m 2.l 80] It must be stressed that the severity of the toxicity was also linked to the dose escalation, this revealing a depending dynamic correlation .

Acknowledgements We wish to expre ss our gratitude to Mrs Corinne GallionRenault, Mrs Janine Debs-Durrenberger, Miss Mire ille Pelegrin and Miss Laurence Linger for their skilful assistance. Mrs Madeleine Hoehn provided expert secretarial assistance.

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45 . Van Tcllingen 0 , Kuijpers A, Beijnen JH, et al. Bio-analysis of vinorelbine by high-performance liquid chromatography with fluorescence detection. J Chromatogr Biomed Appl 1992; 573 : 328-32 46. Van Belle SJP, De Smet M, Monsaert C. et al. High-performance liquid chromatographic determination of navelbine in M04 mouse fibrosarcoma cells and biological fluids . J Chromatogr Biomed Appl 1992; 576: 351-7 47 . Mouchard-Delmas C, Gourdier B, Vistelle R. Determination of vinorelbine in rabbit plasma by high-performance liquid chromatography with coulometric detection . J Chromatogr Biomed Appl 1995; 663: 390-4 48 . Debal V, Morjani H, Millot JM , et al. Determination of vinorelbine (Navelbine) in tumour cells by high-performance liquid chromatography. J Chromatogr Biomed Appl 1992 ; 581: 93-9 49. Leveque D, Quoix E, Dumont P, et al. Pulmonary distribution of vinorelbine in patients with non-small-cell lung cancer. Cancer Chemother Pharmacol 1993; 33: 176-8 50. Hodes ME, Rohn RJ, Bond WH, et al. Vincaleukoblastine: III. Clinical trial with the oral preparation. Cancer Chemother Rep 1961; 14: 129-33 51. Korst DR, Nixon Jc. Oral administration of vinblastine sulfate (NSC-49842) to cancer patients. Cancer Chemother Rep 1965; 45: 53-6 52. MacDonald Jr CA , Lacher MJ. Oral vinblastine sulfate in Hodgkin's disease . Clin Pharmacol Ther 1966; 7: 534-41 53. Wilson HE, Louis J. The response of Hodgkin 's disease to treatment with oral vinblastine sulfate . Ann Int Med 1967; 67: 303-8 54. Takasugi BJ, Jones SE, Robertone AB. Phase II trial of vinzolidine, an oral vinca alkaloid in Hodgkin 's disease and nonHodgkin 's lymphoma. Cancer Treat Rep 1984; 68: 1399-40 I 55. Sarna G, Mitsuyasu R, Figlin R, et al. Oral vinzolidin e as therapy for Kaposi's sarcoma and carcinomas oflung, breast, and colon/rectum. Cancer Chemother Pharmacol 1985; 14: 12-4 56. Pinedo HM, van Groeningen CJ. Vinorelbine: a horse of a different color? J Clin Oncol 1994; 12: 1745-7 57. Rahmani R, Zhou XJ, Bore P, et al. Oral administration of [3H]navelbine in patients : comparative pharmacokinetics using radioactive and radioimmunologic determination methods. Anticancer Drugs 1991; 2: 405-10 58. Zhou XJ, Bore P, Monjanel S, et al. Pharmacokinetics of navelbine after oral administration in cancer patients . Cancer Chernother Pharmacol 1991; 29: 66-70 59. Zhou XJ, Zhou-Pan XR, Favre R, et al. Relative bioavailability of two oral formulations of navelbine in cancer patients. Biopharm Drug Dispos 1994; 15: 577-86 60. Wargin WA,Lucas VS. The clinical pharmacokinetics of vinorelbine (Navelbine). Semin Oncol 1994; 21 Suppl. 10: 21-7 61. Rowinsky EK, Noe DA, Trump DL, et al. Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors . J Clin Oncol 1994; 12: 1754-63 62 . Vokes EE, Rosenberg RK, Jahanzeb M, et al. Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer. J Clin Oneol 1995; 13: 637-44 63. Lucas S, Rowinsky E, Wargin W, et al. Results of a study of the effect of food on the bioavailability (BA) and pharmacokinetics (PK) of navelbine" (NVB) liquid-filled soft gelatin capsules [abstract]. Proc Am Soc Clin Oncol 1993; 12: 160

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64. Hunter J, Jepson MA, Tsuruo T, et al. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells . J Bioi Chern 1993; 268 : 14991-7 65. Hunter J, Hirst BH, Simmons NL. Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers. Pharm Res 1993; 10: 743-9 66. Winer EP, Chu L, Spicer DV. Oral vinorelbine (Navelbine) in the treatment of advanced breast cancer. Semin Oncol 1995; 22 Suppl. 5: 72-9 67. Urien S, Bree F, Breillout F, et al. Vinorelbine high-affinity binding to human platelets and lymphocytes: distribution in human blood. Cancer Chemother Pharmacol 1993; 32: 231-4 68. Rosazza JPN, Duffel MW, EI-Marakby S, Ahn SH. Metabolism of the Catharanthu s alkaloids : from Streptomyces griseus to monoamine oxidase B. J Nat Prod 1992; 55: 269-84 69. Zhou-Pan XR, Scree E, Zhou XJ, et al. Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions. Cancer Res 1993; 53: 5 J21-6 70. Zhou XJ, Zhou-Pan XR, Gauthier T, et al. Human liver microsomal cytochrome P450 3A isozymes mediated vindesinc biotransformation. Biochem Pharmacol 1993; 45 : 853-61 71. Jehl F, Quoix E, Leveque D, et al. Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography. Cancer Res 1991; 51: 2073-6 72. Leveque D, Jehl F, Quoix E, et al. Pharmacokinetic profile of vinorelbine, a new semi-synthetic vinca alkaloid, determined by high-performance liquid chromatography. Xenobiotica 1993; 23: 1325-33 73. Leveque D, Merle-Melet M, Bresler L, et al. Biliary elimination and pharmacokinetics of vinorelbine in micropigs. Cancer Chemother Pharmacol 1993; 32: 487-90 74. Rahmani R, Bruno R, I1iadis A, et al. Clinical pharmacokinetics of the antitumor drug navelbine (5'-noranhydrovinblastine). Cancer Res 1987; 47: 5796-9 75. Rahmani R, Gueritte F, Martin M, et al. Comparative pharmacokin etics of antitumor vinca alkaloids: intravenous bolus injections of navelbine and related alkaloids to cancer patients and rats . Cancer Chemother Pharmacol 1986; 16: 223-8 76. Marquet P, Lachatre G, Debord J, et al. Pharmacokinetics of vinorelbine in man. Eur J Clin Pharmacol 1992; 42: 545-7 77. Robieux I, Sorio R, Vitali V,et al. Pharmacokinetics of vinorelbine in breast cancer patients with liver metastases [abstract] . Proc Am Soc Clin Oncol 1995; 14: 458 78. Khayat D, Covelli A, Variol Ph. Phase I and pharmacologic study of intravenous (i.v.) vinorelbine (VRL) in patients (PTS) with solid tumors [abstract]. Proc Am Soc Clin Oncol 1995; 14: 469 79. Lengsfeld AM, Dietrich J, Schultze-Maurer B. Accumulation and release of vinblastine and vincristine by HeLa cells : light microscopic, cinematographic, and biochemical study. Cancer Res 1982; 42 : 3798-805 80. Ferguson PJ, Cass CE oDifferential cellular retention of vincristine and vinblastine by cultured human promyelocytic leukemia HL-60/CI cells: the basis of differential toxicity . Cancer Res 1985; 45: 5480-8 81. Singer WD, Himes RH. Cellular uptake and tubulin binding properties of four vinca alkaloids . Biochem Pharmacol 1992; 43: 545-51

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Correspondence and reprints: Dr Dominique Leveque, Department of Pharmacokinetics, Institute of Bacteriology, 3 rue Koeberle, 67000 Strasbourg, France.

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