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© 2000 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of Oral PaclitaxelFrom the Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL. Address reprint requests to Mirte M. Malingré, PharmD, The Netherlands Cancer Institute/Slotervaart Hospital, Department of Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; email apmmg{at}slz.nl
PURPOSE: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). PATIENTS AND METHODS: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m2 as a 3-hour infusion. RESULTS: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m2. Dose escalation of oral paclitaxel from 60 to 300 mg/m2 resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values ± SD after 60, 180, and 300 mg/m2 of oral paclitaxel were 1.65 ± 0.93, 3.33 ± 2.39, and 3.46 ± 1.37 µmol/L·h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 ± 3.26 µmol/L·h. CONCLUSION: The MTD of oral paclitaxel was 300 mg/m2. However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m2, the oral paclitaxel dose of 180 mg/m2 in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.
PACLITAXEL IS AN important antitumor agent widely applied in the treatment of advanced ovarian and breast cancer.1,2 The intravenous (IV) administration is, however, inconvenient to patients and associated with a number of unpredictable side effects. Severe hypersensitivity reactions have been observed after IV infusion of paclitaxel, and it is now well established that the pharmaceutical vehicle Cremophor EL contributes largely to this effect.3-6 Oral administration of paclitaxel is very attractive, because it is convenient and practical for patients and it may circumvent systemic exposure to the vehicle Cremophor EL. Furthermore, oral administration may enable development of chronic treatment schedules, which would result in sustained plasma concentrations above a pharmacologically relevant threshold level. Paclitaxel, however, has poor oral bioavailability because of its affinity for the membrane-bound drug efflux pump P-glycoprotein (P-gp), which is abundantly present in the gastrointestinal tract.7-10 P-gp in the mucosa of the small and large intestines limits the oral uptake of paclitaxel and mediates direct excretion of the drug into the intestinal lumen.10 In addition, presystemic elimination in the liver by the cytochrome P450 (CYP) isozymes 3A4 and 2C8 may play an important role in the low oral bioavailability of paclitaxel.11-13 Preclinical and clinical proof of concept studies carried out at our Institute revealed that coadministration of oral cyclosporine (CsA), an efficacious inhibitor of P-gp, and CYP 3A4–mediated drug metabolism, resulted in an approximately eight-fold increase in the systemic exposure of oral paclitaxel.14-16 In this study, we investigated dose escalation of oral paclitaxel in combination with dose increment and scheduling of CsA to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT).
Patient Population Patients with a histologic proof of cancer for whom no standard therapy of proven benefit existed were eligible for the study. Previous radiotherapy or chemotherapy other than taxoid therapy was allowed as long as the last treatment was at least 4 weeks prior to study entry and any resulting toxicities were resolved. Patients had to have acceptable bone marrow (WBC count > 3.0 x 109 cells/L; platelet count > 100 x 109 cells/L), liver (serum bilirubin level  25 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 2. Patients were excluded if they suffered from uncontrolled infectious disease, neurologic disease, bowel obstruction, or symptomatic brain metastases. Further 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 gave written informed consent.
Study Design
Drug Administration The IV formulation of paclitaxel (Paxene, paclitaxel 6 mg/mL dissolved in Cremophor EL and ethanol 1:1 wt/vol, Baker Norton Pharmaceuticals, Miami, FL) was used for both IV and oral administration of paclitaxel. Before oral paclitaxel administration, patients received oral CsA (Neoral, Novartis, Basel, Switzerland). At dose levels 1 to 3, patients ingested CsA as an oral solution 10 minutes before paclitaxel administration. At dose level 3, CsA was administered bid 10 minutes before and 2 hours after oral paclitaxel administration. Because of the bitter taste of the oral solution, patients at subsequent dose levels (4 to 9) received CsA in capsules, administered 30 minutes before oral paclitaxel administration. Oral paclitaxel was administered after an overnight fast, and a standard breakfast was served 2 hours after paclitaxel administration. To prevent hypersensitivity reactions, patients were premedicated with dexamethasone 20 mg orally 12 and 6 hours before, clemastine 2 mg IV and cimetidine 300 mg IV 30 minutes before both IV and oral paclitaxel administration. Because Cremophor EL levels after oral administration of paclitaxel seemed undetectable in plasma, three patients at dose level 8 and all patients at dose level 9 did not receive premedication before oral paclitaxel administration. To prevent nausea and vomiting after oral paclitaxel administration, which occurred more frequently at dose levels 6 and 7 and higher, four patients at dose level 8 and all patients at dose level 9 received 1 mg oral granisetron (Kytril, SmithKline Beecham Pharmaceuticals, Collegeville, PA) 1 hour before CsA administration. As nausea and vomiting continued, two patients at dose level 8 and all patients at dose level 9 received additionally a light breakfast at least 2 hours before oral paclitaxel administration.
Patient Evaluation
Pharmacokinetics Noncompartmental pharmacokinetic methods were applied to process the results.24 The area under the concentration-time curve (AUC) was estimated by the trapezoidal rule with extrapolation to infinity using the terminal rate constant k. The apparent bioavailability of oral paclitaxel was calculated as the ratio of the mean AUC values after oral and IV administration with a correction for the difference in dose. Other parameters to be assessed were maximal concentration, time to maximal concentration, time above threshold concentrations of 0.05 µmol/L and 0.1 µmol/L (T > 0.05 µmol/L and T > 0.1 µmol/L), and terminal half-life. Maximal concentration and time to maximal concentration were determined graphically, T > 0.05 µmol/L and T > 0.1 µmol/L were determined using linear logarithmic interpolation, and terminal half-life was calculated as ln2/k. The percentage of the administered dose recovered in the urine was calculated as the amount excreted in the urine divided by the actual administered dose times 100%. Statistical analysis of the data was performed using the nonparametric Jonckheere-Terpstra test,25 the Mann-Whitney U test, and the Spearman correlation coefficient. The a priori level of significance was P = .05.
Patients and Treatment A total of 53 patients (21 males and 32 females) were enrolled onto the study. At study entry, the median age of the patients was 54 years (range, 25 to 78 years) and the median WHO performance status was 1 (range, 0 to 2). Primary tumor types included breast (n = 17), ovarian (n = 5), gastric (n = 6), non–small-cell lung cancer (NSCLC) (n = 4), colorectal cancer (n = 4), adenocarcinomas of unknown primary site (n = 8), and other tumors (n = 9). Four patients were cytotoxic therapy–naive, whereas all other patients had received prior surgical therapy, radiotherapy, and/or chemotherapy. Two patients were not assessable because they went off study before they had received oral paclitaxel. Six patients were considered not assessable for pharmacokinetic analysis because of vomiting within 2 hours after ingestion of oral paclitaxel. Toxicities observed after oral administration of paclitaxel were generally mild (grades 1 to 2). The principal hematologic toxicities after oral intake of paclitaxel were leukocytopenia and granulocytopenia (data listed in Table 2). Thrombocytopenia grade 2 was observed in one patient at dose level 250 mg/m2. Anemia was observed in 35 patients, which was often pre-existing and never exceeded grade 2 in severity. The nonhematologic toxicities after oral intake of paclitaxel are listed in Table 3. Main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which occurred more frequently at dose levels 210 to 250 mg/m2 and higher. Vomiting occurred mostly only once within 30 minutes after intake of oral paclitaxel. Toxicities clearly associated with CsA administration were not observed. During subsequent treatment with IV paclitaxel, granulocytopenia, arthralgia/myalgia, neurotoxicity, and allergic reactions were observed, which were typically related to paclitaxel and its formulation. Toxicities observed after IV administration of paclitaxel were generally mild, with the exception of one patient who experienced an acute allergic reaction grade 4 despite premedication. This patient developed hypotension, bronchospasm, tachycardia, sweating, and flushes, which were reversed with adrenaline, dexamethasone, clemastine, and salbutamol within 1 hour.
Partial responses were observed in three patients, which were documented after the third course (ie, one oral and two IV courses). One patient with fluorouracil-refractory advanced gastric cancer developed a substantial volume reduction of a large supraclavicular lymph node after a first course with oral paclitaxel 180 mg/m2. A partial response was documented after two additional IV courses. Another patient with advanced breast cancer showed significant reduction of cutaneous metastases after a first oral course of 210 mg/m2. A partial response was documented after the third course. A third patient developed a partial remission of advanced platinum-resistant ovarian cancer after the oral and two IV courses of paclitaxel.
Pharmacokinetics
The pharmacokinetic data of IV paclitaxel (175 mg/m2 as a 3-hour infusion) were in good agreement with earlier observations.26-28 The mean ± SD AUC and T > 0.1 µmol/L values were 15.39 ± 3.26 µmol/L·h and 17.1 ± 4.9 hours, respectively (n = 39). The mean ± SD urinary excretion of IV paclitaxel calculated as fraction of the administered IV dose was 6.6% ± 3.1% (n = 19).
Pharmacokinetic parameters of CsA are outlined in Table 5. Dose escalation of oral paclitaxel did not produce significant differences in the pharmacokinetics of CsA. Maximal blood ethanol concentrations were reached within 1 hour after oral administration of paclitaxel in the IV formulation. Paclitaxel doses of 60 and 120 mg/m2, corresponding with 5 and 10 mL/m2 ethanol, respectively, resulted in maximal ethanol concentrations of less than 0.1% vol/vol. Paclitaxel doses of 180, 210, 250, 300, and 360 mg/m2 (15, 17.5, 21, 25, and 30 mL/m2 of ethanol, respectively) resulted in mean (± SD) maximal ethanol concentrations of 0.31
Preclinical and clinical proof of concept studies carried out at our Institute clearly revealed that coadministration of oral CsA, an efficacious inhibitor of P-gp as well as CYP 3A4–mediated drug metabolism, resulted in a significantly enhanced systemic exposure to oral paclitaxel.14-16 The most plausible explanation for the observed increase of the oral uptake of paclitaxel is inhibition of P-gp in the gut wall by CsA. In addition, inhibition of CYP 3A4–mediated paclitaxel metabolism may play a significant role as we observed altered paclitaxel metabolism after CsA coadministration.16 The first promising clinical results at low paclitaxel dosages of 60 mg/m2 encouraged us to further increase the systemic exposure of orally administered paclitaxel by dose escalation of paclitaxel and dose increment and scheduling of CsA and to explore the MTD and DLT of oral paclitaxel. Toxicities observed after oral administration of paclitaxel were generally mild (grade 1 or 2). The principal hematologic toxicities after oral intake of paclitaxel were leukocytopenia and granulocytopenia. Four patients experienced grade 4 granulocytopenia (dose levels 120, 180, and 250 mg/m2), which was short-lasting, uncomplicated, and did not reach DLT. The main nonhematologic toxicities after oral intake of paclitaxel were nausea, vomiting, and arthralgia/myalgia. One patient experienced myalgia grade 3 (dose level 120 mg/m2), and one experienced diarrhea grade 3 (dose level 360 mg/m2). However, these toxicities were uncomplicated, short-lasting, and not considered as DLT. To prevent symptoms of nausea and vomiting, four patients at dose level 300 mg/m2 and all patients at dose level 360 mg/m2 received 1 mg oral granisetron 1 hour before CsA administration. Two patients at dose level 300 mg/m2 and all patients at dose level 360 mg/m2 received additionally a light breakfast at least 2 hours before oral paclitaxel intake to further reduce occurrence of nausea and vomiting. An interval of at least 2 hours was chosen to exclude the influence of food on the pharmacokinetics of oral paclitaxel. At the dose level of 300 mg/m2, the administration of a light breakfast 2 hours before oral paclitaxel administration had no measurable influence on the pharmacokinetic parameters of paclitaxel. Despite antiemetic therapy and the additional light breakfast, four of five patients at the dose level of 360 mg/m2 continued to experience acute nausea and vomiting. Apparently, an oral paclitaxel dose of 360 mg/m2 produced acute gastrointestinal toxicity that resulted in acute nausea and massive vomiting. We considered the dose level of 360 mg/m2 to be the DLT. The MTD of oral paclitaxel was determined to be 300 mg/m2. Toxicities clearly associated with CsA administration were not observed. Partial responses to paclitaxel were observed in three patients, which were documented after the third course. In at least two of these three patients, there were strong indications of activity of oral paclitaxel. Pharmacokinetic analysis of oral paclitaxel revealed that dose escalation of oral paclitaxel from 60 to 300 mg/m2 resulted in significant increases in both AUC and T > 0.1 µmol/L; however, these increases were moderate and not proportional with the increases in dose. This nonlinear pharmacokinetic behavior of oral paclitaxel is most likely a result of a maximum in absorption from the gastrointestinal tract. Nonlinear absorption pharmacokinetics have been observed for oral drugs that (1) have poor aqueous solubility and limited dissolution or (2) are absorbed via transport mechanisms that were able to be saturated.29 In this study, paclitaxel was administered as a solution, which suggests that dissolution of the drug was not involved in absorption of orally administered paclitaxel. However, it is possible that, after ingestion, paclitaxel was released from its pharmaceutical formulation and precipitated as a result of its poor aqueous solubility. Consequently, limited dissolution may have caused the observed nonlinear absorption. A similar nonlinear pharmacokinetic absorption pattern because of poor aqueous solubility that resulted in limited dissolution was observed for the oral anticancer drugs etoposide and the platinum complex JM216.30,31 An alternative explanation is that saturation of active transport mechanisms is responsible for the observed nonlinear absorption pharmacokinetics of oral paclitaxel. A similar pattern of absorption with saturation of active transport mechanisms has been observed for riboflavin, ascorbic acid, and amino-beta-lactam antibiotics.32 Because neither in vitro nor in vivo studies have shown the presence of active inward transport mechanisms of paclitaxel and because it is very unlikely that both active inward and outward transport mechanisms for the same drug exist, we hypothesize that the maximum in absorption of oral paclitaxel is caused by its poor aqueous solubility in the gastrointestinal tract and not by saturation of putative active transport mechanisms. Increasing the dose from 15 to 30 mg/kg and splitting the dose of CsA into 2x 15 mg/kg to achieve higher and more sustained levels of the inhibitor did not result in a further increase in the systemic exposure to paclitaxel. Apparently, P-gp inhibition by CsA was maximal at a single dose of CsA of 15 mg/kg. It remains unclear whether CsA was adequate to inhibit P-gp completely. Incomplete P-gp inhibition by CsA may necessitate the use of more potent modulators, such as certain nonimmunosuppressive analogs of CsA.33 Incomplete distribution of CsA over the mucosa wall may also contribute to the possible incomplete inhibition of P-gp by CsA. Increases in paclitaxel dose and, thus, increases in the amount of ethanol administered did not result in equivalent increases in blood ethanol levels. Maximal ethanol concentrations were significantly correlated with maximal paclitaxel concentrations, and hence, ethanol seems to follow the nonlinear absorption profile of orally administered paclitaxel. A maximum in ethanol absorption has not been observed before and is of interest for further investigation. Cremophor EL levels were undetectable at all oral paclitaxel dose levels. Apparently, Cremophor EL is not absorbed after oral administration of the paclitaxel IV formulation. This is important because systemic exposure to Cremophor EL can induce severe hypersensitivity reactions.3-6 No hypersensitivity reactions were observed in patients who did not receive premedication before oral paclitaxel administration (n = 8). Evidently, paclitaxel can be administered orally without premedication directed to prevent hypersensitivity reactions. Furthermore, Cremophor EL is responsible for the nonlinear pharmacokinetic behavior of IV paclitaxel.34-38 It increases the affinity of paclitaxel to plasma components, which results in a more than proportional increase in plasma paclitaxel levels with increasing doses. However, these higher total drug levels in plasma do not result in higher drug levels in tissues. This pseudo-nonlinearity38 of IV paclitaxel has two important implications for the pharmacology of oral paclitaxel. First, it will result in a significant underestimation of the true bioavailability of oral paclitaxel. In this study, the bioavailability of oral paclitaxel at a dose of 60 mg/m2 was determined to be 31%. In a dose-finding study performed by Huizing et al,27 a mean AUC of 5.8 µmol/L·h for IV paclitaxel at a dose of 100 mg/m2 was reported. Recalculation of the bioavailability of 60 mg/m2 oral paclitaxel with the application of the dose-adjusted AUC found by Huizing et al results in an oral bioavailability of 47%.16 Second, the pseudo-nonlinearity of IV paclitaxel implies that after oral administration, when Cremophor EL is not systemically present, plasma levels of paclitaxel represent a higher fraction of free drug, which will result in enhancement of the availability of paclitaxel for the (tumor) tissues.38 Therefore, interpretation of differences between paclitaxel plasma levels after oral and IV administration, without and with Cremophor EL in the systemic circulation, respectively, should be done with great caution. In summary, the MTD of oral paclitaxel was 300 mg/m2. However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear oral pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m2, the oral paclitaxel dose of 180 mg/m2 in combination with 15 mg/kg of oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good. Additional studies will focus on multiple dose regimens and combinations with other P-gp inhibitors.
Supported by the Dutch Cancer Society, Amsterdam, the Netherlands. We thank Harm van Tinteren, MSc, for assistance with the statistical analysis of the data. We also express our gratitude to the medical and nursing staffs of the Antoni van Leeuwenhoek Hospital for the care and support of the patients in this study.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
(± 0.21
