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    Plasma docetaxel concentration–time relationship in tumor-bearing dogs treated with concurrent administration of CSA (5 mg/kg) and docetaxel at 1.5 (n = 6 dogs), 1.625 (3), or 1.75 (7) mg/kg. Data are presented as mean ± SD.

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Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing dogs

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  • 1 Section of Oncology, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 2 Section of Oncology, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 3 Section of Clinical Pharmacology, Department of Medicine, Dartmouth Medical School and Dartmouth Hitchcock Medical Center, Lebanon, NH 03766.
  • | 4 Section of Oncology, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 5 Section of Clinical Pharmacology, Department of Medicine, Dartmouth Medical School and Dartmouth Hitchcock Medical Center, Lebanon, NH 03766.
  • | 6 Section of Oncology, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 7 Section of Oncology, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Abstract

Objective—To determine the maximum tolerated dose and characterize the pharmacokinetic disposition of an orally administered combination of docetaxel and cyclosporin A (CSA) in dogs with tumors.

Animals—16 client-owned dogs with metastatic or advanced-stage refractory tumors.

Procedures—An open-label, dose-escalation, singledose, phase I study of docetaxel administered in combination with a fixed dose of CSA was conducted. Docetaxel (at doses of 1.5, 1.625, or 1.75 mg/kg) and CSA (5 mg/kg) were administered concurrently via gavage twice during a 3-week period. Plasma docetaxel concentrations were quantified by use of high-performance liquid chromatography, and pharmacokinetic disposition was characterized by use of noncompartmental analysis. Dogs' clinical signs and results of hematologic and biochemical analyses were monitored for evidence of toxicosis.

Results—No acute hypersensitivity reactions were observed after oral administration of docetaxel. Disposition of docetaxel was dose independent over the range evaluated, and pharmacokinetic variables were similar to those reported in previous studies involving healthy dogs, with the exception that values for clearance were significantly higher in the dogs reported here. The maximum tolerated dose of docetaxel was 1.625 mg/kg. Gastrointestinal signs of toxicosis were dose limiting.

Conclusions and Clinical Relevance—The absence of myelosuppression suggested that the docetaxelCSA combination may be administered more frequently than the schedule used. Further studies are warranted to evaluate combination treatment administered on a biweekly schedule in dogs with epithelial tumors.

Abstract

Objective—To determine the maximum tolerated dose and characterize the pharmacokinetic disposition of an orally administered combination of docetaxel and cyclosporin A (CSA) in dogs with tumors.

Animals—16 client-owned dogs with metastatic or advanced-stage refractory tumors.

Procedures—An open-label, dose-escalation, singledose, phase I study of docetaxel administered in combination with a fixed dose of CSA was conducted. Docetaxel (at doses of 1.5, 1.625, or 1.75 mg/kg) and CSA (5 mg/kg) were administered concurrently via gavage twice during a 3-week period. Plasma docetaxel concentrations were quantified by use of high-performance liquid chromatography, and pharmacokinetic disposition was characterized by use of noncompartmental analysis. Dogs' clinical signs and results of hematologic and biochemical analyses were monitored for evidence of toxicosis.

Results—No acute hypersensitivity reactions were observed after oral administration of docetaxel. Disposition of docetaxel was dose independent over the range evaluated, and pharmacokinetic variables were similar to those reported in previous studies involving healthy dogs, with the exception that values for clearance were significantly higher in the dogs reported here. The maximum tolerated dose of docetaxel was 1.625 mg/kg. Gastrointestinal signs of toxicosis were dose limiting.

Conclusions and Clinical Relevance—The absence of myelosuppression suggested that the docetaxelCSA combination may be administered more frequently than the schedule used. Further studies are warranted to evaluate combination treatment administered on a biweekly schedule in dogs with epithelial tumors.

Docetaxel has become well-established as an effective drug for the treatment of multiple types of tumors in humans but has not been extensively evaluated in dogs because of the risk of acute hypersensitivity induced by the drug vehicle, a complication encountered in association with IV administration.1,2 Docetaxel is poorly absorbed after oral administration because of the abundance of Pgp (product of the multiple-drug–resistance gene ABC-B1) on the luminal border of enterocytes. P-glycoprotein on the luminal cell surfaces results in secretion of substrate back into the intestinal lumen and substantially blocks absorption of the drug.3–5 In addition, docetaxel is metabolized in enterocytes via activity of the P450 isoenzyme CYP3A, which reduces the quantity of active parent compound that reaches the systemic circulation.5 A number of strategies interfere with the actions of Pgp and CYP3A and enhance the bioavailability of docetaxel after oral administration have been reported6 in mice, rats, dogs, and humans. Cyclosporin A modulates Pgp and CYP3A functions, and the potential for combined administration of docetaxel and CSA to yield higher plasma concentrations of docetaxel and improve patient comfort has been investigated clinically in humans.7

Oral administration of docetaxel and CSA results in therapeutic plasma concentrations of docetaxel and minimal signs of toxicosis in healthy dogs.8 The bioavailability of orally administered docetaxel alone (2 mg/kg) in dogs is approximately 20% but approaches 100% with the addition of CSA (5 mg/kg, PO). The increased bioavailability results in myelosuppression and diarrhea. The purpose of the present study was to determine the maximum tolerated dose of docetaxel when administered orally in combination with CSA in tumor-bearing dogs.

Materials and Methods

The study protocol was approved by the Cornell University Institutional Animal Care and Use Committee, and written informed consent was obtained from owners before dogs were enrolled in the study. Histologic confirmation of neoplastic disease was required for eligibility. Dogs with or without evidence of metastatic disease were enrolled if tumors had been refractory to previous chemotherapy, if no known chemotherapeutic regimen was proven to be efficacious, or if the owner had declined other treatments. Additional inclusion criteria were that values on hematologic and biochemical analyses were within reference range and imaging (thoracic radiography or abdominal ultrasonography) had been performed for measurement and staging of tumors. Dogs had received no chemotherapy for 4 weeks prior to enrollment and had a minimum life expectancy of 12 weeks.

The lowest dose of docetaxel evaluated was 1.5 mg/kg; that dose was 25% less than the dose used in a previous investigation8 involving healthy dogs. Drugs were administered via gastric gavage. Docetaxela was prepared as instructed by the manufacturer, with an initial dilution of the drug concentrate in 13% ethanol to a concentration of 10 mg/mL and final dilution to 1 mg/mL in saline (0.9% NaCl) solution. Cyclosporin Ab was administered orally at a dose of 5 mg/kg immediately prior to administration of docetaxel. The cyclosporin solution prepared for oral administration was a microemulsion with a concentration of 100 mg/mL and was not diluted further prior to administration. To facilitate drug administration, all dogs were anesthetized with propofol (5 mg/kg, IV) and a feeding tube was inserted into the stomach, through which the CSA emulsion was administered, followed by 5 to 15 mL of saline solution. The docetaxel solution was administered through the same tube, followed by 20 to 40 mL of saline solution. Dogs recovered from anesthesia and were discharged from the hospital after collection of blood samples for up to 6 hours after docetaxel administration. Two docetaxel-CSA treatments were planned at a 3-week interval unless progressive disease was reported.

A schedule of dose escalation was planned after signs of toxicosis were evaluated in cohorts of 3 dogs. The dose of docetaxel was increased in 0.25 mg/kg increments if signs of toxicosis in dogs in a given treatment cohort were graded as 0 or 1. If 1 or 2 dogs had moderate (grade 2) or severe (grade 3 or 4) signs of toxicosis, an additional 3 dogs were evaluated at that dose level and subsequent dose adjustments were determined. If all 3 dogs experienced moderate or severe signs of toxicosis, docetaxel doses were reduced by a 0.25 mg/kg decrement.

Monitoring of dogs for signs of toxicosis consisted of weekly evaluations that included a CBC on days 8, 15, and 21 after each of the 2 treatments and a serum biochemical analysis on day 21 after each treatment. An additional serum biochemical profile on day 8 was added to the monitoring protocol after signs of gastrointestinal toxicosis were observed in dogs that received the 1.75 mg/kg dose. Signs of gastrointestinal toxicosis were reported by owners, and depending on severity of signs, additional treatments were administered (ie, famotidine at a dosage of 0.5 mg/kg, PO, q 12 to 24 h; metoclopramide at 0.2 to 0.5 mg/kg, PO, q 8 h; and loperamide at 0.1 mg/kg, PO, q 8 to 12 h) or dogs were hospitalized and given IV fluid support, antimicrobials, and additional treatment if indicated. The groups that received higher doses (ie, 1.75 mg/kg) of docetaxel were treated preemptively for vomiting and diarrhea with famotidine, metoclopramide, and dolasetron (0.6 mg/kg, IV, before and after docetaxel administration). Signs of toxicosis were categorized according to World Health Organization criteria.9

External tumor measurements in 3 dimensions were recorded prior to initiation of treatment and at 3-week intervals, although tumor response was not a primary end point in the study. Tumor volume was calculated as (height × width × depth) × (π/6). Tumor dimensions were measured from imaging studies when feasible. A complete response was defined as total reduction in measured tumor volume, and a partial response was defined as ≥ 50% reduction in tumor volume that was maintained for a minimum of 3 weeks. Stable disease was defined as < 50% reduction in tumor volume or < 25% increase in tumor volume, and progressive disease was defined as ≥ 25% increase in tumor volume.

Pharmacokinetic sampling and measurement of docetaxel concentrations—Whole-blood samples were collected prior to administration of docetaxel and CSA and 0.5, 1.0, 2.0, 3.0, 4.0, and 6.0 hours after treatment for determination of plasma docetaxel concentrations. Samples were immediately centrifuged, and plasma was separated and stored at −80°C until assayed. Docetaxel concentrations were measured by use of high-performance liquid chromatography. The assay used was a modification of a previously described method10 for assaying paclitaxel. In the present study, docetaxel was measured as the unknown and paclitaxel was used as the internal standard. The lower limit of quantification of the docetaxel assay was 15 ng/mL. Standard curves were used at the beginning and end of the unknown samples, and quality-assurance samples were evaluated over the range of the standard curve run at the beginning, midpoint, and end of the unknown samples. The docetaxel standard curve was linear over the range of 25 to 750 ng/mL. Intraday assay variability ranged from 7% to 10%, and interday assay variability ranged from 7% to 14%. Docetaxel recovery was 91.7%.

Pharmacokinetic methods—Plasma docetaxel concentrations after the initial oral dose of docetaxel were inspected on a semilogarithmic plot of concentration versus time for each dog. Values for Cmax and Tmax were observed values from raw data for plasma docetaxel concentration. A pharmacokinetic software programc was used for estimation of pharmacokinetic variables. Docetaxel concentration-versus-time data were analyzed by use of an open noncompartmental model with extravascular input.d The ke was determined via linear regression of the terminal 2 to 5 points of the log plasma concentration-versus-time plot and a weighting paradigm of 1/Y. Terminal elimination t1/2 was estimated as 0.693/ke. The AUC to the last datum point was estimated by use of the linear-log trapezoidal rule and extrapolated to infinity by adding the Wagner-Nelson correction (Clast/ke). The Cl/F was calculated as dose/AUC0–∞. The Vdz/F was calculated as Cl/ke,,and MRT was estimated as the ratio of AUMC/AUC.

Data for plasma docetaxel concentrations from an earlier study8 of healthy dogs were compared with data from the present study by applying the same pharmacokinetic methods as were used in the present study to the earlier data.

Statistical analysis—Differences among pharmacokinetic variables as a function of dose groups (1.5, 1.625, 1.75, and 2 mg of docetaxel/kg) were evaluated by 1-variable ANOVA. Further comparisons of pharmacokinetic variables among dogs in the 1.75 mg/kg dose group and healthy dogs evaluated in the earlier study8 were made by use of an unpaired Student t test. Values of P < 0.05 were considered significant. Associations between pharmacokinetic variables and toxicity data were evaluated by use of linear regression analysis, and the correlation coefficient was defined. Analyses were performed with statistical software.e

Results

Sixteen dogs were enrolled in this phase I study. Twelve of the 16 dogs received 2 doses of docetaxel, and 4 dogs received 1 dose. One dog was treated at 2 dose levels; blood samples from that dog were used in pharmacokinetic evaluation for both doses. Seven dogs were treated with 1.5 mg/kg, 6 dogs were treated with 1.75 mg/kg, and 3 dogs were treated with 1.625 mg/kg of docetaxel. Median age of dogs was 9 years (range, 2 to 13 years). Nine of 10 female dogs were spayed, and 5 of 6 male dogs were neutered. Median body weight was 29.3 kg (range, 8.5 to 45.1 kg). Tumor types included carcinomas (n = 11; of nasal, mammary gland, thyroid, lung, liver, salivary gland, and digital origin), sarcomas (2; osteosarcoma and undifferentiated sarcoma), 1 malignant melanoma, 1 disseminated histiocytic sarcoma, and 1 heart-base neuroendocrine tumor. Fourteen dogs had metastatic disease. Previous interventions included surgery (10 dogs) and chemotherapy (4).

Toxicity—Signs of gastrointestinal toxicosis were dose limiting. Adverse gastrointestinal signs observed after the first dose of docetaxel were summarized (Table 1). Four of 7 dogs treated with the 1.5 mg/kg dose had occasional, mild, and self-limiting gastrointestinal signs. Severe (grade 3 or 4) signs of gastrointestinal toxicosis, including vomiting and diarrhea, were observed in 4 of 6 dogs treated at the 1.75 mg/kg dose level; those dogs required hospitalization, whereas the remaining 2 dogs had mild (grade 1) or moderate (grade 2) signs. Preemptive medical treatment (with metoclopramide, famotidine, and dolasetron) was instituted for signs of nausea, vomiting, and diarrhea in that cohort of dogs, but treatments did not completely obviate the signs of drug toxicity. Results of serum biochemical analysis on day 8 revealed mild (grade 1) signs of toxicosis in 2 dogs treated with 1.75 mg of docetaxel/kg (increased serum amylase activity in 1 dog and increased serum alkaline phosphatase activity in 1 dog) and in 2 dogs treated with 1.625 mg of docetaxel/kg. No evidence of toxicosis was observed in dogs on the basis of serum biochemistry analyses performed on day 21. Three dogs treated with 1.5 mg of docetaxel/kg had no signs of toxicosis and yielded 6 data sets for pharmacokinetic analysis after receiving 2 treatments at that dose. As a result of the steep doseeffect relationship for gastrointestinal signs of toxicosis (ie, minimal drug toxicity at 1.5 mg/kg but unacceptable toxicity at 1.75 mg/kg), 3 additional dogs were treated with an intermediate (1.625 mg/kg) dose at the end of the study so that the dose-toxicity relationship could be better evaluated. Only 1 dog in the 1.625 mg/kg dose group had severe gastrointestinal signs of toxicosis. Adverse gastrointestinal signs resolved within 5 to 7 days of onset, although 1 dog had persistent diarrhea. Only 1 of the 16 study dogs had evidence of myelotoxicosis; that dog was the only dog in the 1.625 mg/kg dose cohort with severe gastrointestinal signs of toxicity. That dog was also concurrently receiving meloxicam,f a nonsteroidal anti-inflammatory drug that also undergoes metabolism via P450 enzymes.11

Table 1—

Summary of gastrointestinal signs of toxicosis in 16 tumor-bearing dogs that were treated with an orally administered combination of docetaxel and CSA. Severity of clinical signs was graded according to World Health Organization9 criteria. All dogs received the same dose (5 mg/kg) of CSA.

No. of dogsDocetaxel dose (mg/kg)Grade 0Grade 1Grade 2Grade 3Grade 4
71.524010
31.62510101
61.7501113

Tumor response—Tumor responses to combination treatment with docetaxel and CSA were assessed 3 weeks after the second dose of docetaxel or were recorded earlier if there was evidence of progressive disease. No complete or partial responses were observed. Nine dogs had progressive disease, 6 dogs had stable disease, and tumor response could not be assessed in 1 dog.

Docetaxel pharmacokinetics—Measurable plasma docetaxel concentrations were detected in 15 of 16 sample sets from study dogs (1 of those 15 dogs was treated twice). In blood from the remaining dog, an unknown peak was coeluted with docetaxel and interfered with analysis of all samples. Terminal t1/2 and other pharmacokinetic variables could not be determined in 4 dogs because of undetectable plasma concentrations at later time points; in those dogs, only Tmax and Cmax were defined. The estimate of AUC0– was determined by use of the linear-log trapezoidal rule with the Wagner-Nelson correction. In the 11 data sets for which full pharmacologic assessment was possible, the extrapolated percentage of AUC beyond Clast was < 16% (range, 1.8% to 15.4%). No differences in pharmacokinetic variables as a function of dose group were observed (Table 2).

Table 2—

Summary of pharmacokinetic variables in healthy and tumor-bearing dogs that were treated with a combination of orally administered docetaxel and CSA. Data are given as mean ± SD. There were no significant differences for variables among dose groups in dogs with tumors, but clearance was significantly different between healthy and tumor-bearing dogs.

Dose groupTmax(h)Cmax(ng/mL)t1/2(h)AUC(ng•h/mL)Cl/F(L/h)Vd/F(L)MRT(h)
1.5 mg/kg (n = 6)0.8 ± 0.3403.6 ± 188.50.9 ± 0.6639.4 ± 270.579.1 ± 47.984.7 ± 44.01.8 ± 0.8
1.625 mg/kg (n = 3)1.0 ± 0.0362.8 ± 144.30.5 ± 0.2411.9 ± 220.2100 ± 65.762.7 ± 36.11.4 ± 0.4
1.75 mg/kg (n = 6)1.4 ± 0.5465.7 ± 345.90.8 ± 0.3549.0 ± 263.1101.1 ± 22.6*191.3 ± 160.92.3 ± 0.8
2.0 mg/kg (n = 6; given to healthy dogs)0.67 ± 0.3403.6 ± 128.73.0 ± 1.0788.6 ± 243.224.6 ± 9.1*102.4 ± 32.23.7 ± 1.6

P = 0.002.

Given to healthy dogs. Adapted from McEntee M, Silverman JA, Rassnick K. Enhanced bioavailability of oral docetaxel by co-administration of cyclosporin A in dogs and rats. Vet Comp Oncol 2003;1:105–112. Values for healthy dogs were calculated from data obtained in a previous study.

In 10 of 11 treatments, plasma concentration–time curves decayed in a monoexponential pattern. In 1 dog that received the highest docetaxel dose, a biexponential pattern of decay in plasma concentrations was observed, with an estimated β-elimination t1/2 of 4.4 hours. Comparison of values for pharmacokinetic variables in dogs in the present study and those from healthy dogs in a previous study8 revealed similar plasma concentration–time curves (Figure 1). Values for all variables were similar, with no significant (AUC, P = 0.27; Cmax, P = 0.92; Vdz/F, P = 0.19) differences between the groups except for Cl/F values (Table 2). Tumor-bearing dogs in the present study had significantly (P = 0.002) greater docetaxel clearance, compared with clinically normal dogs (101.1 ± 22.6 L/h vs 24.6 ± 9.1 L/h, respectively). The dog that was receiving meloxicam concurrently with docetaxel had the highest value for dose-adjusted Cmax, the shortest value for elimination t1/2, and the third-lowest value for Cl/F after oral administration in that study group.

Figure 1—
Figure 1—

Plasma docetaxel concentration–time relationship in tumor-bearing dogs treated with concurrent administration of CSA (5 mg/kg) and docetaxel at 1.5 (n = 6 dogs), 1.625 (3), or 1.75 (7) mg/kg. Data are presented as mean ± SD.

Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.1057

Discussion

Intentional modification of the biochemical barrier to drug absorption in the small intestine is a valuable strategy for use with antineoplastic agents that are substrates for the P450-CYP3A detoxification enzymes and enterocyte Pgp transporters. Orally administered chemotherapy may enhance ease of treatment and patients' comfort level because lengthy IV infusions and the need for attendant premedication to reduce signs of anxiety, emesis, or hypersensitivity reactions can be avoided.12 Successful development of long-term oral administration regimens for antineoplastic agents may also provide an opportunity for further investigation of metronomic dosing strategies or drug-radiation interactions.6,12–14

Concurrent administration of docetaxel and CSA resulted in pharmacologically effective plasma docetaxel concentrations in older tumor-bearing dogs at doses of docetaxel with acceptable toxicity profiles, a finding that was similar to previous findings in clinically normal dogs. In the present study population, the dose-limiting manifestation of drug toxicity was gastrointestinal disturbances. Dogs appeared to have greater propensity for gastrointestinal signs of toxicosis after docetaxel administration than other species,1 and data indicated that there was a steep dose-effect relationship. Gastrointestinal signs observed in dogs in the present study were likely the result of systemic and local effects of docetaxel. Intestinal signs of toxicosis have been reported1 to be the primary manifestation of drug toxicity in dogs receiving docetaxel IV. It is possible that gastrointestinal signs of toxicosis are increased when docetaxel is administered concurrently with CSA because of CSA's inhibitory effects on the actions of CYP3A and Pgp.15 Higher intracellular docetaxel concentrations at the level of the enterocyte when the drugs are administered concurrently may also increase toxicity. Although the dose-limiting sign of toxicosis in humans receiving parenterally administered docetaxel is myelosuppression (manifested as neutropenia), lifethreatening signs of gastrointestinal toxicosis have also been reported.16,17 Gastrointestinal signs of toxicosis may result from enterocytes being affected by docetaxel's primary action of causing mitotic arrest via formation of stable, nonfunctional microtubule bundles.16 It is also possible that there are adverse gastrointestinal effects associated with the polysorbate 80 and ethanol used in preparation of docetaxel, although the increase in amount of vehicle that dogs were exposed to would be limited given the narrow dose range of docetaxel administered.

Older tumor-bearing dogs that were otherwise healthy were more sensitive to gastrointestinal signs of toxicity than clinically normal dogs,8 as reflected by the nearly 20% difference in maximum tolerated dose (1.625 mg/kg in dogs with tumors vs 2.0 mg/kg in clinically normal dogs) between the groups. This may reflect a general difference in sensitivity to chemotherapy among dogs in a clinical population but may also be a result of age-related changes in expression of Pgp or CYP3A (a change that could affect the intended drug interaction in enterocytes) or nonoptimal scheduling of docetaxel and CSA treatments such that inadequate time elapses between administration of CSA and docetaxel. In elderly humans with cancer, docetaxel pharmacokinetics after IV administration are not different from the pharmacokinetics in younger patients, although older patients appear to be more sensitive to docetaxel-induced neutropenia.18 Substantial interpatient variability exists in AUC and drug clearance among humans receiving docetaxel, leading to individualization of patient doses19–21; such an approach may also be warranted in dogs. One method of individualizing the docetaxel dose in humans is to calculate the dose on the basis of an individual's CYP3A activity, which can be estimated by measuring the urinary metabolite (6-β-hydroxycortisol) of exogenous cortisol.21

In addition to the increased intestinal signs of toxicosis in the population of dogs reported here, compared with the healthy dogs involved in an earlier study,8 dogs in the present study also had higher values for docetaxel clearance. Neutropenia was commonly observed after IV and oral administration of docetaxel during preclinical studies1,8 in Beagles and is the doselimiting manifestation of the drug's toxicity in humans.22 The fact that neutropenia was not a clinically important toxic effect in dogs in the present study may indicate that the frequency of administration of the docetaxel-CSA combination should be increased. Possible explanations for the differences in pharmacokinetic disposition and toxic effects observed between the healthy dogs featured in a previous study8 and the dogs with tumors in the present study include that a brief period of anesthesia was induced in the tumorbearing dogs for ease of docetaxel administration, a different formulation of docetaxel was used in the study involving healthy dogs, and the drug was administered in a larger volume of diluent in the healthy dogs.

Features of the combination treatment strategy that have not been thoroughly investigated in dogs include determination of the optimal CSA dose and the timing of CSA administration relative to docetaxel administration is necessary to maximize absorption of docetaxel. In a human clinical study,23 decreasing the dose of CSA from 10 to 5 mg/kg was associated with a significant decrease in AUC for paclitaxel, whereas an increase in dose from 15 to 30 mg/kg did not result in increased systemic exposure to paclitaxel. In subsequent clinical trials in humans, doses of CSA of 10 or 15 mg/kg have been used. It is possible that adjusting the CSA dose in dogs would further improve the oral bioavailability of docetaxel.

Cyclosporin A was administered immediately prior to docetaxel in the present study and previous study,8 in which we evaluated the drug combination in healthy dogs, but the effects of CSA on docetaxel absorption may be enhanced if administration of the 2 drugs is separated. In humans, CSA is administered 10 to 30 minutes prior to docetaxel. The protocol used in the present study entailed a brief period of general anesthesia and passage of a gastric tube to ensure that CSA and docetaxel were placed directly in the stomach, and the drugs were administered concurrently to minimize anesthetic time. Healthy dogs in the previous study were also orogastrically intubated to facilitate drug administration but were not anesthetized. Administration of CSA 15 to 30 minutes prior to docetaxel administration may alter drug interactions at the level of the enterocyte such that a therapeutic advantage would be obtained. An alternative formulation of docetaxel in which the drug could easily be ingested and the episode of anesthesia could be eliminated could also alter drug absorption and first-pass metabolism.

Finally, simultaneous administration of meloxicam, which is also metabolized via the P450, CYP2C9, and CYP3A isoenzyme systems,11 may have altered docetaxel and CSA absorption or distribution in the 1 dog in the present study that had severe signs of gastrointestinal toxicosis and developed neutropenia. The authors presently require that dogs not be treated with medications that could interfere with P450 enzyme system activity for ≥ 1 week prior to docetaxel administration. Meloxicam also reduces expression of multiple-drug–resistance genes (MDR1) in hepatocytes and tumor cells.24,25

Phase II clinical trials of the docetaxel-CSA combination are warranted to evaluate efficacy in tumorbearing dogs despite the fact that no changes in tumor measurements were observed in the present study. Only 2 doses of docetaxel were administered in the present study, and additional treatments may be required to detect efficacy. Dose intensification by means of shortening the administration intervals may also improve efficacy of the orally administered docetaxel-CSA combination. Investigation of the drugs in treatment of epithelial tumors, such as salivary, pancreatic, pulmonary, and oral-cavity carcinomas, all of which respond to taxane drugs in humans, is warranted in dogs. Humans with angiosarcoma that are treated with taxane drugs respond favorably to treatment with docetaxel-CSA,26,27 suggesting that further investigation of the combination for treatment of hemangiosarcoma in dogs is also warranted.

ABBREVIATIONS

Pgp

P-glycoprotein

CSA

Cyclosporin A

Tmax

Time to maximum plasma concentration

Cmax

Maximum plasma concentration

ke

Terminal elimination rate constant

t1/2

Half-life

AUC

Area under the plasma concentration–time curve

Vdz/F

Apparent volume of distribution, where F = bioavailability

Cl/F

Clearance of docetaxel after oral administration

MRT

Mean residence time

AUC0–∞

Area under the curve from time 0 to infinity

AUMC

Area under the moment of the curve

a.

Taxotere, Aventis Pharmaceutical Products Inc, Collegeville, Pa.

b.

Neoral, Novartis Pharmaceutical Inc, East Hanover, NJ.

c.

WinNonlin, version 2.0, Pharsight Corp, Mountain View, Calif.

d.

WinNonlin model 200, Pharsight Corp, Mountain View, Calif.

e.

GraphPad Prism, version 4.00 for Windows, GraphPad software, San Diego, Calif.

f.

Metacam, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.

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Contributor Notes

Supported by grant No. D02CA-55 from The Morris Animal Foundation, Denver, Colo. Dr. Lewis and Mr. Beaulieu are supported in part by NIHP 30 CA23108.

Address correspondence to Dr. McEntee.