Annals of Oncology Advance Access originally published online on October 3, 2006
Annals of Oncology 2007 18(1):190-195; doi:10.1093/annonc/mdl315
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© 2006 European Society for Medical Oncology
phase I and pharmacokinetics |
Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone
1 The Albert Einstein Comprehensive Cancer Center
2 Department of Molecular Genetics
3 Department of Molecular Pharmacology, Albert Einstein College of Medicine
4 Comprehensive Cancer Center of NYU School of Medicine, New York University, New York
5 Bristol-Myers Squibb, Wallingford
6 Cancer Therapy Evaluation Program of the National Cancer Institute, Bethesda
7 University of Pittsburgh Cancer Institute, Pittsburgh, USA
* Correspondence to: Dr S. Mani, Department of Oncology, Weiler Hospital, Room 2S-49, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel: +1-718-904-2529; Fax: +1-718-904-2892; E-mail: smani{at}montefiore.org
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Abstract |
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Background: We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken.
Patients and methods: Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK.
Results: Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n = 27) and tumor cells (n = 9), peak MBF occurred at the end of infusion; however, at 24–72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50 = 109.65 ng/ml; r2 = 0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P = 0.050).
Conclusions: Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.
Key words: neuropathy, neutropenia, pharmacodynamics, tubulin
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontributorsAcknowledgementsReferences |
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Ixabepilone is a semisynthetic analog of epothilone B and is currently being evaluated in clinical trials as a treatment of breast cancer and other solid malignancies [1–8]. We carried out a clinical phase I study that defined the recommended phase II dose (RPTD) of ixabepilone (40 mg/m2 administered over 1 h) for patients with advanced solid tumors [9]. As part of that phase I study, we evaluated correlative findings associating drug pharmacokinetic (PK) parameters with microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) and in one tumor sample specimen [10]. Our findings indicated a positive linear correlation of cycle 1 area under the plasma time–concentration curve (AUC0–24) (r2 = 0.51) and negative correlation of clearance (CL0–24) (r2 = 0.61) with peak (end of infusion) number of PBMCs with MBF. Similar findings were established for the number of cells with microtubule bundles observed at 24 h after drug infusion. Therefore, for the exposure range studied (AUC0–24 0–2000 ng/h/ml; CL0–24 200–2000 ml/min/m2), we concluded that the extent of MBF in PBMCs was related to amount of drug exposure. A second finding of considerable importance was that in one patient with breast cancer, from whom we obtained serial chest mass biopsies before and after drug infusion, there were differential kinetics of MBF in PBMCs versus tumor cells that was delayed but then sustained in tumor cells. However, peak levels of PARP cleavage (a marker for cell death) were not observed until 24 h after drug infusion, implying that cell death in tumor cells occurred after binding to the drug target, tubulin. These data led to the hypothesis that drug target effects could be quantified in human cells and this measure could be used to further ‘titrate’ a blood concentration of ixabepilone that is optimized for response and toxicity. The drawbacks of the initial study included limited sample size evaluations for both PBMCs and tumor cell estimates. Specifically, plasma PK was studied over a wide dose range (14.8–59.2 mg/m2) with only six patients treated at the RPTD of 40 mg/m2 [10].
During the completion of the phase I study, we expanded the RPTD cohort (n = 47) to include three groups of patients (i.e. those with breast, gynecologic, and other solid malignancies) so as to define group-specific antitumor response characteristics and toxic effects [11, 12]. In this expansion, we obtained serial collections of blood for PK and PBMCs (n = 29 patients) and tumor biopsies (n = 9 patients). This work is an extrapolation of our pilot study [10] and is the first report examining the relationship between plasma PK and MBF in blood and tumor tissue compartments for patients treated at the RPTD of ixabepilone.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontributorsAcknowledgementsReferences |
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multidisease group phase I/II clinical evaluation of ixabepilone
All patients enrolled in the expansion phase of the RPTD of our previously published phase I study were eligible for this analysis [9]. Six of the patients described in our published pilot study [10] were also included in the analyses described in this article. Patient inclusion criteria are described elsewhere [9]. Before beginning therapy, all patients gave written informed consent for study participation according to federal and institutional guidelines.
dosage and drug administration
Ixabepilone was administered i.v. over 1 h at a starting dose of 40 mg/m2 with hypersensitivity prophylaxis and repeated every 21 days (one course) [9]. Patients who experienced dose-limiting toxicity could continue to receive ixabepilone after dose reduction by one level, in accordance with phase I de-escalation rules [9, 12]. Prophylactic use of growth factors was not permitted. However, at the discretion of the treating physician, granulocyte colony-stimulating factor was used for febrile neutropenia, sepsis with neutropenia, or recurrent grade 4 neutropenia.
pretreatment and follow-up studies
Standard physical and laboratory assessments were carried out as described in our previously published phase I study [9]. Objective antitumor response assessments were ascertained using previously published criteria [13].
plasma sampling and analytical assay
PK sampling, analysis, and schema have been described previously for total drug concentrations [9]. Extensive blood sampling for up to 48 (n = 38), 72 (n = 34), and 120 (n = 21) h after infusion was carried out. PK studies were carried out in both treatment cycles 1 and 2. Whole blood was obtained in CPT vacutainer tubes (BD Biosciences, San Jose, CA) for isolation of PBMCs in both cycle 1 (n = 29) and cycle 2 (n = 8) before drug infusion and at 1, 24, 48, and 72 h from the start of drug infusion. The end-of-infusion sample approximated 59.5 min for the majority of patients, although the range was between 30 (n = 21) and 90 (n = 1) min. Cytospin preparations were carried out according to our protocol as published previously [10].
tumor biopsies
Serial tumor biopsies were carried out on select patients who demonstrated skin or s.c. tumor deposits or accessible adenopathy. These sites were known to contain virtually pure tumor cell populations as evidenced by pretreatment biopsies of the site for routine hematoxylin–eosin histopathology. Patients underwent either a Tru-Cut (18G) core biopsy for nodal disease (obtaining two cores per sampling) or a 1- or 5-mm skin punch biopsy directly on a tumor nodule (single punch sample per time point). Biopsies were obtained once before drug infusion and then from the same or adjacent site at the end of infusion and at 24, 48, and 72 h from the start of infusion. Touch preparations of tumor cells were carried out as previously described [10].
immunohistochemistry
All PBMC cytospins and tumor touch preparations on slides were rehydrated, blocked in normal goat serum and processed for immunofluorescence, as previously described [10]. Approximately 400 PBMCs were counted per sample time point. Microtubule bundles represented areas of densely polymerized tubulin and were characteristic of cells treated with microtubule-stabilizing drugs. Their localization was cytoplasmic. A representative pictograph is shown (supplemental Figure 1S, available online) and additional images of PBMCs bearing MTB have been published previously [10].
statistical analysis
Descriptive data summaries were tabulated and graphed using Analyse-it Software (Analyse-it Software Ltd, Leeds, UK). PK data were analyzed using Kinetica 4.2 and two-dimensional linear and nonlinear regression analysis were carried out using SigmaPlot 9.0 (Systat Software Inc.)
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontributorsAcknowledgementsReferences |
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clinical summary
Table 1 summarizes patient characteristics. According to study enrollment criteria, the majority of patients had either an ovarian or breast malignancy. The other solid tumor categories included colon, non-small-cell lung, melanoma, or pancreatic adenocarcinoma.
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MBF in PBMCs
In cycle 1 of therapy, 29 (62%) patients were eligible for assessment of baseline MBF in PBMCs. Due to sampling errors, only 27 of those patients were assessable for end-of-infusion MBF in PBMCs. In cycle 2, fewer patients (n = 16) consented to PBMCs collection; however, only eight patients (50%) had adequately collected and processed PBMCs for evaluation of MBF. A representative pictograph is shown in supplemental Figure 1S (available online).
Figure 1 and Table 2 summarize the statistics of MBF in PBMCs collected from patients on study. The mean (± standard deviation) MBF in PBMCs at the end of infusion in cycle 1 (n = 27) and cycle 2 (n = 8) are approximately equivalent [49% (± 10%) versus 57% (± 12%), paired two-tailed t-test P = 0.7761]. The geometric means are also not significantly different for cycles 1 and 2. At 48 h after drug infusion in cycle 1, three patient samples were collected; however, only two samples were processed adequately. The average number of cells with MBF was 
4%. At 72 h after drug infusion in cycle 1, two patient samples were collected, and both were processed adequately. The average number of MBF for these two patients was 0.1%.
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Interobserver values for each sample were obtained by three different laboratory personnel trained by one investigator (HM) at the start of this study. Intra and intervariability were low.
MBF in tumor cells from patients with advanced cancer
In cycle 1 of therapy, nine (19%) patients were eligible for assessment of baseline MBF (day 1) in tumor cells. All tumor cells were obtained from metastatic lesions accessible to percutaneous biopsy. Five patients had a breast malignancy, and other tumor types biopsied included uterine adenocarcinoma (n = 1), abdominal adenocarcinoma of unknown origin (n = 1), metastatic melanoma (n = 1), and colorectal adenocarcinoma (n = 1). Full serial biopsy sampling from baseline for up to 48 and 72 h was only possible in four and three patients, respectively. Unlike PBMCs, there were no microtubule bundles observed at baseline. The peak number of tumor cells with MBF was seen at the end of infusion and was 29% (n = 9), which was 59% of the number of PBMCs with MBF. In contrast to PBMCs, however, the mean percentage of MBF in tumor cells at 24 h was not significantly different from that obtained at the end of infusion (29% versus 23%, paired t-test, two-tailed p = 0.1370). At 48 h after drug infusion in cycle 1 (n = 4), the mean percentage of tumor cells with MBF was 10% which diminished to 3% by 72 h after infusion (Figure 2).
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PK summary
Table 2 summarizes all cycle PK parameters of ixabepilone in the 43 patients who underwent complete PK assessments in cycles 1 (n = 43) and 2 (n = 41). Inspection of the mean plasma concentration versus time curves for cycles 1 and 2 showed no difference in the multicompartment distribution and elimination of ixabepilone (data not shown). There was no significant association between ixabepilone dose and AUC, clearance, Cmax, or Vss, respectively. In similar analyses grouped by cycles 1 or 2, again there was no significant association in these PK parameters and the dose range of ixabepilone administered in this study (data not shown).
PK and drug target effect relationships
peripheral blood mononuclear cells.
Figure 3 describes the relationship between the percentage of PBMCs with MBF and ixabepilone concentration in plasma. A Hill model (r2 = 0.94) with the following parameters fit this relationship, EC50 = 109.65 ng/ml; Emax = 68%; E0 = 2%. Ixabepilone AUC and Cmax also showed correlations (r2 > 0.3) with MBF in PBMCs at the end of infusion and 24 h from the start of drug infusion.
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MBF in PBMCs and tumor cells and toxicity correlations.
The principal dose-limiting toxic effects of ixabepilone are neutropenia and neuropathy [2]. For neutropenia, in cycle 1, there is a weak negative correlation between percentage of PBMCs with microtubule bundles at the end of infusion and the absolute neutrophil count (ANC) nadir (r2 = 0.12; Figure 4A). The mean percentages of PBMCs with MBF for those patients with grade 0–1 and 2–4 neutropenia were 41% and 53%, respectively (P = 0.050; Figure 4B).
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tumor cells.
Since plasma concentrations were not available for all nine patients at the exact time of tumor biopsy, we could not carry out or develop a Hill model, as in the case of PBMCs. However, plasma drug exposure could be evaluated over the biopsy period (0–24 h). Plasma ixabepilone AUC was negatively correlated (r2 = 0.32) with the number of tumor cells with MBF. Plasma drug clearance (CL) was positively correlated (r2 = 0.42) with the end-of-infusion count of MBF in tumor cells. Finally, plasma Cmax was negatively correlated (r2 = 0.53) with the number of MBF in tumor cells at 24 h from the start of drug infusion.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontributorsAcknowledgementsReferences |
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This is the first and only study carried out to date that comprehensively analyzes both plasma drug PK and the drug target effect in normal and tumor cells using a single RPTD of ixabepilone (40 mg/m2) infused over 1 h. The most significant conclusion of this study is that plasma ixabepilone concentrations correlated with the percentage of PBMCs with microtubule bundles. The Hill plot (Figure 3) validated our published pilot data, indicating that across a large dose and exposure range, ixabepilone concentrations correlate with the percentage of PBMCs with MBF [10]. The Hill plot further validates our original hypothesis that drug binding to cellular microtubules in PBMCs is a fast, reversible dose- and time-responsive event.
The plots in Figure 4A demonstrates that there is a tentative relationship between the percentage of PBMCs with MBF and either ANC nadir or (Figure 4B) the severity of neutropenia as defined using toxicity grades grouped as 0–1 and 2–4. The relationship is weak and population pharmacokinetics–pharmacodynamics models of larger databases are currently underway to estimate a true relationship between PK and neutropenia. However, a stronger relationship may exist if the whole blood could be fractionated into neutrophils. Formal studies are ongoing to assess the impact of neutrophil MBF as a function of hematologic toxicity. From the present dataset (Figure 4B), assuming that patients demonstrating a mean percentage of MBF of >55% in PBMCs at the end of drug infusion have neutropenia (i.e. ANC < 1000, see Figure 4B), then a corresponding prediction for that level of MBF formation by the Hill plot gives us an ixabepilone plasma concentration of >625 ng/ml. Therefore, patients demonstrating an end-of-infusion ixabepilone concentration exceeding 625 ng/ml may be at risk for developing grade 2–4 neutropenia. This potentially could be monitored in large clinical trials by determining MBF in PBMCs at the end of infusion. This type of model needs validation in larger clinical studies. Furthermore, we speculate that in alternative regimens of BMS-247550 (five times qd and weekly) [14], the exposure to concentrations above 625 ng/ml is limited and of minimal duration, providing another potential reason why these regimens may be less toxic in the clinical setting.
By contrast, in tumor cells, there was no correlation between ixabepilone plasma concentrations and MBF (data not shown), albeit for a small sample size. In fact, ixabepilone AUC (r2 = 0.32) and CL (r2 = 0.42) correlated negatively and positively, respectively, with peak MBF formation. These data could imply differential kinetics seen in PBMCs and tumor cells. PBMCs are suspended in blood and are readily exposed to drug, while the drug has to penetrate multiple layers and compartments to access microtubules in the tumor. Therefore, MBF will occur at a critical drug concentration that probably differs for each cell type and is related to differences in accessibility to microtubules, inherent differences in tubulin isotype expression, the intrinsic extent of tubulin polymerization, and microtubule dynamicity. Therefore, analysis of a larger dataset is being carried out to determine the relationship between antitumor response and MBF in tumor cells. Attempts to model MTB in ex vivo cultured PBMCs were noninformative.
Despite these concerns, an overall model of drug distribution and elimination from various body compartments can be made. First, after drug enters the plasma compartment, there is rapid distribution to PBMCs and tumor tissue. A similar disposition is likely to occur in organs such as the liver but there drug extraction likely undergoes a more complex model due to metabolism, transport, and enterohepatic circulation. There seems to be prolonged retention of MBF in tumors, indicating that the drug is likely retained in tumors for a longer period of time than in PBMCs. Alternatively, intravascular PBMCs with microtubule bundles may be cleared from the circulation by phagocytosis. This process may not be as efficient in tumors, or tumor cells may tolerate the microtubule bundles, due to inherent genetic aberrations.
There is precedence in the literature to indicate that microtubule-stabilizing drugs have particular avidity for the tumor compartment, which is completely disconnected from the plasma compartment. A recent paper by Li et al. [15] shows that for [3H]paclitaxel in rodent tumor models, peak plasma concentrations are achieved within 2 h of i.v. dosing but are undetectable at 5 h after dosing. In contrast, between 2 and 24 h after dosing, tissue concentrations of paclitaxel in liver, kidney, and spleen/muscle/lung dropped 50-, 26-, and 9-fold to 11-fold, respectively. In contrast, in this interval, tumor concentrations of paclitaxel dropped only 1.6-fold. By 24 h, the concentration of paclitaxel was higher in tumor than any other tissue compartment and remained as such for 144 h after dosing [15]. A similar retention of drug in tumor has been reported for docetaxel with a tumor half-life of 22 h: long after the drug has been eliminated from plasma compartment [16]. For epothilones, there is no published data demonstrating prolonged tumor retention; however, Lichtner et al. [17], have demonstrated that epothilone epoxides (e.g. BMS-247550) are more effectively retained within tumor cells than are olefin analogs. Furthermore, verapamil-sensitive transporters, not identical with P-glycoprotein, may recognize and export epothilone analogs, although analyses of cancer cell lines grown as monolayers indicates cellular uptake saturation by 2 h, although epoxides are retained better than other analogs [17].
In this study, an analysis of dose (milligram) and PK variables was conducted and there was no significant association, probably due to significant variability in PK parameters (50-fold > 1000-fold) and limited dose range (50–100 mg). Similarly, this two-fold dose range was also limited in describing a relationship with MBF present in PBMCs.
In summary, our study has validated the hypothesis that plasma ixabepilone concentrations effectively predict for the percentage of PBMCs with MBF. Furthermore, our study has generated the hypothesis that the percentage of PBMCs with microtubule bundles also predicts the severity of neutropenia. While MTB assays demonstrate proof of concept, alternate methods including the analysis of tubulin post-translational modifications that indirectly correlate with tubulin polymerization, such as acetylation, as demonstrated elsewhere [14], may also have utility. Either assay may be incorporated into the clinical development of novel microtubule-binding agents as they are technically simple and cost effective and they provide data that may predict toxicity.
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contributors |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontributorsAcknowledgementsReferences |
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S. B. Horwitz and M. J. Egorin were cosenior authors and S. Mani and H. M. McDaid contributed equally to this study.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontributorsAcknowledgementsReferences |
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We thank Scott Wadler (Principal Investigator of the New York Phase II Consortium) for his critical comments while preparing the manuscript. We also acknowledge the technical assistance of Heng-Jia Shen and Eva Lippaine-Horvath. This study was supported by National Institutes of Health grants CA 13330-30, U01 CA76642-01, R03 CA 86807, CA 39821, and CA 77263 (SBH); GCRC M01 RR00096 (FM); and GCRC M01-RR12248 (Albert Einstein College of Medicine of Yeshiva University). HMD was supported by a postdoctoral fellowship from the Susan G. Komen Foundation (99-3064). SM was supported by a clinical investigator award from the Damon Runyon Cancer Research Foundation (CI: 15-02).
Received for publication February 7, 2006. Revision received July 12, 2006. Accepted for publication July 24, 2006.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontributorsAcknowledgementsReferences |
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