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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS
Department of Pharmaceutical Sciences (D.L.G., E.L.B.-P., A.L.M., J.A.Z.) and the Cancer Center (D.L.G.), University of Colorado Health Sciences Center, Denver, Colorado
Received February 2, 2006; accepted April 24, 2006.
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Abstract |
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450 µM) and 161 µg/g (340 µM), respectively. Tumor levels ranged from 27 to 71 µg/g at Cmax levels across the three dose ranges, and ZD6474 was distributed to all of the tissues in a dose-dependent manner. Analysis of putative ZD6474 metabolites in feces found four, with the N-demethyl-piperidinyl-ZD6474 metabolite being the most prominent but still accounting for less than 2% of the total amount of ZD6474 present. The lack of significant metabolism of ZD6474 is consistent with the relatively long half-life in mice (30 h), as well as that seen in humans (120 h), and the primary method of drug elimination appears to be unchanged in the feces (25%). The incorporation of an empirical approach to dosing in mouse models of cancer in preclinical studies may allow for better prediction of clinical efficacy for ZD6474 alone and in combination with other therapeutic modalities based on equivalent drug exposure.
). Strategies to disrupt RTK signaling pathways for cancer therapy have included antigrowth factor antibodies, receptor antagonists, antireceptor monoclonal antibodies, antisense, and small molecule tyrosine kinase inhibitors (Levitzki and Gazit, 1995; Ciardiello and Tortora, 2001). The success of signal transduction inhibitors, such as imatinib (Gleevec) (Druker et al., 2001), gefitinib (Iressa) (Herbst et al., 2002), erlotinib (Tarceva) (Soulieres et al., 2004), and bevacizumab (Avastin) (Hurwitz et al., 2004), in cancer therapy has had a dramatic effect on the design of clinical trials for new therapeutic regimens.
ZD6474 belongs to a class of synthetic 4-anilinoquinazolines that are orally available and bind to the intracellular kinase domain of RTK, preventing phosphorylation and disrupting signal transduction (Hennequin et al., 1999, 2002). ZD6474 has shown potent and selective activity against the key angiogenesis vascular endothelial cell growth factor receptor (VEGFR2, Flk1/KDR) (Wedge et al., 2002) and the epidermal growth factor receptor (Hennequin et al., 1999). ZD6474 single-agent preclinical models have shown tumor regression against a number of xenograft models (Wedge et al., 2002), as well as enhanced activity of cytotoxic chemotherapy (Ciardiello et al., 2003) and radiation (Gustafson et al., 2004; Williams et al., 2004; Damiano et al., 2005). ZD6474 has also been shown to act as a chemopreventive agent, blocking the formation of chemical-induced preneoplastic and neoplastic lesions in a rat model of mammary carcinogenesis (Heffelfinger et al., 2004).
The use of molecularly targeted agents such as ZD6474 in the clinic will probably involve combinations with other therapeutic modalities. Recent successful clinical trials combining cetuximab (Erbitux) with radiation therapy in squamous cell carcinoma of the head and neck (Bonner et al., 2006), as well as results with trastuzumab (Herceptin) in combination with cytotoxic chemotherapy in breast cancer (Piccart-Gebhart et al., 2005), highlight therapeutic advantages gained. Considering that large numbers of potential combinations exist with various molecular targets, therapeutics, treatment schedules, and a number of other factors, the importance of well planned preclinical studies to limit and optimize combinations that proceed to clinical trial is critical. Preclinical studies should be designed with dose levels and schedules that mimic both response and exposure, either predicted or previously determined, in human patient populations. This approach could potentially increase the correlation between preclinical and clinical successes for treatments and help negate the effect of effective dose intensities in animal models that are irrelevant to the human condition. However, this type of approach requires reliable and intensive pharmacokinetic studies in animal models. To this end, we have carried out a multiple-dose, time course pharmacokinetic study in tumor-bearing nude mice for ZD6474. Drug levels were measured in plasma and tissues after p.o. dosing of 10, 25, and 50 mg/kg, and putative metabolites were analyzed in feces, liver, and plasma.
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Materials and Methods |
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MCF-7 Xenografts. Female 6- to 8-week-old BALB/c athymic nude mice were purchased from Simonsen Laboratories (Gilroy, CA). Animals were housed in polycarbonate cages and kept on 12-h light/dark cycle. Food and water were given ad libitum. All of the studies were conducted in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals, and animals were housed in a facility accredited by the American Association for Accreditation of Laboratory Animal Care. Animals were allowed to acclimate for 7 days before any handling.
Animals were implanted with slow-release Silastic 17
-estradiol pellets at least 24 h before MCF-7 tumor cell inoculation. In brief, animals were anesthetized with 75 mg/kg ketamine and 15 mg/kg xylazine (Vedco, St. Joseph, MO) via i.p. injection. When animals no longer responded to toe pinch, Silastic estradiol pellets were implanted s.c. between the shoulders. The incision was closed with 9-mm wound clips (Kent Scientific, Torrington, CT).
MCF-7 cells were harvested and resuspended in a 3:1 mixture of serum-free RPMI 1640 medium and Matrigel (BD Bioscience, Bedford, MA). Five million cells per mouse were injected s.c. into the rear flank using a 23-gauge needle. Tumors volumes, measured by digital calipers, were calculated by eq. 1.
 | (1) |
Silastic Estradiol Pellets. Silastic estradiol pellets were prepared as described previously by Sartorious et al. (2003). Silastic tubing (1.98 mm ID x 3.18 mm OD, Dow Corning, Midland, MI) was cut into 1-cm pieces and autoclaved. One end of the 1-cm pieces was sealed with clear silicone rubber and allowed to dry overnight. 17-Estradiol (Sigma, St. Louis, MO) was added to 
-cellulose (Sigma) at a ratio of 1:4 (w/w) and then mixed and ground into a fine powder with a mortar and pestle. The powder was packed into the tubing pieces with a sealed Pasteur pipette, and the open end was sealed with clear silicone rubber and allowed to dry overnight. Pellets contain approximately 2 mg of 17-estradiol.
Pharmacokinetic Studies. ZD6474 for p.o. administration was made as a suspension in sterile filtered 1% Tween 80 by gentle mixing with 4-mm borosilicate glass beads overnight. Mice were manually randomized into treatment groups with a weight at the beginning of study of 24.8 ± 1.9 g (median = 25.2 g) and a tumor volume of 193.2 ± 125.8 mm3 (median = 170.9 mm3) and treated with a single dose of 10, 25, or 50 mg/kg ZD6474 by p.o. gavage. Gavage volumes varied between 90 and 120 µl based on animal weight (4 µl/g body weight). After drug dosing, three mice per treatment group were sacrificed at 0.25, 0.5, 1, 4, 8, 24, 48, and 72 h by cardiac stick exsanguinations under isoflurane anesthesia, and plasma and tissue samples were collected (liver, kidney, lung, heart, intestine, fat, muscle, brain, and tumor). Collected samples were rinsed in phosphate-buffered saline and immediately frozen in liquid nitrogen and stored at -80°C before sample preparation for drug analysis. Animals to be sacrificed at 24, 48, and 72 h post-treatment were housed in metabolic cages to collect feces. Urine could not be collected because of evaporation before reaching the collection vesicle. For the multiple dosing pharmacokinetic analyses, four MCF-7 tumor-bearing nude mice were treated with 25 mg/kg ZD6474 for 7 consecutive days, and animals were sacrificed and tissues collected as described 4 h after the last dose.
Liquid Chromatography/Tandem Mass Spectrometry Analysis of ZD6474 and Metabolites. Analysis of ZD6474 in mouse plasma and tissues was carried out using liquid chromatography/tandem mass spectrometry analysis as described previously (Zirrolli et al., 2005). In brief, 50-µl plasma samples were mixed with 50 µl of 10 mM ammonium acetate, pH 9.6, and 50 µl of 1 µg/ml trazodone (internal standard), followed by extraction with 1 ml of 1:1 ethyl acetate/pentane. For tissues, samples were homogenized using a Potter-Elvehjem Tissue Grinder with a polytetrafluoroethylene pestle bottom in 10 mM ammonium acetate, pH 9.6, at approximately 100 mg/ml (w/v); 100-µl aliquots were transferred to another tube containing 50 ng of trazodone, followed by extraction with 1 ml of 1:1 ethyl acetate/pentane. The organic layer was collected following extraction, evaporated to dryness, and reconstituted in 1 ml of acetonitrile/water (1:1, v/v). Samples were analyzed with an API-3000 triple quadrupole mass spectrometer (PE Sciex, Foster City, CA) with a turbo ionspray source interfaced to a PE Sciex 200 highperformance liquid chromatography system. The mobile phase was isocratic with 80% acetonitrile containing 10 mM ammonium acetate and 0.1% acetic acid at a flow rate of 200 µl/min, and a Discovery HS F5, 5 µm, 120 Å, 50 x 2.1-mm column (Supelco, Bellafonte, PA) was used. Samples were quantitated by internal standard reference in multiple reaction monitoring (MRM) mode by monitoring the transition m/z 475 
112 for ZD6474 and the transition m/z 372 176 for the internal standard (trazodone). For the extraction of feces, total collected fecal pools were mixed with water (2:1, water/feces, w/v) to make a homogenous paste that was extracted as described above.
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Saline to Tissue Partitioning. The estimation of ZD6474 saline to tissue partitioning (KpT) was done as described previously (Jepson et al., 1994) with some modification. In brief, 1- to 2-mm3 tissue pieces were incubated in phosphate-buffered saline with gentle shaking at 37°C for 16 h. Saline and tissue were separated by centrifugation at 1500g for 10 min, and the tissue and saline were collected. The saline portion was filtered using a 10,000 Da molecular mass cutoff filter (Centricon YM-10) by centrifugation. Tissue and saline portions were extracted and analyzed for ZD6474 as described earlier.
Pharmacokinetic and Statistical Analysis. Analysis of data for the calculation of pharmacokinetic parameters was carried out using noncompartmental analysis with WinNonlin v. 4.1 (Pharsight Corp., Mountain View, CA). Statistical analyses (Pearson correlation, linear regression) were carried out using Prism v. 4.02 (Graph-Pad Software, Inc., San Diego, CA).
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), clearance (CL/F), and extrapolated volume of distribution (Vz/F) were consistent across doses, in line with the relationship between dose and AUC and Cmax in that all were features of drugs that follow linear kinetics. The time to reach Cmax (Tmax) decreased with dose (Fig. 2, inset). One possible explanation for this is that ZD6474 was dosed as a p.o. suspension, and the compound is more soluble under acidic conditions (Hennequin et al., 2002). Therefore, at higher doses a more rapid peak might have been reached because of increased dissolution and rapid absorption in the stomach before gastric emptying into the more pH-neutral intestinal tract, where the dissolution rate is slower. This idea is supported by the early time course profile shown in Fig. 2, inset, in that an early peak is achieved, followed by a gradual decline and then a gradual increase to a second, smaller peak.
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Tissue Distribution of ZD6474. The time courses of ZD6474 distribution in liver, lung, intestine, kidney, fat, brain, muscle, and s.c. tumor xenografts were determined. The results are shown in Fig. 3, and a summary of tissue pharmacokinetics appears in Table 2. Tissue accumulation, in accordance with plasma data, was linear with dose across all of the tissues, with liver and lung tissue accumulating the highest concentrations. Liver drug levels at Cmax ranged from 40 (84 µM) to 212 µg/g (446 µM) at the 10 and 50 mg/kg doses, respectively. Analysis of saline to tissue partitioning showed that ZD6474 solubility does not vary widely among tissues ranging from 8.3 to 4.8 (drug in tissue/drug in saline). Taking these modest differences in partitioning in account with tissue blood flow (Brown et al., 1997), correlations with both AUC and Cmax in tissues were obtained. The correlation across the tissues analyzed of tissue AUC versus the product of tissue-specific partitioning (KpT) and tissue blood flow (QT) was significant (P < 0.001) with a correlation coefficient (Pearson r value) of 0.925. The same analysis using tissue Cmax values was also significant (P < 0.0013) with a correlation coefficient (Pearson r value) of 0.918. These data strongly suggest that ZD6474 tissue uptake and distribution are perfusion-limited with minimal impact of tissue diffusion.
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Fecal Elimination of ZD6474. Accumulation of ZD6474 in feces was measured to determine drug elimination via this route. Fecal elimination of ZD6474 was measured for 0 to 24, 24 to 48, and 48 to 72 h (Table 3). Cumulative elimination over the 72-h period was linear with dose (r2 = 0.996). Interestingly, the amount of ZD6474 excreted from 48 to 72 h was similar across dose levels. This may be because of the fecal deposition of drug that was never absorbed from the gastrointestinal tract. The time for the entire contents of the mouse gastrointestinal tract to be completely eliminated has been measured at approximately 3 days (Schwarz et al., 2002); thus, the accumulation of unabsorbed drug in the feces would be within this time frame.
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Identification and Relative Measurement of ZD6474 Metabolites. Fecal extracts were analyzed for four putative metabolites as shown in Fig. 1, and all four were detected. It was not possible to accurately quantify the extent of metabolism without valid reference standards for each metabolite, but the relative tandem mass spectrometry response of each metabolite to the parent drug, ZD6474, is shown in Table 4. It was clear that ZD6474 is not extensively metabolized. This conclusion assumes that the extraction, ionization, and CID efficiencies of metabolites were similar to ZD6474, which is probably valid because the ionization and CID processes are directed by the very basic piperidinyl group, and the addition of a hydroxyl group and/or demethylation is not likely to have a large impact on ethyl acetate/pentane solubility. Several metabolites were also detected in plasma and liver samples but at much lower levels (Table 4).
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To verify that the MRM analyses were accurately detecting metabolites, product ion and precursor ion scans were performed with the feces samples. Conclusive product ion spectra were obtained for the two most abundant metabolites, N-demethyl-piperdinyl-ZD6474 ([M+H]+, m/z 461, 463) (Fig. 4A) and 6-OH-methoxy-ZD6474 ([M+H]+, m/z 491, 493) (Fig. 5A). Surprisingly, the products ions of the N-demethyl-piperdinyl-ZD6474 included an ion pair at m/z 364, 366, indicating the loss of neutral methylene-piperidine (M 97) with charge retention on the methoxy-phenyl-4-amino-quinazoline (Fig. 4A). This product ion spectrum was obtained with Q1 in low resolution and Q3 in unit resolution to show that the ion pair at m/z 364, 366 retained the bromine isotopic pattern. The product ion spectra of 6-OH-methoxy-ZD6474 was obtained with both Q1 and Q3 in unit resolution mode and clearly shows that the molecular weight of the metabolite increased by 16 atomic mass units ([M+H]+, m/z 491, 79Br-isotopomer), but the CID fragment ion remained at m/z 112, indicating that the site of hydroxylation was not the N-methylpiperidinyl group. The remaining metabolites did not yield conclusive product ions because of their low abundance.
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Prediction and Validation of Steady-State ZD6474 Plasma and Tissue Concentrations Based on Single-Dose Pharmacokinetic Data. Using the pharmacokinetic data generated from the single-dose studies, predictions were made as to the steady-state levels of ZD6474 in plasma and tissues. Using a half-life value of 28 h, which is the average of the values across doses shown in Table 1, an accumulation factor was calculated with eq. 2:
 | (2) |
is the elimination rate constant based on the terminal half-life (0.693/t1/2) and T is the dosing interval (24 h). From this equation, an accumulation factor of 2.2 was calculated for daily dosing of ZD6474 in nude mice. The accumulation factor was multiplied by the average value at 4 h from the single-dose study at 25 mg/kg, and this tissue concentration is compared with that obtained after 7 days of consecutive dosing of ZD6474 (Fig. 6). The predicted values showed good agreement with the measured values across tissues and validated the pharmacokinetic parameters calculated from the single-dose studies for use in future dose and dosing schedule extrapolations.
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Discussion |
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; Holden et al., 2005) and in phase II trials at doses of 100 and 300 mg/day (Miller et al., 2005). The results from these studies have shown that ZD6474 is slowly absorbed (relatively small Ka), widely distributed (large volume of distribution), and slowly eliminated with an elimination half-life of approximately 120 h (Minami et al., 2003; Holden et al., 2005). More recent pharmacokinetics studies in humans have suggested that the terminal half-life is longer, approaching 200 h (Miller et al., 2005). The long elimination half-life of ZD6474 leads to accumulation with daily dosing until a steady-state level is achieved. Accumulation in Japanese patients when comparing AUC of the first dose versus AUC on day 28 of daily dosing showed a 6 to 14-fold accumulation with elimination half-lives varying from 72 to 167 h (Minami et al., 2003). An approximate 7- to 10-fold accumulation has also been shown in other human studies (Holden et al., 2005).
ZD6474 tissue distribution, metabolism, and fecal elimination in tumor-bearing mice were addressed in the studies presented here. The results show that ZD6474 accumulated in tissues at levels up to 100 times that of plasma (liver and lung) in a manner proportional to the dose. Analysis of feces for putative metabolites identified some metabolites, but they accounted for a very small proportion of the total drug in feces with the majority being parent drug. This lack of substantial in vivo metabolism is consistent with in vitro metabolism studies we have performed using mouse liver microsomal preparations that showed no significant loss of ZD6474 after 2-h incubation (data not shown). One limitation of mouse studies is the inability to quantitatively collect urine, even with the use of standard metabolic cages, because of evaporation before reaching the collecting vesicle. The fact that ZD6474 is highly protein bound (95%) in the plasma, as well as highly lipophilic and thus likely to undergo substantial reabsorption along the nephron, argues against substantial urinary elimination. Furthermore, using the tissue levels that we determined and the measured fecal levels, we can account for 58% of the administered dose after 24 h while only summing 65% of the total mass of the mouse. This argues against extensive urinary elimination and suggests that the major route of ZD6474 elimination in the mouse is fecal excretion of parent drug.
Using human pharmacokinetic data for ZD6474 from clinical trials and the data in mice determined from this study, we can calculate daily dosing in mice that will reflect human parameters in terms of drug exposure. To accomplish this, we used an accumulation factor of 7.8 calculated on a median half-life of 120 h and applied this factor to the Cmax, Cmin, and AUC dose-dependent values reported for single doses in humans. The calculated steady-state values were compared with those calculated in mice with the 2.2-fold accumulation factor, and the human and mouse data are shown in Fig. 7. Based on these calculations, to simulate daily dosing Cmax levels that occur in humans at the 300-mg dose, mouse dosing would be 17.4 mg/kg; to simulate Cmin levels, mouse dosing would be 48.6 mg/kg; and to simulate AUC, a dose of 17.8 mg/kg should be used in mice. The calculation of these doses can be easily changed to reflect the purported longer 200-h half-life that has recently been reported (Miller et al., 2005) by calculating an accumulation factor based on the 200-versus 120-h half-life.
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Doses in mice with ZD6474 in preclinical studies have ranged from 12.5 to 150 mg/kg/day (Wedge et al., 2002; Ciardiello et al., 2003; Taguchi et al., 2004; Damiano et al., 2005). In most cases, pronounced inhibition of tumor growth or induction of tumor regression has occurred at doses above the 25 mg/kg/day level, with doses at or below this level generally leading to a slowing of tumor growth (Wedge et al., 2002). Another issue with dosing in mice is the use of i.p. dosing as a substitute for the p.o. route. Although i.p. dosing has similarities with p.o. delivery in terms of absorption of drug mostly via the intestines and the delivery of drug initially to the liver by way of the splanchic circulation, there are differences that can have dramatic effects on pharmacokinetics. Comparison of i.p. dosing with p.o. gavage in terms of ZD6474 pharmacokinetics in mice has been studied in our laboratory. Dosing via the i.p. route leads to an approximate 2-fold increase in the obtained Cmax value (2.06 versus 1.09 µg/ml at 25-mg/kg dose) and 30% increase in AUC compared with the p.o. route (data not shown). Presumably, this is because of a more rapid absorption of drug caused by the increased surface area presented when drug is dispensed in the peritoneal cavity as opposed to being contained within the gastrointestinal tract. This difference points out the complexity of dosing scenarios in animal models and the importance of pharmacokinetically directed guidelines.
ZD6474 is a novel, poly-targeted tyrosine kinase inhibitor that has shown activity in preclinical animal models and is currently undergoing phase III evaluation for the treatment of cancer. The clinical development of ZD6474 and similar agents will involve the use of multidrug and modality therapy, with cytotoxic chemotherapy and radiation likely companions to its use. Studies have been carried out and are ongoing in animal models on the use of ZD6474 with chemotherapy (Ciardiello et al., 2003; Morelli et al., 2005) and radiotherapy (Gustafson et al., 2004; Williams et al., 2004; Damiano et al., 2005). Carrying out animal studies with rational doses and dosing schedules of drugs comparable with use in humans is an invaluable and often ignored component of preclinical studies. The use of enormous doses with no relevance to the human condition is a common criticism of animal models of cancer (Leaf, 2004) and a valid one.
The clinical development of agents for the treatment of cancer is a long process with the added complexity of drug and treatment combinations along with utility in the advanced or adjuvant setting. Optimization of animal models in this process is an important component. With a drug such as ZD6474, for which human pharmacokinetic data are available, comparative studies of drug disposition in animal models are a reasonable mechanism to ensure that studies are carried out using relevant doses. To this end, we have carried out pharmacokinetic studies in tumor-bearing nude mice of ZD6474. The results of these studies were that ZD6474 shows linear pharmacokinetics within the relevant dose range, was minimally metabolized, and that simple multipledose models can be used to extrapolate both mouse and human ZD6474 pharmacokinetics to calculate dosing scenarios that relate dosing in mice to humans. The application of this information in mouse models will allow for a more sound design and assessment of preclinical animal results when planning clinical trials.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: RTK, receptor tyrosine kinase(s); ZD6474, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-quinazolin-4-amine; MRM, multiple reaction monitoring; CID, collision-induced dissociation; AUC, area under the curve.
Address correspondence to: Dr. Daniel L. Gustafson, School of Pharmacy, C-238, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80220. E-mail: daniel.gustafson{at}UCHSC.edu
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) calculated from the terminal, linear portion of the curves.
