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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2901-2908
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.10.163
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Comparison of Pharmacokinetics and Pharmacodynamics of Docetaxel and Cisplatin in Elderly and Non-Elderly Patients: Why Is Toxicity Increased in Elderly Patients?

Hironobu Minami, Yuichi Ohe, Seiji Niho, Koichi Goto, Hironobu Ohmatsu, Kaoru Kubota, Ryutaro Kakinuma, Yutaka Nishiwaki, Hiroshi Nokihara, Ikuo Sekine, Nagahiro Saijo, Kazuhiko Hanada, Hiroyasu Ogata

From the Divisions of Oncology/Hematology and Thoracic Oncology, National Cancer Center Hospital East, Kashiwa; Division of Internal Medicine, National Cancer Center Hospital; Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan

Address reprint requests to Hironobu Minami, MD, Division of Oncology/Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan; e-mail: hminami{at}east.ncc.go.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: Following phase I studies of docetaxel and cisplatin in patients with non–small-cell lung cancer, the recommended doses of docetaxel were different for elderly (≥ 75 years) and non-elderly (< 75 years) patients. To elucidate the mechanism of the difference, the pharmacokinetics of docetaxel and cisplatin were investigated in two phase II studies separately conducted in elderly and non-elderly patients.

PATIENTS AND METHODS: Twenty-seven elderly and 25 non-elderly patients were treated with three weekly administrations of docetaxel and cisplatin every 4 weeks. Doses of docetaxel were 20 and 35 mg/m2 for elderly and non-elderly patients, respectively. All patients received 25 mg/m2 of cisplatin. The pharmacokinetics and pharmacodynamics of docetaxel and cisplatin were compared in elderly and non-elderly patients.

RESULTS: There were no differences in pharmacokinetics of docetaxel or cisplatin between elderly versus non-elderly patients with regard to clearance and volume of distribution. In the pharmacodynamic analysis, neutropenia was positively correlated with the area under the concentration-time curve for docetaxel but not for cisplatin. In evaluating the relationship between neutropenia and the area under the concentration-time curve of docetaxel, elderly patients experienced greater neutropenia than those predicted by a pharmacodynamic model developed in non-elderly patients; the residual for prediction of the percent change in neutrophil count was –11.2% (95% CI, –21.8 to –0.5%).

CONCLUSION: The pharmacokinetics of docetaxel and unchanged cisplatin were not different between elderly and non-elderly patients. The elderly patients were more sensitive to docetaxel exposure than the non-elderly patients, resulting in the different recommended doses for the phase II studies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
The elderly population has increased in recent years with the prolongation of the average life span, and the incidence of cancer in elderly people is also increasing. Accordingly, the number of elderly patients with cancer is expanding. Although most cancers occur in elderly individuals, elderly patients have been underrepresented in clinical trials of cancer chemotherapy.1-5 Furthermore, many elderly patients have not been referred to medical oncologists and have been under-treated in oncologic practice because of concerns over toxicity.5-9 Frequencies and severities of toxicity associated with cancer chemotherapy are higher in elderly patients than in younger patients.10-14 Despite the increased susceptibility to toxicity in elderly patients, limited investigations have been conducted on changes in the pharmacokinetics of anticancer agents associated with aging.15-18 In addition, few studies have focused on the alterations of pharmacodynamics in elderly patients. Altered pharmacokinetics, increased pharmacodynamic sensitivity, or both can theoretically cause increased toxicity. It is important, therefore, to elucidate the pharmacokinetics and pharmacodynamics of anticancer agents in elderly patients in comparison to those of younger patients in terms of their increased toxicities.

Previous reports have stressed that in the elderly, physiologic age is more important than chronological age, and that age by itself is not a contraindication to cancer chemotherapy.19,20 Some retrospective studies of chemotherapy failed to demonstrate an increased risk of toxicity among elderly patients; it has been claimed that elderly patients can tolerate chemotherapy as well as younger patients when they fulfill eligibility criteria for clinical studies of cancer chemotherapy, such as good performance status and normal organ functions.21-24 However, in a feasibility study of chemotherapy for elderly patients with lung cancer, 71% of patients aged 75 years or older were excluded from the study because of comorbidity or poor performance status; furthermore, severe myelotoxicity was observed, even in patients who fulfilled the eligibility criteria.25 Therefore, we believe that doses of anticancer agents for elderly patients should be determined by phase I studies, specifically conducted in such patients.

When we determined recommended doses of cisplatin and docetaxel administered weekly for 3 consecutive weeks in patients with non–small-cell lung cancer, we conducted two individual phase I studies for elderly patients aged 75 years or older and for non-elderly patients younger than 75 years.26 The only difference in eligibility criteria for these two phase I studies was age. The recommended dose of cisplatin was 25 mg/m2 for both patient groups, but doses of docetaxel were different for elderly (20 mg/m2) and non-elderly (35 mg/m2) patients. Based on this information, two separate phase II studies against non–small-cell lung cancer were conducted in elderly patients and non-elderly patients, using the different recommended doses.27,28 Eligibility criteria for the phase II studies were the same as those for phase I studies, except that a measurable disease for response evaluation was required for the phase II studies. To elucidate mechanisms of the difference in recommended doses of docetaxel for elderly and non-elderly patients, we investigated the pharmacokinetics and pharmacodynamics of docetaxel and cisplatin in the two phase II studies and compared them between elderly and non-elderly patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Selection
Eligibility criteria for the two phase II studies were identical except for age: 75 years or older for elderly patients and 20 to 74 years for non-elderly patients. Other eligibility criteria included histologically and/or cytologically confirmed non–small-cell lung cancer, stage IV or IIIB without an indication for curative radiotherapy, Eastern Cooperative Oncology Group performance status 0 or 1, no prior chemotherapy, the presence of measurable lesions, adequate hematologic function (WBC 4,000 to 12,000/µL; absolute neutrophil count ≥ 2,000/µL; platelet count ≥ 100,000/µL; hemoglobin ≥ 9.0 g/dL), adequate hepatic function (total bilirubin < 1.1 mg/dL; AST and ALT < 60 U/L), and adequate renal function (creatinine < 1.2 mg/dL; creatinine clearance > 60 mL/min). Exclusion criteria were active infection, severe heart disease, uncontrolled hypertension or diabetes mellitus, active concomitant malignancy, pleural and/or pericardial effusion requiring drainage, and pregnant/nursing women. In addition to written informed consent to the phase II studies with docetaxel and cisplatin, written informed consent to the pharmacologic study was required before patients were enrolled onto this study. These studies were approved by the institutional review board at the National Cancer Center (Tokyo, Japan).

Treatment and Follow-Up
After premedication with intravenous dexamethasone (16 mg) and granisetron (3 mg), docetaxel was infused over 30 minutes. Cisplatin was given as a 15-minute infusion 90 minutes after completion of the docetaxel infusion, and a total volume of 1,500 mL saline was infused on the day of chemotherapy for diuresis. The dose of docetaxel was 20 mg/m2 for elderly patients and 35 mg/m2 for non-elderly patients. All patients received cisplatin at a dose of 25 mg/m2. These were the recommended doses determined by the phase I studies. Docetaxel and cisplatin was administered weekly for 3 consecutive weeks followed by 1 week of rest. This 4-week course was repeated until there was evidence of disease progression or unacceptable toxicity. Treatment with docetaxel and cisplatin was not given if WBC was less than 2,000/µL and/or platelet count was less than 50,000/µL on the day of chemotherapy.

Physical examination and toxicity assessment included complete blood cell counts with differential counts as well as platelet counts, blood chemistry, and urinalysis. These were performed before treatment and repeated at least weekly during the chemotherapy. Toxicity was graded according to the Japan Clinical Oncology Group criteria,29 which are basically the same as the National Cancer Institute Common Toxicity Criteria.

Antitumor response was evaluated in lesions with a diameter ≥ 2 cm by carrying out a computed tomography scan according to WHO criteria.30

Pharmacokinetic Analysis
Blood sampling for pharmacokinetic analysis was performed after the first administration of the first course as follows: (1) blood samples for the measurement of docetaxel concentrations were obtained at the end of a docetaxel infusion, and 0.17, 1, 1.75, 3.25, 5.75, and 24 hours after the docetaxel infusion; (2) for analysis of the pharmacokinetics of cisplatin, blood was drawn at the end of a cisplatin infusion, and 0.25, 0.75, 1.5, 4, and 22.25 hours after the cisplatin infusion. Blood was immediately centrifuged and an aliquot of plasma was ultrafiltered using UFC3GC membranes (Japan Millipore, Tokyo, Japan). Plasma and ultrafiltrate samples were frozen at –80°C until analyzed.

The concentration of docetaxel in plasma was determined by using a previously reported high-performance liquid chromatography (HPLC) method,31 and the concentration of unchanged cisplatin in the ultrafiltrate was measured according to a HPLC method with on-line postcolumn derivatization, as reported previously.32,33

Because concentrations in plasma at the terminal phase could not be measured in some patients, pharmacokinetic parameters for individuals were calculated by Bayesian estimation after population pharmacokinetic parameters were estimated in the entire population. These calculations were performed using the NONMEM program (version V, level 1.1). A three-compartment open model with zero-order administration and first-order elimination (ADVAN 11 and TRANS 4) was used to describe the plasma concentration-time course for docetaxel in the entire population, and a one-compartment open model (ADVAN 1 and TRANS 2) was used for unchanged cisplatin in the ultrafiltrate. Assuming a log-normal distribution for inter-individual variability in pharmacokinetic parameters, the inter-individual variability was modeled as (eg, for clearance) CLj = L exp({eta}jCL), where CLj and L are the estimated values in an individual j and the population mean for clearance, respectively, and {eta}jCL is the individual random perturbation from the population mean. Intrapatient residual variability was also described by a log-normal distribution model. Similarly inter- and intra-individual variability was modeled for the volume of the third compartment (docetaxel) or the central compartment (cisplatin). The area under the concentration-time curve (AUC) was calculated as dose divided by clearance in each patient.

Pharmacodynamic Analysis
Pharmacodynamic analysis was conducted using the AUC for docetaxel and unchanged cisplatin in individual patients. Neutrophil counts were monitored at least weekly and the nadir count during the first course was recorded. The percent change in neutrophil counts (dANC) was defined as:

and the relationship between dANC and the AUC of docetaxel or unchanged cisplatin was investigated using a sigmoid Emax model:

The Emax represents the maximal effect, and EC50 is the AUC value at which the effect is 50% of the maximum effect. The exponent r is a shape factor that determines the steepness of the response curve. These values were determined by using the computer program, WINNonlin (version 4.01, Scientific Consultant, Apex, NC).

Statistical Methods
Continuous variables, including pharmacokinetic parameters, were compared between elderly (75 years or older) and non-elderly patients (74 years or younger), using the Mann-Whitney U test. Differences in distribution of patient characteristics between the two groups were evaluated with the {chi}2 test or Fisher's exact test, where appropriate. P values less than .05 were regarded as statistically significant, and all reported P values are two-tailed.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Of 33 elderly and 36 non-elderly patients who received docetaxel and cisplatin in the phase II studies, the pharmacokinetic study was performed in 25 and 27 patients, respectively (Table 1). There were no differences between the two groups in the distribution by sex, performance status, or the proportion of patients who had been treated with radiotherapy before entry into the study. Elderly patients had slightly lower levels of total protein, albumin and {alpha}1-acid glycoprotein, and neutrophil counts than non-elderly patients, but the differences were small. Patients with hepatic or renal dysfunction were excluded from the phase II studies and there were no differences between groups in these functions except for ALT.


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  		Table 1. Patient Characteristics

 
Because of technical problems with blood sampling or with HPLC systems, pharmacokinetic data for docetaxel and cisplatin could not be obtained in two non-elderly patients and one elderly patient, respectively. Therefore, pharmacokinetic parameters for docetaxel in 25 elderly patients and 25 non-elderly patients and those for unchanged cisplatin in 24 elderly patients and 27 non-elderly patients were compared (Table 2). There was no difference in the clearance or volume of distribution of docetaxel between the elderly and non-elderly patients. Similarly, the clearance and volume of distribution of unchanged cisplatin were similar in both patient groups. The elderly and non-elderly patients were treated with different doses of docetaxel (20 and 35 mg/m2, respectively), though the clearance of docetaxel was the same for both populations. Therefore, the AUC of docetaxel in the non-elderly patients was greater than that in the elderly patients.


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  		Table 2. Pharmacokinetic Parameters

 
Despite the fact that the AUC of docetaxel was higher in the non-elderly patients than in the elderly patients, the neutropenia observed was similar for the two groups of patients, with regard to toxicity grades and actual nadir counts (Table 3). Although administrations of docetaxel and cisplatin were omitted on day 8 or 15 of the first course in one elderly patient and in seven non-elderly patients, there was no difference in age between the eight patients who did not receive the treatment on day 8 or 15 and the other 44 patients who were administered chemotherapy three times (63.4 ± 9.9 years v 67.4 ± 12.8 years; P = .41). When the AUC of cisplatin and docetaxel was compared between patients who did or did not receive all administrations, the AUC of docetaxel was significantly higher for patients who missed a dose than patients who received all administrations (1.57 ± 0.88 v 1.03 ± 0.53 µg/mL x hour; P = .03), while the AUC of cisplatin was similar (90.6 ± 15.2 v 93.4 ± 11.5 µg/mL x min; P = .54).


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  		Table 3. Neutropenia in the First Course

 
The relationship between the AUC of docetaxel or cisplatin and percent changes in neutrophil counts was evaluated using a sigmoid Emax model in the elderly or non-elderly patients. The AUC of cisplatin was not correlated with the percent change in neutrophil counts in either elderly or non-elderly patients (Fig 1). On the other hand, the AUC of docetaxel was positively correlated with the percent change in neutrophil counts (dANC) in the non-elderly patients (Fig 2), and the relationship was described as:



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  		Fig 1. Relationship between the area under the curve (AUC) of cisplatin and percent changes in neutrophil counts in the elderly ({circ}) and the non-elderly (•) patients.

 


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  		Fig 2. Relationship between the area under the curve (AUC) of docetaxel and percent changes in neutrophil counts in the elderly ({circ}) and the non-elderly (•) patients. The solid line represents predictions by a sigmoid Emax model in the non-elderly patients.

 
Because the distribution range of the docetaxel AUC in the elderly patients was narrow, a sigmoid relationship between the AUC of docetaxel and the percent change in neutrophil counts was not apparent (Fig 2), and parameters in the sigmoid Emax model could not be calculated in the elderly group.

To investigate whether the pharmacodynamic relationship between the AUC of docetaxel and neutropenia for the elderly patients was different from that of the non-elderly patients, percent changes in neutrophil counts were predicted in the elderly patients. This was done using the sigmoid Emax model developed in the non-elderly patients, and residuals of the prediction (predicted value – observed value) were calculated. The neutropenia observed in the elderly patients was greater than that predicted by the model with a mean of residual of –11.2% (95% CI, –21.8% to –0.5%), while the model predicted neutropenia without bias in the non-elderly patients with a mean residual of 0.21% (95% CI, –7.4% to 7.8%), as expected. Elderly patients had a lower docetaxel AUC than non-elderly patients, and there were two non-elderly patients with a high docetaxel AUC who seemed to be outliers. Therefore, we analyzed the data after excluding non-elderly patients with AUC > 1.53 µg/mL x hour (the maximum value in elderly patients) or after excluding the two outliers. Both reanalyzed models also underestimated neutropenia in the elderly patients: –13.5% (range, –26.2% to –0.8%) and –12.5% (range, –23.7% to –1.3%), respectively.

Partial responses were observed in eight of 27 non-elderly patients, and among 25 elderly patients, a complete response and partial responses were documented in one and 12 patients, respectively. When the AUC of docetaxel and unchanged cisplatin was compared between responders and nonresponders, no differences were observed. The AUC values for docetaxel in responders and nonresponders were 1.02 ± 0.39 and 1.14 ± 0.70 µg/mL x hour, respectively, and the AUC values for unchanged cisplatin were 91.5 ± 12.8 and 94.0 ± 11.5 µg/mL x min, respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
The purpose of the pharmacologic study was to elucidate mechanisms of the difference in recommended doses of docetaxel in combination with cisplatin in elderly patients and non-elderly patients. We investigated the pharmacokinetics and pharmacodynamics of docetaxel and unchanged cisplatin in two subsequently conducted phase II studies.27,28 For both docetaxel and cisplatin, the pharmacokinetics did not differ between elderly patients and non-elderly patients. While exposure to cisplatin was not correlated to the extent of neutropenia, there was a sigmoidal relationship between the AUC of docetaxel and neutropenia in the non-elderly patients. However, the relationship between the AUC of docetaxel and neutropenia in the elderly patients was different from that in the non-elderly patients. Although elderly patients had smaller AUC values than non-elderly patients, the same extent of neutropenia was observed in both patient groups (Table 3), and nonhematologic toxicities were mild and similar in both groups.27,28 These observations suggest that elderly patients were more sensitive to the exposure of docetaxel than non-elderly patients.

There was no difference in docetaxel clearance between elderly and non-elderly patients (Table 2). This conclusion was not changed after the clearance of docetaxel was adjusted for body-surface area (29.6 and 28.2 L/h/m2, for elderly and non-elderly patients, respectively). These values fall within the range of docetaxel clearance values previously published.34-37 Furthermore, docetaxel clearance was not correlated to age as a continuous variable, and age was not a significant covariate in the population pharmacokinetic model. These observations seem to be inconsistent with those of a previous report, which found that age was inversely correlated to the clearance of docetaxel in a population pharmacokinetic model.38 Although the exact reasons for this discrepancy are not clear, ethnic difference or coadministration of cisplatin might explain it. However, the estimated coefficient of age in the population model was small in the previous report. A difference of 20 years in age (the difference in the median ages of the elderly and the non-elderly groups in our study) would yield less than a 10% difference in the clearance of docetaxel. The previous population model was developed by using data from 547 patients, while in our study, data from 52 patients were used. It was possible that the smaller number of patients in our study precluded the detection of a small difference in docetaxel clearance between elderly and non-elderly patients. However, the difference in the dose of docetaxel between elderly patients (20 mg/m2) and non-elderly patients (35 mg/m2) did not seem to be explained by a less than 10% difference in docetaxel clearance values.

Although the concentration of ultrafiltrable platinum was measured in most of the pharmacokinetic studies with cisplatin, measuring the concentration of unchanged cisplatin is clinically more relevant because ultrafiltrable platinum contains inactive low molecular-weight metabolites.39 The pharmacokinetics of unchanged cisplatin were not different between elderly and non-elderly patients, and there was no correlation between age and the clearance of cisplatin. The clearances of unchanged cisplatin for elderly and non-elderly patients in our study were similar to those reported previously.40-44

In the pharmacodynamic analysis in the present study, exposure to docetaxel was correlated to the extent of neutropenia in the non-elderly patients, but the relationship between docetaxel exposure and neutropenia was unclear in the elderly patients. Therefore, for comparison of pharmacodynamics between the elderly and non-elderly patients, we applied the pharmacodynamic model developed in the non-elderly patients to the data from the elderly patients. The residuals of prediction by the model were less than zero in the elderly patients, indicating that the model underestimated the extent of neutropenia in the elderly patients. Although this analysis might be exploratory because uncertainty in the estimates of model parameters was not considered, the results suggest that elderly patients are more sensitive to neutropenia induced by docetaxel than non-elderly patients. This is further supported by observations that the elderly patients and non-elderly patients experienced neutropenia to the same extent, despite the fact that the AUC of docetaxel was greater in the non-elderly patients than the elderly patients.

We used a sigmoid Emax model for pharmacodynamic analysis. Since it is a nonlinear model, parameter estimation may depend on the distribution of variables. Because elderly patients had lower docetaxel AUC than non-elderly patients, and because there were two outliers in the non-elderly patients, we reanalyzed the data after excluding data of non-elderly patients with AUC greater than the maximum for elderly patients, or excluding the two outliers. The results of these reanalyses were the same and confirmed that elderly patients are more sensitive to neutropenia induced by docetaxel. Another approach would be modeling the all data simultaneously and investigating interaction between age and parameters in the model. However, incorporation of age into a sensitivity parameter (EC50) or a shape parameter (r) did not improve model performance (data not shown).

These findings are in agreement with clinical observations in many previous reports; elderly patients experienced more profound myelotoxicity and had greater risk of chemotherapy-related death than younger patients in various cancers.10,13,14,45-48 We showed that the greater risk of hematologic toxicity in the elderly patients was related to the greater sensitivity of bone marrow function to combination chemotherapy of docetaxel and cisplatin using a weekly schedule without altered pharmacokinetics. The greater sensitivity of myeloid cells to chemotherapeutic agents in the elderly was also in agreement with our previous pharmacodynamic analysis of leukopenia.49 In that study, we developed a novel pharmacodynamic model relating the entire time course of leukopenia to the time course of drug concentration. A parameter corresponding to the sensitivity of myeloid cells to chemotherapeutic agents showed a significant correlation with age, and myeloid cells of elderly patients showed greater sensitivity than those of younger patients without altered pharmacokinetics of anticancer agents.49,50 Furthermore, in a pharmacologic analysis of etoposide, elderly patients had greater sensitivity with regard to neutropenia than younger patients at the same level of drug exposure.18 These observations were in accordance with those made in the current study.

The exact reason why bone marrow function of elderly patients showed greater sensitivity to chemotherapeutic agents than that of younger patients is not clear. Factors stimulating neutrophil production, such as granulocytopoietic cytokines, should be increased during the neutropenic period after chemotherapy. However, the production of these cytokines is reduced in the elderly,51 and a decreased response to granulocytopoietic stimuli in infection has been reported in aged mice and humans.52-54 These factors may explain the greater sensitivity of elderly patients to chemotherapeutic agents, although kinetics of cytokines after chemotherapy would also need to be investigated.

Potential drawbacks of this study may be the small number of patients and low incidence of significant neutropenic events, which might be explained by divided doses of docetaxel and restriction of eligibility to patients with a good performance status. It is unclear whether difference in the sensitivity to neutropenia could fully explain the difference in the dose of docetaxel between the elderly patients and the non-elderly patients, considering that the observed neutropenia was moderate. However, nonhematologic toxicities were mild and similar in both groups26 despite the fact that the AUC of docetaxel was greater in the non-elderly patients than in the elderly patients. These observations suggest that elderly patients are more sensitive to toxicities than non-elderly patients.

It is notable that a high response rate was observed in elderly patients, though a reduced dose of docetaxel was used, compared to non-elderly patients. Further studies of chemotherapy in elderly patients with non–small-cell lung cancer are warranted.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Supported in part by Grants-in-Aid from the Ministry of Health and Welfare for the 2nd-Term Comprehensive 10-Year Strategy for Cancer Control.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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Submitted October 24, 2003; accepted April 14, 2004.


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