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Originally published as JCO Early Release 10.1200/JCO.2005.09.161 on December 7 2004 © 2005 American Society of Clinical Oncology. Model Describing the Relationship Between Pharmacokinetics and Hematologic Toxicity of the Epirubicin-Docetaxel Regimen in Breast Cancer PatientsFrom the Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Sweden; Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden; Radiumhemmet, Karolinska Institute and Hospital, Stockholm, Sweden Address reprint requests to Marie Sandström, MSci Pharm, PhD, Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden; e-mail: marie.sandstrom{at}farmbio.uu.se
PURPOSE: The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients. PATIENTS AND METHODS: Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m2. Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m2) or reduced (minimum, 40/50 mg/m2). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment. RESULTS: In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data. CONCLUSION: The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.
The efficacy of the anthracycline epirubicin (EPI) and the taxane docetaxel (DTX) when given as single drugs, as well as the absence of cross-resistance between the two drugs, has resulted in substantial interest in the combination for breast cancer therapy.1-9 Different dose combinations and schedules have been evaluated. Dosing strategies have been based on the maximum-tolerated doses (MTD) of each drug when given as single therapy as defined by previous studies, and also on the results from the combination of the related drugs doxorubicin and paclitaxel.10 In the process of investigating the EPI-DTX combination, the pharmacokinetics (PK) of the components have been characterized following combination treatment.8,11,12 An indication of a redistribution phenomenon of EPI when followed immediately by DTX administration was found in a study on 11 patients.12 This phenomenon was not apparent from the data presented in another study in which the same schedule was used; whereas in that study, a different metabolic pattern was found for EPI in the combination, compared with single-drug administration.11 However, no obvious clinically relevant PK interaction between the two parent compounds has been demonstrated. Knowledge of PK may help in the optimization of dose and schedule selection of polychemotherapy combinations.13 However, optimizing the dosing requires knowledge of the contribution of the component drugs to the antitumoral effect and toxicity. The former is usually not definable from clinical data; therefore, dosing individualization has to be based on dose-limiting toxicity rather than desirable effect. In the case of EPI and DTX, one of the dose-limiting and joint toxicities is hematologic toxicity. The hematologic toxicity from each drug alone has been previously described, and for both drugs, a relationship between exposure in terms of area under the concentration-time curve (AUC) and hematologic toxicity has been shown.14-17 However, no report on the characterization of the relationship between PK and hematologic toxicity for the EPI-DTX combination has been published. Hence, the contribution of each drug to hematologic toxicity in the combination therapy has not yet been quantified. The aims of the present study were (1) to characterize the PK of both component drugs and (2) to describe the relationship between PK and the dose-limiting hematologic toxicity for the EPI-DTX regimen in breast cancer patients, as this regimen has promising clinical utility.
Patients and Treatment Forty-four breast cancer patients with advanced breast cancer were treated at Akademiska Hospital, Uppsala (n = 24), or at Karolinska Institute (n = 20), Stockholm, according to a phase II protocol with the registered drugs EPI (supplied as Farmorubicin; former Pharmacia AB, Stockholm, Sweden) and DTX (supplied as Taxotere; former Rhône-Poulenc, Antony, France) from 1997 to 2000. The study protocol was approved by the ethical committees of Uppsala University Hospital and Karolinska Institute in Stockholm, and the Swedish Medical Products Agency. At time of analysis, data were not yet available for one patient. Patient characteristics are specified in Table 1. Creatinine clearance was calculated according to Cockroft and Gault.18 Data on pilot patients treated exactly according to the protocol, but before the approval, are included in the Table. All patients, including the pilot patients, were given oral and written information and agreed to participate before inclusion. At treatment day 1, EPI was given as a 1-hour infusion. After a 1-hour free interval, a 1-hour infusion of DTX followed. The treatment was repeated every third week for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m2 (dose level 1). The following doses were modified based on WBC and platelet counts and were escalated to 90/80 mg/m2 (dose level 2), 105/90 mg/m2 (dose level 3), and to a maximum of 120/100 mg/m2 (dose level 4); reduced to 60/60 (dose level –1) or 40/50 mg/m2 (dose level –2); or remained on the same dose level, depending of the individual hematologic toxicity. Patients who developed febrile neutropenia or a nadir WBC of less than 1.0 x 109/L lasting for more than 5 days received granulocyte colony-stimulating factor (G-CSF; lenograstim) from day 3 until day 12 in association with the remaining treatment cycles. All patients received prophylactic antibiotic therapy with ciprofloxacin 500 mg twice daily for 10 days starting at day 5. Premedication with peroral betamethasone 8 mg was given at 12 hours and 1 hour prior to DTX treatment. Oral betamethasone 8 mg was thereafter administered twice daily throughout 2 days. The patients also received antiemetic agents according to the investigator’s routine practice, but 5-HT3 receptor antagonists were recommended.
Pharmacokinetic Sampling Blood samples for PK were collected in EDTA-coated Vacutainer tubes (Becton Dickinson, Plymouth, United Kingdom) at five time points within the following sampling windows: immediately before the end of the EPI and DTX infusions, respectively; 30 to 60 minutes after the end of DTX infusion; 5 to 8 hours and 15 to 27 hours after the start of EPI infusion. However, deviations occurred due to practical reasons or patient convenience, but the actual time of sampling was recorded and used in the data analysis. The samples were immediately put in an ice-water bath and were centrifuged at 4°C within 20 minutes to obtain plasma that was stored at –70°C until analysis. Sampling for determination of WBC was scheduled for days 1 (dosing day), 8, 11 or 12, 15, and 22 in association with each treatment occasion. However, for practical reasons, the true sampling times diverged ± 1 to 2 days from those scheduled.
Drug Assays
Data Analysis The modeling was performed in steps. First, the PK models were developed using the ADVAN 11 subroutine. In the PK-PD analysis that followed, the individual PK parameter estimates from the final PK models were fixed, and the predicted individual drug concentration-time profiles were used as input functions in the pharmacodynamic model. PK in the individuals from whom PK information was missing was assumed to be the same as in the typical individual in the studied population. For this part of the analysis, the ADVAN 6 was used. Since it is well known that EPI and DTX show three-compartment PK,19,23 only such models were considered in the PK part of the analysis. During the development of the DTX PK model, variability terms including interoccasion variability were tried sequentially on all PK parameters and where kept in the model only when significant on the P < .01 level. EPI data did not support a three-compartment model. Therefore, EPI data were analyzed using the PRIOR routine within NONMEM.24 Parameter estimates from a previous PK analysis of data from a similar population of 79 breast cancer patients (unpublished data) were used as frequentist priors, where a penalty is added to the objective function on deviation from these priors. The structural and statistical parts of the previously developed model were kept when characterizing the EPI data. The estimate used as prior for total-body clearance (CL) and the intercompartmental clearances (Q2 and Q3) were (with coefficient of variation [CV%] in parentheses) 71.7 (2.7) L/h, 70.6 (3.9) L/h, and 17.8 (10) L/h, respectively; whereas the estimates for central volume of distribution (V1) and the peripheral volumes of distribution (V2 and V3) were 13.1 (7.5) L, 776 (3.7) L, and 14.6 (7.4) L, respectively. The estimates used for interindividual variability in CL, interoccasion variability in V1, and residual error were 15% (39), 73% (16), and 25.7% (7.7), respectively.
Model Describing Hematologic Toxicity The model consists of five compartments, of which one represents proliferating cells. That compartment is linked to a compartment representing circulating leukocytes via a maturation chain that is composed of three sequential compartments (Fig 1). The prediction at any time (t) after dose in the fifth compartment, WBC(t), is hence fit to the WBC observations obtained from the patients.
The rate at which an average cell moves (matures) from one compartment (stage) to another is governed by the first-order maturation rate constants (kMTT). The product of the proliferation rate constant (kprol) and the baseline value of the amount of proliferative cells needs (from mass balance considerations) to equal the product of the elimination rate constant for circulating leukocytes (kcirc) and the baseline WBC. Without loss of generality, kpro1 was set to equal kMTT, resulting in a baseline value of the amount of proliferative cells equaling the baseline leukocyte count.15 The circulating WBC elimination rate constant (kcirc) was, as a default, fixed to be the same value as kMTT. This is a procedure that has been used before to handle the lack of information in this parameter from this type of clinical data.15 The lack of information about kcirc stems from the fact that the rate-limiting step for the temporal aspects of the leucopenia profile is the maturation time, not the half-life of leukocytes in circulation. In addition to the default procedure, kcirc was fixed to a value corresponding to a half-life of 6 hours, a value previously reported in the literature.25 Since the present maturation chain consists of three compartments, the average time it takes for a cell to mature and appear in the systemic circulation (ie, the mean transit time through the chain [MTT]) is equal to 4/kMTT.
Also included in the model is a feedback mechanism that imitates the endogenous colony stimulation factor feedback system. The system responds to a decrease in blood-cell concentration, and it is modeled as a function of the baseline WBC (WBCbase) and WBC(t) according to (WBCbase/WBC[t])
No data were available from patients receiving EPI as single therapy in the present study. Therefore, to assess whether the assumption of additivity of EPI and DTX effects was appropriate, a model which as well as the effects of EPI and DTX alone also included an effect component from the product of the two drug concentrations was compared with the final model. In addition, the estimated SEPI was evaluated versus previously published data.17 The WBC-time profile after the doses given in that study was simulated, and the model-predicted decrease in WBC 12 days after administered dose was compared with the observations obtained 10 to 14 days after given dose. Doses used in the simulation were hence 40, 60, 90, and 135 mg/m2.
Investigated Correlations
Pharmacokinetics On average, 4.5 pharmacokinetic samples per patient were drawn at 38 occasions from 16 patients for measurement of EPI (170 observations) and DTX (134 observations). Observed concentrations of EPI and DTX versus time are displayed in Figure 2A and 2D. The concentration-time profiles in the typical individual, predicted by the population parameter estimates, are shown as solid lines in Figure 2. Model predicted as well as individual model predicted concentrations versus the observed concentrations are also shown (Fig 2B and C, and 2E and F). The population parameter estimates from the final models are presented in Table 2. No significant correlation was found between the clearances of EPI and DTX.
One individual showed unexplainable diverging DTX PK compared with the remaining patients during the third and last occasion (Fig 2D). The data from that patient at that occasion were therefore excluded from the data set and analyzed separately. The DTX clearance was estimated to 6.3 L/h compared with the estimates from the first and second occasion (26.9 and 24.1 L/h, respectively). The EPI PK parameters did not differ, and the EPI clearance for that individual was estimated to 74 L/h, which is near the population parameter estimate of 69.6 L/h.
Hematologic Toxicity
The leukocyte count at baseline (ie, observed WBC at the start of therapy during the first occasion, was on average (CV and range within parentheses) 6.8 x 109/L (27%; 3.9 to 12 x 109/L). WBC nadir (ie, the lowest observed count between dosing occasions, occurred on average at 10 days (23%; 7 to 14 days) after treatment and averaged 1.2 x 109/L (47%; 0.3 to 3.3 x 109/L).
Exposure-Toxicity Relationships No significant correlation between the sum of EPI and DTX doses and SF was found when considering either all dosing occasions or the first occasion only. Relationships between different exposure measurements and SF were evaluated separately for the dosing occasions from which PK was available. For those occasions, regardless of considering all doses or the first dose only, no significant relationship was found between SF and any dose measurement, whereas a significant correlation was obtained when instead the sum of the AUCs was considered as a predictor for SF.
The PK/PD Model for Hematologic Toxicity
Well-defined dose-response relationships in patients are seldom clarified for anticancer agents. The relative gain of increasing dose-intensity has been questioned30 and in addition some recent studies point to that low doses might be sufficient to induce desirable effects.31 However, others support the, in clinical practice, often hold theory that the higher the dose-intensity delivered to the patient, the higher the probability of achieving effective exposure of the tumor.32-34 On the other hand, the higher probability of reaching increased antitumoral effect by higher dose has to be carefully balanced against the increased risk of obtaining fatal toxicity, such as hematologic toxicity.
WBC count at nadir, and other toxicities, have previously been suggested as biologic markers for the adjuvant chemotherapy efficacy in breast cancer patients.35-37 Accordingly, the dosing strategy in the present patient cohort was to treat the patients with individualized doses that resulted in equivalent hematological toxicity in terms of a nadir WBC of If highest dose possible were the aim of the therapy, the ideal would be to rapidly determine the MTD for an individual patient, if not possible already before the first dosing occasion, at least during the first course of therapy. The variability in the pharmacokinetic parameter clearance was for both drugs in the present study found to be less within than between individuals. Hence, therapeutic drug monitoring (TDM) is a possible method to use, provided that a target concentration or exposure profile has been defined. TDM has been successfully carried out in anticancer therapy.13 However, the fact that anticancer regimens often include drugs with overlapping toxicity and that models that accounts for the contribution of more than one drug to the pharmacodynamic profile has been lacking, have precluded the use of TDM for most drug combinations. Development and implementation of PK/PD models, as the model proposed in the present study, might increase the chance of successfully performing TDM. On the other hand, measuring WBC only and obtaining individualized PK/PD parameter estimates may be sufficient for predicting the outcome of future courses under joint escalation/reduction of DTX and EPI. However, no evaluation of various prospective strategies for dose individualization was performed on the present data and any possible benefit of TDM using this model needs to be established in future studies. The superior correlation between the sum of the respective drug’s AUC and SF compared with the between sum of doses and SF in the patients from which PK was available, indicates that part of variability in hematologic toxicity is explained by variability in PK. This result is in accordance with previous studies in which EPI and DTX were administered as single drugs.14,16,17 Estimation of the effect of each drug was not possible without using data from another study as prior information in the modeling process. The fractional decreases in WBC 12 days after dosing of EPI alone were, by the model, predicted to be 0.3, 0.42, 0.56, and 0.72, after the doses 68, 102, 153, and 230 mg, respectively, which could be compared with those reported previously (ie, 0.45, 0.52, 0.60, and 0.70, respectively),17 for comparative exposures. The estimated value for docetaxel slope was 7.74 L/mg, which is close to the value of 7.91 L/mg which has been previously shown to adequately describe the leukopenia profile in 601 patients.15 In addition, the model in which multiplicative effects between the drug concentrations were allowed did not result in an improved fit. Thus, the developed model, with additive effects between epirubicin and docetaxel, can describe not only combination treatment, but also monotherapy with epirubicin and with docetaxel. However, for the combination treatment, only a limited dose range was investigated and caution in extrapolation of the results to combinations of the two drugs at other doses should be exercised. The lower variability within than between individuals in clearance of the studied drugs found in the present study and, in addition, the significant correlation between the sum of the respective drug’s AUC and fractional decrease of leukocyte count at nadir, suggests that individual clearance estimates of the component drugs in the studied regimen may be used to individualize therapy. By in addition estimating the SEPI and SDTX in an individual patient, the chance of defining the MTD early in drug therapy may increase. The presently proposed model describes the whole time-course of WBC after combination therapy consisting of the two drugs EPI and DTX. The delay in the observed effect is well captured by the model and furthermore, the estimated time at which nadir occurs is in agreement with the observations. Hence, the model might offer the benefit of being predictive of the duration of leukopenia and thus it might be used to calculate the doses of the drugs in the combination to administer.
The authors indicated no potential conflicts of interest.
We are grateful to the patients who kindly participated in the study. We also thank Britt Jansson, Ingrid Fallenius, Jessica Nilsson, Carina Andersson, Rita Grönberg, Tina Fornbrandt, Birgitta Ohlander, Gunvor Svensson, and Clementine Molin for technical assistance.
Supported by the Swedish Cancer Society. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, feedback system which is a function of baseline WBC and the WBC at any given time.
1.0 * 109/L. This was carried out by stepwise dose escalation/reduction, based on the hematologic toxicity. Using this principle, it was previously demonstrated that individually tailored and dose escalated FEC (fluorouracil, epirubicin, cyclophosphamide) resulted in statistically significantly fewer breast cancer relapses compared with standard FEC followed by marrow supported high-dose therapy.
