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1 Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Slotervaart Hospital, and 2 Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
ABSTRACT
Purpose: Paclitaxel is a taxane derivative with a profound antitumor activity against a variety of solid tumors. In a previous clinical study in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel, it was shown that paclitaxel plasma concentrations of 0.1 µmol/liter for 
15 h were associated with prolonged survival. The purpose of this study was to evaluate the feasibility of Bayesian dose individualization to attain paclitaxel plasma concentrations >0.1 µmol/liter for 15 h.
Experimental Design: Patients with stage IIIb-IV NSCLC were treated with paclitaxel and carboplatin once every 3 weeks for a maximum of six courses. During the first course, a standard paclitaxel dose of 175 mg/m2 was administered i.v. in 3 h. In subsequent courses, the paclitaxel dose was individualized based on observed paclitaxel concentrations in plasma during the previous course(s) using a Bayesian algorithm. The paclitaxel dose of a subsequent course was increased to the lowest dose for which the predicted time period during which the paclitaxel plasma concentration exceeds 0.1 µmol/liter was >15 h.
Results: A total of 25 patients have been included in the study (92 evaluable courses). During the first course, the median time period above the threshold concentration was 16.3 h (range, 7.6–31.6 h), and was <15 h for 9 patients (36%). During subsequent individualized courses, the time period above the threshold concentration was <15 h in 23% (5 of 22), 14% (2 of 14), 23% (3 of 13), 11% (1 of 9), and 11% (1 of 9) of the patients in the second, third, fourth, fifth, and sixth course, respectively. Dose increments, ranging from 5 to 65 mg/m2, were performed in 29 of the 67 individualized courses. Patients with increased individualized doses had similar regimen related toxicities compared with those remaining at a dose of 175 mg/m2. Toxicity was reversible and manageable, and was mainly hematological (granulocytopenia CTC grade 3/4 in 80% of the patients). The objective response rate was 20%.
Conclusions: The results indicate that the applied pharmacokinetically guided dosing strategy for paclitaxel is safe and technically feasible. A randomized study is necessary to demonstrate whether dose individualization may result in improved activity and efficacy in patients with NSCLC.
Introduction
Paclitaxel (Taxol®) is a taxane derivative that acts on microtubular structures by binding directly to tubulin, causing microtubular stabilization that arrests cell division in the G2-M phase of the cell cycle. The drug has a profound antitumor activity against a variety of solid tumors, especially against lung, breast, ovarian, and head and neck tumors (1 , 2) . Paclitaxel administered as a 3-h infusion has been shown to result in equivalent efficacy as a 24-h infusion scheme but is associated with significantly less myelosuppression (3) . The combination of paclitaxel with a platinum compound, cisplatin or carboplatin, is a frequently used combination in the treatment of patients with advanced non-small cell lung cancer (NSCLC; Ref. 4 ). To offset cisplatin-related toxicity, cisplatin is often substituted by carboplatin (4 , 5) .
The combination of paclitaxel and carboplatin administered to 55 nonpretreated patients with advanced NSCLC in a Phase I design resulted in a significant positive relationship between exposure to paclitaxel and overall survival. Favorable survival figures were observed in patients with a time period above a chosen threshold paclitaxel concentration of 0.1 µmol/liter >15 h, compared with a time period above the threshold concentration of <15 h (6) . Significant relationships between plasma pharmacokinetics and pharmacodynamics of paclitaxel have also been reported in ovarian cancer patients receiving paclitaxel monotherapy whereby myelotoxicity was related to the time period during which paclitaxel concentrations in plasma were >0.05 or 0.1 µmol/liter (7 , 8) .
Due to substantial interindividual pharmacokinetic variability, individuals may obtain different paclitaxel plasma concentrations over time after fixed doses of paclitaxel [e.g., after administration of 175 mg/m2 in 3 h, a 4–5-fold difference in paclitaxel area under the concentration-time curve (AUC) was reported; Ref. 6 ]. Pharmacokinetically guided dosing can assist in attaining desired plasma levels by tailoring individual dosages based on estimated individual pharmacokinetic parameters. We developed previously a population pharmacokinetic model for paclitaxel (9) . On the basis of this population analysis, Bayesian predictions of the pharmacokinetics of an individual can be made with only a few collected blood samples. The use of pharmacokinetically guided dosing to obtain desired plasma levels has been studied for several anticancer agents, with promising results (10) .
The aim of this study was to evaluate the performance and the technical feasibility of pharmacokinetically guided dosing of paclitaxel, administered as a 3-h infusion, in attaining paclitaxel concentrations >0.1 µmol/liter for 15 h. Moreover, toxicity and antitumor activity using this approach for the first-line treatment of advanced NSCLC were determined.
Patients and Methods
Patients.
Patients with histologically proven NSCLC stage IIIB or stage IV were included in the study. Eligibility criteria included a performance status 
2 on the WHO scale, life expectancy of 3 months to allow adequate follow-up of toxicity, adequate hematopoietic (absolute neutrophil count 1.5*109/liter and platelet count 100*109/liter), hepatic (total bilirubin 25 µmol/liter, aspartate amino transferase and alanine amino transferase 2.5 times the normal upper limit; in case of liver metastasis aspartate amino transferase and alanine amino transferase 5 times the normal upper limit) and renal function (serum creatinine 140 µmol/liter and creatinine clearance 50 ml/min). Exclusion criteria consisted of active bacterial infections, clinical signs of active brain tumor involvement or leptomeningeal disease, known alcoholism, drug addiction, and/or psychotic disorders leading to inadequate follow-up, pregnancy, or breast-feeding. Written informed consent was obtained from all of the patients. The study was approved by the Medical Ethics Committee of the Institute.
Treatment.
Patients were treated with carboplatin (Paraplatin; Bristol-Myers Squibb, Syracuse, NY) and paclitaxel (Taxol®; Bristol Myers Squibb) for a maximum of six courses every 3 weeks. All of the courses consisted of a carboplatin i.v. infusion in 30 min followed by administration of paclitaxel in a 3-h infusion. In each course, the carboplatin dosage was calculated based on the Calvert formula (11)
with a target AUC of 6 mg/ml*min:
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Standard premedication with dexamethasone (20 mg orally at 12 and 6 h before paclitaxel administration), clemastine (2 mg i.v. 30 min before paclitaxel administration), and cimetidine (300 mg i.v. at 30 min before paclitaxel administration) was administered to prevent potential hypersensitivity reactions. Granisetron (1 mg i.v.) was administered as antiemetic agent. Treatment was discontinued in case of patient refusal, noncompliance of the patient with the protocol, serious adverse events, and progressive disease. Both paclitaxel and carboplatin doses were reduced by 25–50% in case of severe toxicity in a preceding cycle.
Pharmacokinetics and Bioanalysis.
Pharmacokinetic sampling for paclitaxel was performed during all of the courses. During the first course, blood samples were collected in heparinized tubes before start; 1.5 h after the start of the paclitaxel infusion; at the end of the infusion; and 0.5, 1, 2, 4, 6, 9, and 19 h after the end of the infusion, to obtain accurate information on the pharmacokinetics of the respective individual. During subsequent courses of paclitaxel, blood samples were obtained before the start of the paclitaxel infusion, at the end of the infusion, and 9 and 19 h after the end of the infusion. The blood samples were immediately centrifuged at 3000 x g for 5 min. Plasma was transferred to polypropylene tubes and stored at –20°C until analysis.
Paclitaxel was determined in plasma using a validated isocratic high-performance liquid chromatographic method with solid phase extraction as sample pretreatment as described previously (14 , 15) . The quantitation range of the method was 10–10,000 ng/ml.
During each first carboplatin course pharmacokinetic sampling was performed to confirm achievement of the target carboplatin AUC of 6 mg/ml*min. Samples were collected in heparinized tubes before the start of the carboplatin infusion; at the end of infusion; and at 4, 8, and 23 h after the end of the carboplatin infusion. Plasma was separated by centrifuging the samples at 3000 x g for 5 min. Plasma ultrafiltrate was prepared immediately by transferring 1 ml of plasma in an Amicon micropartition system with a YMT-14 membrane (Millipore Corporation, Bedford, MA) and centrifuging the system at 2500 x g for 20 min. Ultrafiltrate was stored at –20°C until analysis. Carboplatin was quantitated using a validated Zeeman atomic absorption spectrometry method (16) . The AUC of carboplatin was determined by noncompartmental analysis using the pharmacokinetic WinNonlin program (Standard Edition Version 3.0, 1999) applying the log-linear trapezoidal method with extrapolation to infinity.
Pharmacokinetically Guided Dosing.
During the first course, paclitaxel was administered in a standard dose of 175 mg/m2. In the second course and subsequent courses the paclitaxel dosage was individualized to achieve a plasma concentration of 0.1 µmol/liter for 15 h after the start of the infusion. Individualized doses were calculated using Bayesian analyses applying a previously developed and validated population pharmacokinetic model (9)
. This population model was developed in our institute based on 100 concentration-time curves from 61 chemonaive NSCLC stage IIIB and IV patients (n = 55) treated with paclitaxel as a 3-h i.v. infusion in combination with carboplatin, and from advanced ovarian cancer patients (n = 6), pretreated with platinum, treated with paclitaxel (24-h i.v. infusion) as single agent. The model was developed using nonlinear mixed effect modeling software (NONMEM, version V 1.1, double precision; Ref. 17
) using the first order method and logarithmically transformed concentration-time data. The population model consisted of a three-compartment model with saturable distribution to one peripheral compartment and Michaelis-Menten elimination from the central compartment, and is schematically represented in Fig. 1
. Interindividual variability and interoccasion variability were estimated using a proportional error model. Interindividual variability was quantified for the volume of the central compartment, maximal transport rate from the central compartment to peripheral compartment 1, and the maximal elimination rate. Interoccasion variability was quantified for the intercompartmental rate constants (k21, k13, and k31) and maximal elimination rate. Simulation studies showed that interindividual variability in the time above the threshold was considerably larger than interoccasion variability. The residual variance was modeled using an additive error model with the assumption that the population was a mixture of two subpopulations (subpopulations 1 and 2) with a different variance. Body surface area (BSA) was significantly correlated with volume of the central compartment and maximal transport rate from the central compartment to peripheral compartment 1 (P < 0.005). The model-predicted population pharmacokinetic parameters are summarized in Table 1
.
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and the individual paclitaxel concentration-time data from previous course(s), were obtained with NONMEM using the POSTHOC option. The obtained individual pharmacokinetic parameter estimates were used to predict the concentration-time data during the subsequent course after the administration of 175 mg/m2. The time period that the paclitaxel concentration was >0.1 µM was derived from these predicted concentration-time data. If the predicted time period of the paclitaxel plasma concentrations >0.1 µmol/L was <15 h in the subsequent course, the paclitaxel dosage was increased until the predicted time period was 15 h (doses were increased in multiples of 5 mg). Due to the presence of interoccasion variability in the population model, it is possible that a patient with a paclitaxel exposure above the target in the first course may receive a dose higher than 175 mg/m2 in the second course based on predictions of the pharmacokinetic parameters in this course. For every course this strategy was repeated. Evaluation of the performance of the dose individualization strategy was performed by estimating the actual time period that the plasma concentrations exceeded 0.1 µmol/liter in the concerning individualized course based on the drawn plasma samples using, again, Bayesian estimation applying the population model.
Patient Evaluation.
Pretreatment evaluation included a complete medical history and complete physical examination (including neurological examination). Before each course, toxicities and performance status were recorded, and a physical examination was performed. Hematological parameters were determined weekly during all of the courses. Blood chemistry including liver and renal function, liver enzymes, serum electrolytes, total protein, albumin, and glucose levels were checked weekly during the first course. During subsequent courses blood chemistry was checked before each course. The observed toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (CTC), Version 1 (18)
. Tumor measurement was performed every other cycle. Responses were evaluated according to the RECIST criteria (19)
.
Relationships between hematological toxicity and the time period that the paclitaxel concentration in plasma is >0.1 µmol/liter, as found in previous studies (7
, 8)
, were evaluated. For this purpose, hematological toxicity was evaluated as a percentage decrease (%D) in granulocyte, leukocyte, or platelet counts using the following equation:
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Results
Patients.
A total of 25 patients with NSCLC stage IIIB or IV were included in this dose individualization study during a period of 17 months. Patient characteristics and biochemical serum values at baseline are summarized in Table 2
. Totally, 9 females and 16 males with a median age of 58 years were included. Two patients were pretreated with surgery (lobectomy and resection of a cerebral metastasis), 7 patients with radiotherapy, and 2 with chemotherapy (both platinum containing chemotherapy).
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Five courses in different patients were administered with a week delay because patients had not recovered sufficiently from toxicity at the planned day of their retreatment. Four of these patients had not received a pharmacokinetically guided paclitaxel dose increment whereas 1 had.
Pharmacokinetically Guided Dosing.
A total of 103 courses of paclitaxel and carboplatin were administered, and 92 were pharmacokinetically monitored for paclitaxel. Patients receiving reduced doses due to toxicity were not pharmacokinetically monitored during the courses with reduced doses (a total of 10 courses). In 1 patient the second course was accidentally not monitored. Drug monitoring was performed during the first cycle (n = 25), second cycle (n = 22), third cycle (n = 14), fourth cycle (n = 13), fifth cycle (n = 9), and sixth cycle (n = 9).
The paclitaxel concentrations in plasma as obtained during the first course, after administration of a standard dose of 175 mg/m2, are presented in Fig. 2
. The time period that the paclitaxel concentration was >0.1 µmol/liter during the first course ranged from 7.6 to 31.6 h. In 9 of these patients (36%), the time period above the threshold concentration was <15 h, ranging from 7.6 h to 13.4 h (Table 3)
.
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15 h after start of the infusion. Dose increments (ranging from 5 to 65 mg/m2; 3–37% adjustment) were performed in 29 of the 67 individualized courses (43%) resulting in total doses of 180–240 mg/m2 (8 x 180 mg/m2, 5 x 185 mg/m2, 3 x 190 mg/m2, 3 x 195 mg/m2, 2 x 200 mg/m2, 1 x 205 mg/m2, 5 x 215 mg/m2, 1 x 230 mg/m2, and 1 x 240 mg/m2). In the remaining 57% of the courses, a dose of 175 mg/m2 was administered. During the second course paclitaxel concentrations were above the threshold concentration for [lt 15 h in 23% of the patients (Table 3)
. In 8 of the 9 patients in whom the time period above the threshold concentration was <15 h during the first course, it was accomplished to obtain a time period >15 h during the second course. During the third course and subsequent courses, the desired time period above the threshold concentration was not achieved in 7 of 45 courses (16%) ranging from 10.9 h to 13.1 h.
In Fig. 3
the concentration-time curves of all six of the courses in a typical patient are shown. This patient received adapted doses during courses two to six, because after the standard dose of 175 mg/m2, the time period that paclitaxel concentrations were above the threshold was only 11.6 h. After dose adaptation during subsequent courses (215 mg/m2) the time period exceeded 15 h. All five of the individualized courses could be administered without delay. In Fig. 4
for all of the individuals and courses the obtained time period that paclitaxel plasma concentrations were >0.1 µmol/liter are depicted. Seven of 13 individualized courses, in which the exposure was too low after dose individualization, were in 2 individuals (with BSA >2 m2).
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Patient Evaluation
Toxicity.
Hematological toxicity consisted mainly of granulocytopenia (range, CTC grade 1–4). Leukocytopenia was mainly CTC grade 1–3, and thrombocytopenia CTC grade 1 and 2 (Table 4)
. The baseline levels of WBCs, granulocytes, and platelets decreased during later courses resulting in more pronounced leukocytopenia, neutropenia, and thrombocytopenia during those courses. Neutropenic fever was observed in 2 patients with granulocytopenia grade 4 after course one in 1 patient (time paclitaxel concentrations >0.1 µmol/liter = 25.6 h with dose 175 mg/m2) and after course two in the other (time paclitaxel concentrations >0.1 µmol/liter = 17.5 h with dose 175 mg/m2), necessitating hospitalization and administration of i.v. antibiotics as well as dose reduction in subsequent courses. A relationship between hematological toxicity, in terms of percentage decrease in cell counts, and the time period that the paclitaxel concentration in plasma is >0.1 µmol/liter (7
, 8)
could not be confirmed in the 25 patients we studied when taking into account first-course data as well as all data (data not shown).
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Both hematological and nonhematological toxicity appeared to be similar in courses with dose increment compared with courses without dose increment.
Response.
In 1 patient the response was not evaluable. The observed tumor response in 24 patients were a confirmed partial response in 5 patients, stable disease in 4 patients, and progressive disease in 15 patients. The objective response rate was 20%. All 5 of the patients showing a partial response completed six courses of chemotherapy, and all but 1 had exposures above the defined target in courses two to five (the 1 with exposures below the target after individualized doses was a patient with BSA >2 m2 as depicted in Fig. 4
). Three patients presenting with metastatic (stage IV) disease died early due to progression, and 22 patients are still alive (at 3–28 months after the start of the first course).
Discussion
The main purpose of this study was to demonstrate the feasibility and the performance of a Bayesian pharmacokinetically guided dosing strategy of paclitaxel to achieve drug concentrations in plasma >0.1 µmol/liter for 15 h. The target exposure was selected based on a study with both paclitaxel and carboplatin resulting in favorable survival figures for patients with paclitaxel exposures above the target (6)
. No relevant upper limit for the time above the threshold could be defined, and therefore more empirical guidelines for dose reductions in case of toxicity were used. To be able to generate Bayesian predictions for individuals, a population pharmacokinetic model for i.v. administered paclitaxel was applied. This population model, together with observed individual paclitaxel plasma concentrations, was used to predict the time period that the paclitaxel concentration in plasma would exceed 0.1 µmol/liter in the subsequent course for an individual.
The population pharmacokinetic model used in this study was developed and validated in our institute, and based on an earlier published model (20)
. It describes nonlinear distribution of paclitaxel from the central compartment to the peripheral tissues (Fig. 1)
, based on measured total plasma paclitaxel concentrations. This nonlinear distribution has been attributed to the presence of Cremophor EL, a soap-like solvent in which the poorly soluble paclitaxel is formulated. Circulating Cremophor EL micelles entrap paclitaxel in the central compartment. This results in a more than proportional increase in plasma paclitaxel levels with increasing doses (and concomitant increasing amount of Cremophor EL), but lower free paclitaxel fraction available for cellular partitioning (21, 22, 23, 24, 25)
. Both our population model as well as the defined pharmacokinetic-pharmacodynamic relationships of paclitaxel (Refs. 6, 7, 8
; on which this study was based) are based on measured total paclitaxel plasma levels, including "free" paclitaxel, and paclitaxel bound to both Cremophor EL and plasma proteins. Because only the fraction of free paclitaxel is available for (tumor) tissue distribution, relationships between the unbound drug concentration and hematological toxicity have also been studied (26
, 27)
. Whether stronger pharmacokinetic-pharmacodynamic relationships can be found when free paclitaxel is monitored should be subject of future studies.
The results of this study show that dose individualization results in a higher percentage of patients with a time period that the paclitaxel concentration of 0.1 µmol/liter was achieved for 15 h compared with standard dosing of the compound. After administration of the standard dose of 175 mg/m2 (n = 25), 36% of the courses (n = 9) did not result in a time period above the threshold >15 h, whereas after individualizing the doses (n = 67) this was 19% (n = 13; Table 3
). From Fig. 4
it becomes clear that 7 of 13 individualized courses in which the exposure was too low after dose individualization are from 2 individuals. In these patients no dose increment was indicated according to the Bayesian predictions of the paclitaxel concentrations in plasma, whereas the time period that the paclitaxel concentration was >0.1 µmol/liter was actually <15 h during each course. It may be noteworthy that both patients had a BSA exceeding 2 m2 (2.1 and 2.25 m2, respectively). In the original patient population used for the development of the population pharmacokinetic model of paclitaxel, in which BSA was included as a covariate, only a few patients had a BSA value >2 m2. Pharmacokinetics of paclitaxel may deviate in patients with high BSA. Because Bayesian fitting initially assumes that each patient is a typical member of the population (defined by the prior values), the applied model cannot predict the pharmacokinetics in patients with BSA >2 m2 adequately. Individualized courses of other patients with concentrations >0.1 µmol/liter <15 h (9%) can be attributed to the interoccasion (course-to-course) variability of the pharmacokinetic parameters (15–39%).
Toxicities encountered during the courses were mainly hematological (primarily granulocytopenia; Table 4
) and comparable with those observed in studies with similar chemotherapy regimens (6
, 7 , 8)
. Patients with an increased individualized dose appeared to have similar toxic events compared with the patient group receiving unchanged doses. However, because the study protocol did not provide pharmacokinetically guided dose reductions, it was expected that patients receiving an unchanged individualized dose (because paclitaxel concentrations were >0.1 µmol/liter for >15 h already) had a greater risk of toxicity than patients with increased individualized dose (who initially had exposures that were too low, but that after individualization obtained exposures around the target). This is suggested by the observation that delayed administration of a subsequent course was only necessary in 1 patient with an increased individualized dose, whereas 4 patients with an individualized dose of 175 mg/m2 had to receive their doses a week after the intended date.
No significant positive relationship was found between exposure to paclitaxel and hematological toxicity, in contrast with previous studies (7 , 8) . An explanation for this discrepancy is that pharmacokinetic variation between patients is decreased due to the dosing strategy applied in this study. Therefore, more uniform exposures are reached, and as a result variation in hematological toxicity is decreased. Elucidation of existing relationships may be hampered by the limited range of paclitaxel exposures as well as the coadministration of carboplatin, which itself is myelotoxic.
Table 4
shows that the severity of the bone marrow toxicity, especially granulocytopenia, was more pronounced during later courses. This can be attributed to decrease of baseline levels of WBCs, granulocytes, and platelets during later courses. This cumulative effect has already been observed in an earlier study in patients with NSCLC treated with the combination of paclitaxel and carboplatin (6)
.
We were able to report the paclitaxel concentrations in plasma during each course and to calculate an individualized paclitaxel dose before the start of the subsequent course. This technical feasibility was mainly due to the short lines between the clinic and laboratory, and a robust analysis method for the quantification of paclitaxel. For the patient, however, the drug monitoring was an extra burden, because the patient needed to be attended to the clinic for a full day and night or return multiple times to the hospital at the indicated sampling times. When patients benefit substantially from the adaptive dosing approach, the inconvenience will be acceptable. From this study no conclusions can be drawn as to whether patients had a prolonged survival due to the dose individualizations. This should be investigated in a significantly powered randomized study comparing standard doses with adaptive pharmacokinetically guided doses.
In conclusion, the results of this study show that Bayesian pharmacokinetically guided dosing of paclitaxel is feasible in achieving a predefined exposure duration above a threshold plasma concentration. With this strategy, patients can be identified who may benefit from higher doses than the standard dose. Furthermore, the dosing strategy appeared technically and logistically feasible. The basis for the execution of future trials should be to test whether our adaptive dosing strategy results in increased response rate, time to progression, or survival.
ACKNOWLEDGMENTS
We thank Rianne Van Maanen and Ciska Koopman-Kroon for analyses of the paclitaxel samples.
FOOTNOTES
Grant support: The Dutch Cancer Society (project NKI 2001-2420) and Bristol Myers Squibb BV, Woerden, the Netherlands.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: M. E. de Jonge, Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, the Netherlands. Phone: 31205124657; Fax: 31205124753; E-mail: apmil{at}slz.nl
Received 8/19/03; revised 11/14/03; accepted 12/12/03.
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-) paclitaxel in course 1, the time period the paclitaxel concentration was above 0.1 µmol/liter was only 11.6 h in this patient. After individualized paclitaxel doses of 215 mg/m2 (-•-) in courses 2–6, the time period above 0.1 µmol/liter ranged from 15.07 to 16.8 h.
- and -x- are patients with body surface area >2 m2.