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© 2002 American Society for Clinical Oncology Comparative Pharmacokinetics of Unbound Paclitaxel During 1- and 3-Hour InfusionsByFrom the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands; and Department of Medical Oncology and Clinical Pharmacology, Tumor Biology Center, and Department of Internal Medicine, University Medical Center, Albert-Ludwigs University Freiburg, Freiburg im Breisgau, Germany. Address reprint requests to Alex Sparreboom, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: sparreboom{at}onch.azr.nl
PURPOSE: The paclitaxel vehicle Cremophor EL (CrEL) profoundly influences the cellular distribution of paclitaxel in human blood in vitro by a concentration-dependent decrease of the unbound drug fraction. Because CrEL clearance increases by extending the infusion duration from 3 to 24 hours, we hypothesized that exposure to unbound paclitaxel might also be schedule-dependent. PATIENTS AND METHODS: CrEL and unbound paclitaxel pharmacokinetics were prospectively analyzed in 29 patients with advanced solid tumors treated with paclitaxel 100 mg/m2 given as a 1-hour (n = 15) or 3-hour (n = 14) intravenous infusion. RESULTS: The systemic exposure (area under the curve [AUC]) to CrEL was significantly higher with the 1-hour as compared with the 3-hour schedule (80.2 ± 24.2 v 48.5 ± 24.1 µL·h/mL; P = .002). In contrast, the AUC of unbound paclitaxel was substantially reduced after the 1-hour infusion (0.50 ± 0.10 v 0.62 ± 0.12 µmol/L·h; P = .009). Similarly, clearance and volume of distribution were significantly dependent on infusion duration (P < .005). A trend was observed toward more severe hematologic toxicity with the 3-hour schedule (P = .053), consistent with increased exposure to unbound drug. CONCLUSION: Overall, these findings explain, at least in part, previous observations that short-infusion schedules of paclitaxel lack significant myelotoxicity, whereas potentially CrEL-related side effects, including peripheral neuropathy, are augmented.
DRUGS EXIST IN the peripheral circulation either as free or unbound fractions or bound to plasma proteins, polysaccharides, and lipids.1 It is generally acknowledged that the unbound drug fraction is capable of diffusing across biologic barriers and interacts with receptor sites in the circulation or extravascular compartment.2 Monitoring of unbound drug concentrations (Cu) is particularly useful when the fraction that is bound is not constant, when there is a variation in Cu within the normal physiologic range of protein levels, when the Cu helps to predict side effects and efficacy, and when there is a valid method to measure the Cu. Because various antiepileptic drugs meet these criteria, Cu monitoring has been successfully implemented in the clinic for a number of such agents, including phenytoin. In the field of clinical oncology, however, this area has been seriously neglected, with the exception of the epipodophyllotoxins etoposide and teniposide,3,4 for which relationships between exposure to Cu and hematologic toxicity have been established.5,6 We believe that the anticancer drug paclitaxel also meets the above mentioned criteria for Cu measurement. However, a practical analytic method for paclitaxel Cu only recently became available.7 This poorly water-soluble drug is currently formulated for clinical use in a mixture of the polyoxyethylated castor oil derivative, Cremophor EL (CrEL), and ethanol. It has been shown in vitro that CrEL can decrease paclitaxel Cu by trapping the drug in micelles composed primarily of polyoxyethylene glycerol triricinoleate.8 Similarly, CrEL has recently also been proposed in vivo to cause the nonlinear pharmacokinetic behavior of paclitaxel in plasma9,10 by decreasing the uptake of drug in RBCs and tissues, thereby interfering with metabolism and biliary secretion.11,12 Because the unbound fraction of paclitaxel is the pharmacologically active form, understanding factors influencing paclitaxel Cu might be important in predicting toxicity and antitumor activity. Furthermore, it has been shown that CrEL clearance significantly increases with extension of the infusion duration from 3 to 24 hours.11 Hence, extension of the paclitaxel administration schedule is expected to be associated with lower CrEL levels and, consequently, increased exposure to paclitaxel Cu. To confirm this hypothesis, we prospectively analyzed CrEL and paclitaxel Cu in plasma samples of patients treated with paclitaxel administered as a 1-hour or 3-hour intravenous infusion.
Eligibility Criteria and Treatment Plan Patients with a histologically confirmed diagnosis of a malignant solid tumor, for whom paclitaxel as monotherapy was a viable therapeutic option (breast, ovarian, head and neck, bladder, and lung cancers) or for whom no other treatment options were available were candidates for this study. Other patient eligibility criteria included the following: (1) patient age  18 years and less than 75 years; (2) World Health Organization performance status 2; (3) life expectancy 3 months; and (4) normal bone marrow function (absolute neutrophil count 1.5 x 109/L and platelet count 75 x 109/L), and adequate renal (serum creatinine  1.5 x upper limit of normal) and hepatic function (total serum bilirubin 1.5 x upper limit of normal). Specific exclusion criteria included the following: (1) previous taxane-containing chemotherapy within a 12-month period before study entry, (2) no other anticancer chemotherapy or radiotherapy for at least 4 weeks, (3) any known signs of preexisting polyneuropathy, (4) a known history of myocardial infarction within the last 6 months and/or atrial or ventricular arrhythmias, (5) any known allergy to CrEL-containing agents (eg, teniposide and cyclosporine), and (6) simultaneous anticancer treatment with hormone or immunotherapy. All patients were randomly assigned at study entry to a weekly regimen of paclitaxel treatment with the drug infused over 1 hour or 3 hours using a random number generator on a computer at the University Medical Center (Freiburg, Germany), and all patients were scheduled to receive a total of six intravenous infusions. After a 2-week rest period, patients responding to the treatment (stable disease or better) received a second cycle. The study protocol was approved by the local ethical committee, and all patients provided written informed consent before entering the study.
Drug Administration
Pharmacokinetic Study Design
Drug Measurement
Pharmacologic Analysis Hematologic pharmacodynamics was assessed by calculation of the area over the curve (AOC) of WBC and absolute neutrophil counts (ANC) after paclitaxel administration, determined on a once-weekly basis (days 1 to 36). The AOC was defined as the area of the WBC or ANC versus time curve below the count immediately before paclitaxel infusion was commenced16 and was calculated for each patient using a macro in the Excel software package (Microsoft Corporation, Redmond, WA). The relative hematologic toxicity for WBC and ANC was defined as follows: % decrease = [(pretherapy value - nadir value)/(pretherapy value)] x 100%. Statistical evaluation was performed with the unpaired (two-tailed) Student’s t test and the 95% confidence intervals for the mean difference using NCSS V5.X (J. Hintze, East Kaysville, UT; 1992). The level of significance was set at P < .05. All pharmacologic data are expressed as mean values ± SD, unless indicated otherwise.
Patient Characteristics The pharmacokinetics of paclitaxel and CrEL was studied in 29 adult patients with various malignant solid tumors treated with a weekly paclitaxel regimen at a dose of 100 mg/m2 (Table 1). The median age was 56 years (range, 22 to 71 years), and the median performance status was 1 (range, 0 to 2). Paclitaxel was administered as a 1-hour infusion in 15 patients and as a 3-hour infusion in 14 patients. Patient characteristics and baseline clinical chemistry values were similar between the two groups (Table 1).
Pharmacokinetics The pharmacokinetics of CrEL could be best described by a linear two-compartment model (Fig 1A), in line with previous findings.17 Elimination of CrEL was characterized by a decay in an apparent bi-exponential manner and indicated no significant differences between the two groups with terminal disposition half-lifes of 34.7 and 30.5 hours, respectively. Similarly, infusion duration had no influence on the Vd of CrEL (Table 2). However, the peak concentration (2.91 ± 0.73 v 2.24 ± 0.39 µL/mL; P = .005) and the AUC of CrEL (80.2 ± 24.2 v 48.5 ± 25.1 µL·h/mL; P = .002) were significantly higher with the 1-hour schedule.
Unbound paclitaxel pharmacokinetics could be best described with a linear three-compartment model in both groups (Figs 1B and 2; r2 = 0.997 ± 0.002; root mean squared error = 12.7% ± 4.28%), whereas one and two-compartment models were significantly biased (not shown). The AUC of paclitaxel Cu after the 1-hour infusion was significantly reduced as compared with the 3-hour infusion group (0.50 ± 0.10 v 0.62 ± 0.12 µmol/L·h; P = .0085), despite higher peak concentrations (0.26 ± 0.07 v 0.15 ± 0.07 µmol/L; P = .002). Similarly, plasma clearance and Vd were significantly dependent on paclitaxel infusion duration (Table 2). The time course of the free fraction of paclitaxel and the relationship between the free fraction and the CrEL concentration are shown in Fig 3.
The systemic exposure to total paclitaxel, as measured by AUC, was not significantly different between the 1-hour and 3-hour infusion groups (5.97 ± 1.09 µmol/L·h v 5.53 ± 2.37 µmol/L·h; P = .51). The time that total plasma concentrations of paclitaxel remained greater than 0.05 µmol/L was also independent on infusion duration (15.8 ± 6.68 v 16.8 ± 7.49 hours; Table 2).18
Pharmacodynamics
In the present study we have described for the first time the human pharmacokinetics of unbound paclitaxel in plasma after 1-hour and 3-hour infusions. The data complement previous knowledge on the clinical pharmacology of paclitaxel and may have important practical implications for its optimal use. Previous studies of the pharmacokinetics of paclitaxel administered either as a 1-hour or 3-hour intravenous infusion have consistently focused on measurement of total paclitaxel plasma concentrations, disregarding any effects caused by its formulation vehicle CrEL on unbound drug levels. The use of a recently developed specific analytic method based on equilibrium dialysis helped to resolve this uncertainty by making it possible to prospectively define unbound paclitaxel pharmacokinetics. During clinical development of paclitaxel, many different infusion durations, ranging from 15 minutes to 7 weeks, were explored in empirical fashion without a proper pharmacologic rationale.21-28 The infusion duration was initially extended because of hypersensitivity reactions observed at the shorter administration schedules. Later, proper premedication and physician’s experience enabled evaluation of the shorter administration schedules. The problems in paclitaxel development, characterized by many different administration schedules, enabled us to learn a lot about the infusion-duration related toxicities and antitumor activity. Previously, the clearance of CrEL in patients was found to be time-dependent and to increase significantly with extension of the infusion duration from 3 to 24 hours.11 Our current finding that CrEL disposition is highly dependent on infusion schedule, with disproportional increases in systemic exposure being associated with shortening of infusion from 3 hours to 1 hour, clearly is in agreement with these prior observations. Our finding that infusion duration has no substantial effect on the terminal disposition half-life suggests that this time-dependent phenomenon is associated with capacity-limited CrEL metabolism within the systemic circulation. Evidence exists that elimination routes of polyoxyethylated surfactants such as CrEL are dictated by serum carboxylesterase-mediated biotransformation, which can be saturated once a certain threshold concentration is exceeded.29 This phenomenon has significant implications for vehicle-related side effects observed with the use of paclitaxel. It has been established, for example, that acute hypersensitivity reactions associated with paclitaxel chemotherapy are directly attributable to complement activation owing to binding of naturally occurring anticholesterol antibodies to the hydroxyl-rich surface of CrEL micelles.30,31 Thus the current trend to pursue shorter schedules of paclitaxel administration can have a much greater impact on complement-activating CrEL levels at the site of infusion and on total CrEL exposure than would be expected in case of time-independent pharmacokinetics. It is particularly noteworthy in this context that paclitaxel administration by 30-minute or 45-minute infusions indicated signs of significant hypersensitivity reactions in all patients, even in the presence of standard antiallergenic premedication.21 A wealth of recent experimental data also show that CrEL can cause peripheral neuropathy, one of the main side effects reported with paclitaxel chemotherapy.32,33 Indeed, CrEL concentrations achieved with therapeutic doses of paclitaxel have been shown to produce axonal swelling, vesicular degeneration, and demyelination in rat dorsal root ganglion neurons exposed to this vehicle34; this is similar to data from electrophysiologic studies in patients with neurotoxicity after treatment with paclitaxel.35 Although the etiology of this side effect has not yet been completely elucidated, it is of particular interest that in a recent comparative trial there was a trend toward more severe peripheral neuropathy in patients receiving paclitaxel as a 1-hour infusion as compared with a 3-hour infusion.36 Additional clinical and pharmacologic information is currently being collected in ongoing trials with paclitaxel as well as retrospectively to further explore the relationship between the schedule dependent CrEL disposition and peripheral neurotoxicity. Of the greatest importance for the antitumor activity of paclitaxel treatment is the disposition of unbound paclitaxel in plasma. The pharmacokinetic model presented here accurately describes the plasma concentration versus time profile of unbound paclitaxel, without any signs of nonlinearity for both the 1-hour and 3-hour schedules. The disappearance of unbound drug from the central plasma compartment was characterized by a terminal disposition half-life of approximately 22 hours. The parallel decline of unbound paclitaxel concentrations between the two groups suggests that the altered clearance is associated with a change in the initial drug distribution immediately after drug administration. This is consistent with the postulated concept that the interference of CrEL with paclitaxel pharmacokinetics is related to a disproportional accumulation process in plasma.12 However, other possible mechanisms for the increased clearance of unbound paclitaxel, including increased metabolism or excretion, cannot be excluded. Overall, the plasma clearance of unbound paclitaxel was approximately 30% faster after the 1-hour infusion, resulting in significant decreases in AUC of unbound drug as compared with the 3-hour infusion. This finding of decreased systemic exposure to unbound paclitaxel with shortening of infusion duration may have considerable ramification with respect to the clinical use of paclitaxel. Previous studies designed to establish relationships between pharmacokinetics and pharmacodynamic outcome for total paclitaxel concentration have revealed that 11.2 hours above a threshold concentration of 0.1 µmol/L37 or 17.4 hours above 0.05 µmol/L9 were predicted to yield a 50% decrease in ANC. However, we have shown recently that when exposure is based on unbound concentrations, AUC could be identified as an important component of the kinetic-dynamic relationship.38 Our current findings indicate that increased exposure to unbound paclitaxel, as a result of prolonging infusion duration from 1 to 3 hours, indeed results in a trend toward more severe hematologic toxicity. In this study, hematologic toxicity was relatively mild and not clinically relevant because of the low paclitaxel dose, precluding detection of statistically significant differences between both groups. More insight will be provided by ongoing studies comparing 1-hour and 3-hour infusions of paclitaxel administered in a 3-weekly schedule at higher doses of 175 to 225 mg/m2, with adequate determination of relationships between pharmacokinetic measures and treatment outcome (ie, side effects and antitumor activity). Collectively, this study demonstrates that CrEL and unbound paclitaxel disposition are subject to considerable variability depending on the paclitaxel infusion duration. Because the AUC of unbound paclitaxel is related to the neutrophil survival fraction, these findings explain, at least in part, previous observations that short-infusion schedules lack significant myelotoxicity, whereas potentially CrEL-related side effects, including acute hypersensitivity reactions and peripheral neuropathy, are augmented. The current findings, coupled with our recently developed population model for paclitaxel pharmacokinetics-pharmacodynamics,38 provide an opportunity to move from empirical-derived observations toward mechanism-based chemotherapy by defining the proper paclitaxel infusion duration.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test to discriminate between models, and the coefficient of correlation was defined as the ratio of the SD computed using the variance-covariance matrix and the parameter value. Both weighted least-squares and extended least-squares methods were evaluated to estimate model parameters minimizing the sum of squared differences between experimental and computed values and the log-likelihood function. The drug disposition half-lifes and the area under the plasma concentration-time curve (AUC = dose/volume [V] x 
i(Ci/Li)) was determined based on the best-fitted curve and used for calculation of apparent plasma clearance (CL), defined as the ratio of dose delivered (in milligrams per square meter) and AUC. The mean residence time (MRT) was calculated as the area under the (first) moment-time curve, and the volume of distribution (Vd) as the ratio of (dose x MRT) and AUC. Pharmacokinetic parameters for total plasma concentrations of paclitaxel were estimated as described elsewhere.
) or 3-hour infusion (•) of paclitaxel at a dose of 100 mg/m2.
