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Coadministration of Cyclosporine Strongly Enhances the Oral Bioavailability of Docetaxel

From the Department of Medical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht; and Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands.

Address reprint requests to Mirte M. Malingré, Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slo-tervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; email: apmmg{at}slz.nl

	ABSTRACT

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PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4.

PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m² with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m².

RESULTS: The mean (± SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m² without CsA was 0.37 ± 0.33 mg·h/L and 2.71 ± 1.81 mg·h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m² was 4.41 ± 2.10 mg·h/L. The absolute bioavailability of oral docetaxel was 8% ± 6% without and 90% ± 44% with CsA. The oral combination of docetaxel and CsA was well tolerated.

CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.

	INTRODUCTION

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IN PAST YEARS, THERE has been an increasing interest in the development of oral treatment regimens of cytotoxic drugs. Patient convenience, practicality, and pharmacoeconomics are major arguments in favor of oral therapy.^1,2 In addition, the oral route facilitates the use of more chronic treatment regimens, which result in prolonged exposure to the cytotoxic agent. For the taxanes paclitaxel and docetaxel, however, the low oral bioavailability has limited development of treatment by the oral route. The low systemic exposure of the taxanes after oral drug administration is, at least in part, due to their high affinity for the multidrug efflux pump P-glycoprotein (P-gp).^3,4 P-gp in the mucosa of the gastrointestinal tract limits the absorption of the orally administered taxanes and mediates their direct excretion into the gut lumen.³ In addition, first-pass elimination by cytochrome P450 (CYP) isoenzymes in the liver and/or gut wall may also contribute to the low oral bioavailability of paclitaxel (CYP 2C8 and CYP 3A4) and docetaxel (CYP 3A4).^5-7

Preclinical experiments performed at the Netherlands Cancer Institute with mdr1a P-gp knockout mice, which lack functional P-gp activity in the gut, have shown significant bioavailability of orally administered paclitaxel³ and docetaxel (unpublished data). Additional studies with wild-type mice revealed good bioavailability after oral administration when paclitaxel⁸ or docetaxel (unpublished data) was combined with cyclosporine (CsA), an efficacious blocker of P-gp and substrate for the CYP 3A4 metabolic enzymes. Recently, we performed a clinical proof-of-concept study of orally administered paclitaxel in combination with oral CsA.^9,10 Coadministration of CsA resulted in a pronounced increase of at least seven-fold in the systemic exposure of paclitaxel. The most plausible explanation for the increase in the systemic exposure is inhibition of P-gp by CsA. In addition, inhibition of paclitaxel metabolism, mediated by CYP 3A4, most likely contributed, as we observed altered paclitaxel metabolism after CsA coadministration.¹⁰ Given our preclinical research and clinical data of oral paclitaxel with CsA, we hypothesized that the systemic exposure of orally administered docetaxel would be increased by coadministration of oral CsA. To investigate this, we initiated a proof-of-concept study in patients with solid tumors.

	PATIENTS AND METHODS

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Patient Population
Patients with a histologically confirmed cancer refractory to current therapies were eligible for the study. Previous radiotherapy or chemotherapy other than taxoid therapy was allowed, provided that the last treatment was at least 4 weeks before study entry and any resulting toxicities were resolved. Eligibility criteria included acceptable bone marrow function (WBC count > 3.0 x 10⁹/L; platelet count > 100 x 10⁹/L), liver function (serum bilirubin level 20 µmol/L; serum albumin level 25 g/L), and kidney function (serum creatinine level 160 µmol/L or clearance 50 mL/min) and a World Health Organization (WHO) performance status of 2. Patients were not eligible if they suffered from uncontrolled infectious disease, neurologic disease, bowel obstruction, or symptomatic brain metastases. Other exclusion criteria were concomitant use of known P-gp inhibitors and chronic use of H2-receptor antagonists or proton pump inhibitors. The study protocol was approved by the medical ethics committee of the Institute, and all patients had to give written informed consent.

Study Design
In the first part of the study, a small cohort of four patients received oral docetaxel without CsA at a dose of 75 mg/m² during course 1 and intravenous (IV) docetaxel at a dose of 100 mg/m² administered as a 1-hour infusion during course 2. In the second part of the study, 10 patients received oral docetaxel 75 mg/m² plus oral CsA 15 mg/kg at one occasion and IV docetaxel at another occasion. In this part of the study, the oral course and IV course were randomized. If it was considered to be in their best interest, patients continued on a 3-weekly schedule of IV docetaxel with a maximum of six IV courses. An oral docetaxel dose of 75 mg/m² (< 100 mg/m²) was selected for safety reasons because preclinical data on oral paclitaxel revealed that coadministration of a P-gp inhibitor and an oral paclitaxel dose can result in a higher systemic exposure than after IV administration of the same dose.¹¹

Drug Administration
The IV formulation of docetaxel (Taxotere; Rhône-Poulenc Rorer/Aventis, Antony, France) was used for both IV and oral administration of the agent. Thirty minutes before oral docetaxel administration, patients ingested the CsA capsules (Neoral; Novartis, Basel, Switzerland). Two patients received the oral solution of CsA (Neoral), which was ingested 10 minutes before intake of docetaxel. Oral drugs were taken with 100 mL of tap water after an overnight fast. Patients remained fasted until 2 hours after oral docetaxel administration. Standard docetaxel pretreatment was given with all courses and consisted of oral dexamethasone 8 mg 1 hour before drug administration and 4 mg every 12 hours (four times) after drug administration. Before oral docetaxel administration, patients received 1 mg of oral granisetron (Kytril; SmithKline Beecham, London, United Kingdom).

Patient Evaluation
Pretreatment evaluation included a complete medical history and complete physical examination. Before each course, an interim history including concomitant medications taken, toxicities, and performance status were registered, and a physical examination was performed. Hematology was checked twice weekly after courses 1 and 2 and weekly after subsequent courses. Blood chemistries, including liver and renal function, serum electrolytes, total protein, and albumin and glucose levels, were checked weekly. All toxicities observed were graded according to National Cancer Institute common toxicity criteria.¹² Dose-limiting toxicity was defined as grade 4 granulocytopenia lasting more than 5 days, grade 4 thrombocytopenia of any duration, or any grade 3 or 4 nonhematologic toxicity except alopecia and untreated nausea and vomiting. Tumor measurements were performed every other cycle but initially after the first two IV courses. Responses were evaluated according to the WHO criteria.¹³

Analysis
Pharmacokinetic monitoring was performed during course 1 and course 2. For plasma docetaxel and metabolite concentrations, blood samples of 5 mL each were collected in heparinized tubes. After oral administration, samples were obtained before dosing, at 15, 30, 45, 60, 75, and 90 minutes, and 2, 3, 4, 7, 10, 24, 30, and 48 hours after docetaxel ingestion. During IV administration, samples were obtained before starting, 30 and 45 minutes after starting, at the end of the infusion, and at 5, 10, 20, 30, 60, and 90 minutes and 2, 3, 4, 7, 10, 24, 30, and 48 hours after infusion. Blood samples were centrifuged, plasma was separated, and samples were immediately stored at -20°C until analysis. Docetaxel and metabolite concentrations in plasma were determined using a validated high-performance liquid chromatography assay.¹⁴ For CsA whole-blood concentrations, blood samples drawn for docetaxel analysis were used. An aliquot of the whole-blood sample was stored at 4°C and analyzed within 1 week using a specific fluorescence polarization immunoassay (TDxFLx; Abbott Laboratories, Amstelveen, the Netherlands).¹⁵

Pharmacokinetics
Noncompartmental pharmacokinetic methods were applied to process the results.¹⁶ The area under the concentration-time curve (AUC) was calculated by the trapezoidal rule with extrapolation to infinity using the terminal rate constant k. Bioavailability of oral docetaxel was calculated as the ratio of the AUC after oral and after IV administration with a correction for the difference in dose. Other parameters to be assessed were the maximal concentration, the time to maximal concentration, the terminal half-life, total plasma clearance after IV administration, and the apparent volume of distribution at steady-state after IV administration. The maximal concentration and time to maximal concentration were observed measured values; the other parameters were calculated using noncompartmental methods.¹⁶ Statistical analysis of the data was performed using the nonparametric Mann-Whitney U test. The a priori level of significance was P = .05.

	RESULTS

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Patient Characteristics
A total of 14 patients (four men and 10 women) was enrolled onto the study (Table 1). At study entry, the median age of the patients was 52 years (range, 31 to 73 years), and the median WHO performance status was 1 (range, 0 to 2). Primary tumor types included breast cancer (n = 8), non–small-cell lung cancer (n = 3), small-cell lung cancer (n = 1), esophageal cancer (n = 1), and stomach cancer (n = 1). All patients had received prior surgical therapy, radiotherapy, and/or chemotherapy.

View larger version (17K): [in this window] [in a new window]   Fig 1. Plasma concentration-time curves of IV-administered docetaxel () and oral docetaxel with CsA (•) and without CsA ( represented as mean ± SD.

View larger version (10K): [in this window] [in a new window]   Fig 2. Chemical structures of docetaxel and its four major human metabolites.

Toxicities
Docetaxel administered orally was very well tolerated. After oral docetaxel administration in combination with CsA (n = 10), the hematologic toxicities observed were anemia (six patients), which was often pre-existing, leukocytopenia (eight patients), and granulocytopenia (six patients) ( Table 5). Hematologic toxicities were relatively mild (grade 1 or 2), except for leukocytopenia and granulocytopenia grade 3 in two patients. The main nonhematologic toxicities after oral intake of docetaxel in combination with CsA were fatigue (seven patients), alopecia (four patients), diarrhea (three patients), nausea (three patients), and flu-like feelings (three patients) ( Table 6). Nonhematologic toxicities did not exceed grade 2 in severity. Toxicities clearly associated with CsA administration were not observed. During the first course of IV-administered docetaxel (n = 10), hematologic toxicities observed were anemia (six patients), which was often pre-existing, leukocytopenia (nine patients), and granulocytopenia (eight patients) (Table 5). Hematologic toxicities were generally grade 3 or less in severity, except for grade 4 granulocytopenia in two patients. One patient developed grade 3 neutropenic fever that required hospitalization and was treated with antibiotics. The principal nonhematologic toxicities after IV-administered docetaxel (n = 10) were fatigue (five patients), alopecia (five patients), arthralgia/myalgia (four patients), flu-like feelings (four patients), infections (three patients), skin reactions (three patients), diarrhea (two patients), and nausea (two patients) (Table 6). Nonhematologic toxicities were relatively mild (grade 1 or 2), except for grade 3 diarrhea in one patient.

	DISCUSSION

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The results presented here show that coadministration of oral CsA strongly enhances the systemic exposure to orally administered docetaxel. Docetaxel administered without CsA exhibits poor oral bioavailability of only 8% ± 6%, whereas oral docetaxel in combination with CsA reaches a bioavailability of 90% ± 44% (P = .011). Furthermore, the coefficient of variation in the systemic exposure after oral drug administration was of the same order as after IV administration, ie, 67% and 53%, respectively. Thus, oral administration did not result in a notable increase in the interpatient difference in systemic exposure.

Our preclinical data obtained in wild-type mice and mdr1ab P-gp knockout mice (unpublished data) combined with these first clinical data indicate that CsA increases the absorption of orally administered docetaxel by effectively blocking P-gp in the gastrointestinal tract. In addition, inhibition of docetaxel metabolism in the gut wall and/or liver by CsA may also contribute to the increased systemic exposure, as both docetaxel and CsA are substrates for the CYP 3A4 metabolic system.^6,7,18,19 The four major metabolites of docetaxel—M1, M2, M3, and M4—originate from successive oxidations of the parent compound by CYP 3A4.^6,7 In in vitro cytotoxicity studies, all four metabolites were significantly less potent than docetaxel.²⁰ Competition for CYP 3A4 by CsA may result in altered plasma levels of docetaxel and metabolites and thereby may result in altered ratios of metabolite to docetaxel. After oral docetaxel administration without CsA, no metabolites were detected in plasma. Therefore, the effect of CsA on the metabolism of orally administered docetaxel could not be determined. Oral ingestion of docetaxel in combination with CsA, however, resulted in an increase of the mean AUC ratio of metabolite M4 to docetaxel compared with IV administration, ie, 0.11 and 0.01, respectively. This relative increase in docetaxel metabolism after oral administration can be explained by the relatively higher initial amount of drug passing through the liver (first-pass effect). Additionally, metabolism of docetaxel in the intestinal wall may also contribute to the higher metabolite levels after oral administration. Increased metabolism after oral drug administration may result in lower levels of the active drug and, possibly, reduced efficacy. However, the results show that the achieved gain in increased uptake largely outweighs the possible loss by the increased metabolism.

The oral combination of docetaxel and CsA was very well tolerated. The main side effects were myelosuppression and fatigue, which were mild to moderate. Theoretically, coadministration of a P-gp inhibitor may cause toxicities due to inhibition of the physiologic protective function of P-gp. P-gp inhibition could cause an increase in the docetaxel levels in P-gp–protected brain tissue and may therefore enhance the risk of central neurotoxicity.^21,22 However, we did not observe any signs or symptoms of central neurotoxicity in our study or in the animal studies. The single oral dose of CsA 15 mg/kg resulted in peak and trough CsA concentrations that were in the therapeutic range for immunosuppression and may be associated with toxicity, particularly renal toxicity. In this study, we did not observe renal toxicity nor any other side effects clearly related to the single administered CsA dose.

After the first IV course of docetaxel, a similar pattern of toxicities was observed as after oral drug administration, which order was randomized. However, myelosuppression seemed to occur more often and to be more severe after IV administration than after oral drug administration. This may be related to the higher peak concentrations and AUC values of docetaxel after IV administration (100 mg/m²) compared with oral drug administration (75 mg/m²). Myelosuppression is often observed after IV administration of docetaxel 100 mg/m² every 3 weeks, and reduction of myelosuppression is one of the reasons for initiation of weekly IV schedules of docetaxel at lower doses. In addition, the hypothesis that dose intensification and more frequent exposure of tumor cells to docetaxel may enhance activity of the drug has also contributed to the start of weekly docetaxel schedules. Recent clinical studies have shown that administration of IV docetaxel on a weekly schedule decreased the hematologic toxicity profile of the drug while therapeutic activity was maintained.^23-25 The feasibility of oral drug administration may stimulate and facilitate the use of weekly treatment schedules of docetaxel. We are currently investigating weekly oral docetaxel in combination with CsA in a phase II study in patients with advanced breast cancer.

These promising results of a substantial increase in the oral bioavailability of docetaxel due to inhibition of P-gp suggests that this concept may well be applied to other drugs, including noncytotoxic agents, that have a high affinity for P-gp and associated poor oral bioavailability, eg, human immunodeficiency virus protease inhibitors.²⁶ At present, it remains uncertain to what extent inhibition of docetaxel metabolism by CsA contributes. In addition, other CsA-induced actions on currently unknown transporters may also contribute to the increase in oral docetaxel bioavailability. Further investigations with more selective P-gp inhibitors are planned to differentiate between inhibition of P-gp and inhibition of drug metabolism.

In summary, coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Furthermore, the interpatient variability was of the same order for orally and intravenously administered docetaxel. The safety of the single oral course was very good. These data are stimulatingfor the further development of a clinically useful oral formulation of docetaxel. A phase II study in patients with advanced breast cancer, aimed at assessment of the antitumor activity of the weekly oral combination of docetaxel and CsA, is currently ongoing.

	ACKNOWLEDGMENTS

 
Supported by the Dutch Cancer Society, Amsterdam, Netherlands Cancer Institute project 98-1799.

We thank J.P. Bizzari, MD (Rhône-Poulenc Rorer/Aventis, Antony, France), for his support of this study. We also express our gratitude to the medical and nursing staffs of the Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute and the Medical Spectrum Twente for the care and support of the patients in this study.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted April 25, 2000; accepted October 27, 2000.

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