Introduction

Cancer predominantly occurs in older adults (1). The proportion of older adults worldwide is increasing, and anti-cancer treatment is ever more used in older patients. However, the elderly subpopulation was markedly underrepresented in most clinical trials (2,3,4,5). Treatment safety and efficacy may differ between older and younger patients, due to a progressive reduction in organ functions and comorbidities (6). Therefore, clinical trial results from younger patients cannot plainly be extrapolated to older patients treated in routine clinical practice. Paclitaxel is a potentially highly toxic chemotherapeutic agent frequently used in daily practice to treat older patients with various cancer types including ovarian cancer, lung cancer, breast cancer, and esophageal cancer. As with older age the fraction of body fat generally increases and hepatic functions may be diminished (7,8), we hypothesized that the pharmacokinetics (PK) of the lipophilic drug paclitaxel may be altered in elderly patients. Although data are limited and results are conflicting, most studies suggest that older patients have an increased risk of developing paclitaxel-induced neutropenia compared to their younger peers (9,10,11). A potential PK basis for these findings has not consistently been established in clinical practice.

In previous studies conducted with data from the Netherlands Cancer Institute (NKI; Amsterdam, the Netherlands) we showed a small but significant effect of age on paclitaxel PK (12,13). However, the total fraction of older patients (≥70 years) in the final pooled analysis from multiple clinical trials was only 6.7% (13). This finding was in line with analyses from clinical trials conducted at the Erasmus Medical Center Cancer Institute (EMC; Rotterdam, the Netherlands), showing no effect of aging on paclitaxel PK (14,15,16). This EMC database consisted of different clinical trials including patients treated with paclitaxel, including 18% of patients being 70 years of age or older.

The aim of the current study was to evaluate whether older patients have an increased exposure to paclitaxel. Therefore, the aforementioned previous databases from the NKI and EMC were combined and enriched with a prospective PK dataset collected in an unselected group of patients aged 70 years or older who were treated with paclitaxel intravenously in routine clinical practice.

Methods

Prospective Data

Patients of 70 years or older who received an intravenous infusion of paclitaxel at the NKI or the Radboud University Medical Centre (Radboud UMC; Nijmegen, the Netherlands) were included in the study if written informed consent was given. The inclusion period was from September 2012 to May 2017, and for PK purposes, additional blood samples were taken according to a flexible sampling scheme, with the first sample collected at the end of infusion. The number of withdrawn blood samples was based on each patient’s availability with a minimum of 1 and a maximum of 10 samples per patient. PK sampling was allowed during any treatment cycle. Paclitaxel plasma concentrations from both hospitals were determined at the NKI using a previously validated high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) detection method, with a validated range of 0.5–500 ng/mL (inter-assay accuracy and precision both <10%) (17).

All paclitaxel containing regimes were administered according to standard procedures of the participating study centers, using fixed infusion times, dose reduction guidelines, and premedication. The prospective part of this study was approved by the institutional ethics committees and was carried out in accordance with ICH Guidelines for Good Clinical Practice (18).

Retrospective Data

Data collected in the prospective study were combined with retrospective data from previous clinical trials conducted at the NKI and EMC. Twelve patients from the NKI retrospective cohort who were treated with 24 h infusions of paclitaxel were excluded from the current analysis. This resulted in a total of 595 patients who were included in previous clinical trials, including 77 (13%) patients aged 70 years or older. These populations were described in detail in previously published articles (12,13,14,15,16).

Population Pharmacokinetic Model

A previously developed 3-compartment population PK model with saturable distribution and saturable elimination (13) was used to describe paclitaxel plasma concentration-time data, with natural logarithmic transformation of the plasma concentrations of paclitaxel, using the following differential equations:

$$ \frac{d{A}_1}{dt}=-\frac{C_1\ast V{M}_{EL}}{\left(K{M}_{EL}+{C}_1\right)}+{K}_{21}\ast {A}_2-\frac{C_1\ast V{M}_{TR}}{\left(K{M}_{TR}+{C}_1\right)}+{K}_{31}\ast {A}_3-{K}_{13}\ast {A}_1 $$
(1)
$$ \frac{d{A}_2}{dt}=\frac{C_1\ast V{M}_{TR}}{\left(K{M}_{TR}+{C}_1\right)}-{K}_{21}\ast {A}_2 $$
(2)
$$ \frac{d{A}_3}{dt}={K}_{13}\ast {A}_1-{K}_{31}\ast {A}_3 $$
(3)

where A1, A2, and A3 represent the amount of paclitaxel in central, first peripheral, and second peripheral compartment, respectively. C1 represents the log-transformed concentration of paclitaxel in central compartment, VMEL represents the maximal elimination rate, KMEL is the plasma concentration at half VMEL, VMTR represents the maximal transport rate from the central to the first peripheral compartment, KMTR is the plasma concentration at half VMTR, and K21, K31, and K13 represent the rate constant of the distribution between the central and first and second peripheral compartment, respectively.

Random Effects Model

Characterization of interindividual variability (IIV) on VMEL, VMTR, KMTR, Q and V3, and inter-occasion variability (IOV) on V1 and VMEL was performed using exponential error models. The magnitude of IIV and IOV was expressed as percent coefficient of variation. In the previously published model (13), the residual error model was characterized using a proportional error model. A separate proportional error was evaluated for each included cohort, i.e. the retrospective NKI cohort, the retrospective EMC cohort, and the prospective cohort, given that different analytical assays had been used. In one of the retrospective databases, observations below the quantification limit of the assay (BQL) were discarded. It could not be retrieved from which patients data were discarded. Therefore, regular methods for handling BQL observations could not be used. However, the sensitivity of the assays was sufficient to quantify all observations at least until 24 h after end of infusion. To mitigate potential (unknown) bias caused by these hidden BQL data in this cohort, only in this cohort an additive error was added. Hence, we considered a proportional error for each cohort, and for one cohort an additive error was estimated together with the proportional error, using the following equation (19):

$$ \ln \left({C}_{ij, obs}\right)=\ln \left({C}_{ij, pred}\right)+\sqrt{{\varepsilon_{ij, prop}}^2+\frac{{\varepsilon_{ij, add}}^2}{{C_{ij, pred}}^2}} $$
(4)

where Cij,obs represents the observed concentration for the ith individual and the jth observations, Cij,pred represents the individual predicted concentration for the ith individual and the jth observations, and εij,prop and εij,add represent the proportional and additive error, respectively, distributed N(0,σ2), where σ2 represents the population variance for the residual unexplained variability.

Evaluation of Age as a Covariate

The previously published model (13) already included age, gender, body surface area (BSA), and total bilirubin (BILI) as significant covariates on VMEL, the primary PK parameter of interest. To evaluate the impact of older age on paclitaxel PK in the current enriched dataset, we evaluated the base model and covariate model without and with inclusion of the covariate age. Age was included both as a continuous and as a dichotomous variable, by dividing the population into two age groups, namely younger patients (<70 years) and older patients (≥70 years). All continuous variables were centered on their median value of the study population, in order for population parameter estimates to represent those of a typical patient. For evaluation of categorical covariates, e.g. gender, on the maximal elimination rate (VMEL) the following equation was used:

$$ V{M}_{EL}={\Theta}_1\ast {\Theta_2}^{GENDER}\ast {\mathit{\exp}}^{\eta i} $$
(5)

where Θ1 represents the maximal elimination rate in females, Θ2 represents the maximal elimination rate in males (GENDER = 1), and ηi represents the interindividual error. This equation was also used to evaluate the impact of age as a dichotomous variable, divided into two age groups. For the continuous variables age, BSA, and bilirubin, respectively, the following equation was used:

$$ V{M}_{EL}={\Theta}_1\ast {\left(\frac{ CO V}{CO{V}_{median}}\right)}^{\Theta_2}\ast {\mathit{\exp}}^{\eta i} $$
(6)

where Θ1 represents the typical population value for the maximal elimination rate, COV represents the continuous covariates age, BSA, and bilirubin, respectively, centered to their population median value of the study population, Θ2 represents the exponential factor per continuous covariate to describe the correlation with the maximal elimination rate, and ηi represents the interindividual error.

For covariates for which there were missing values, a separate estimate for missing values was added to the model. The influence of older age on VMEL was evaluated by statistical significance using the likelihood ratio test with a p value of <0.005 (corresponding to a decrease in objective function (dOFV) of >7.9), a clinically relevant decrease in IIV on VMEL, goodness-of-fit (GOF) diagnostics, visual predictive check (VPC) evaluation with n = 1000, and plausibility of parameter estimates. To evaluate whether the impact of older age on paclitaxel PK could be explained by performance status (PS), the impact of this covariate was evaluated in a model including age. PS was defined using the Eastern Cooperative Oncology Group (ECOG) scale. If the Karnofsky scale was documented in a patient’s medical record, the ECOG PS was calculated using the proposed conversion table by Ma et al. (20). Simulations with the final model were performed to evaluate the impact of age on the time-above-threshold-concentration of 0.05 μmol/L (TC > 0.05, depicted in hours). Hence, a population of n = 1000 was simulated separately for female and male patients, who all received paclitaxel 80 mg/m2 in a 1-h infusion, with all other covariates in the final model set to their population median.

Software

Non-linear mixed effects modeling was performed using NONMEM® (version 7.3.0, ICON Development Solutions, Ellicott City, MD, USA) and Pearl-speaks-NONMEM (version 4.4.8). As estimation method the first order conditional estimation with interaction was used. Piraña® (version 2.9.2) was used as modeling environment and data management and visualization was performed using R (version 3.0.1). Furthermore, on rank sum test and Fisher’s exact test, with a significance threshold of P < 0.05, were used to evaluate patients’ characteristics.

Results

In total, 5895 samples from 684 patients (range: 1–20 per patient per cycle) treated with intravenously administered paclitaxel were included in the population PK analysis, as depicted in Table I. The dataset contained 166 patients aged ≥70 years (24%), of whom 89 patients were prospectively included. Median age of the total cohort was 61 years, ranging from 18 to 84 years old. Median age of the group of older patients (≥70 years) was 73 years, whereas median age of younger patients (<70 years) was 57 years. Administered paclitaxel doses ranged from 38 to 290 mg/m2, administered as an infusion in 1 to 5 h, with blood sampling up to 55.6 h after the start of paclitaxel infusion. Older patients received the 3-weekly paclitaxel scheme significantly less frequent than their younger peers (32% of older versus 67% of younger patients). After grouping patients receiving weekly paclitaxel administrations and those receiving 3-weekly administrations, no large age-related differences in paclitaxel administrations were observed. However, a small but significant difference in weekly-administered dose was observed between both age groups, with a difference in median value of 3 mg/m2 and a difference in mean value of 8 mg/m2. In older patients, the sampling time after paclitaxel administration was shorter with fewer samples per patient per cycle (3 in elderly versus 5 samples in younger patients), with a median sampling time of 3.1 h after start of infusion in the older patient group compared to 4.1 h in the younger patient group. Other baseline characteristics were comparable between both age groups, as shown in Table I. Baseline bilirubin was missing in 25% of patients and appeared to be randomly missing in the dataset. The covariates age, BSA, and gender contained no missing data. In Fig. 1, actual measured paclitaxel plasma concentrations versus time are displayed per age group.

Table I Baseline Patients’ Characteristics
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Fig. 1
figure 1

Measured paclitaxel plasma concentration (μmol/L) versus time (hours) plots per age group, in (a) patients <70 years old, and in (b) patients aged 70 years or older.

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To evaluate the impact of older age on paclitaxel PK, age was introduced as a continuous covariate into the base model, as depicted in Table II. Addition of age to the base model proved to be borderline significant (dOFV = 9) with a decrease in IIV of VMEL of around 1%.

Table II Population Pharmacokinetic Parameters of Paclitaxel of the Base Model, Base Model Including Age, Covariate Model without Age, and Full Covariate Model Including Age
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Subsequently, the effect of age was also estimated in the covariate model including BSA, gender, and bilirubin. Introduction of age as a continuous variable proved to be significant (dOFV = 33), but the decrease in IIV of VMEL was only 1.0%. GOF diagnostics of observed versus predicted log-transformed paclitaxel plasma concentrations and the VPC with n = 1000 of the covariate model including age as a continuous variable are shown in Figs. 2 and 3, respectively. For a typical male or female patient, with median values for BSA and bilirubin, a decrease in VMEL of 5% was calculated for a 10-year increment from the median age, as shown in Fig. 4. The influence of age treated as a dichotomous variable (<70 years versus ≥70 years) was also significant (dOFV = 19) in the covariate model. In this dichotomous age model, VMEL was 17% higher in younger patients than in older patients, with a median VMEL of 30.8 μmol/h in younger and 36.0 μmol/h in older patients. The corresponding decrease in IIV of VMEL was only 0.3%. Inclusion of performance status as covariate did not change the relationships between VMEL and age. Simulations of female and male patients aged between 25 and 90 years old, receiving 80 mg/m2 in a 1-h infusion, revealed that the influence of higher age on the Tc > 0.05μM was small, as depicted in Fig. 5. With a 10-year increment an increase of less than 10% was observed. For instance, the difference between a typical 70-year old and 80-year old female or male patient was 6%.

Fig. 2
figure 2

Goodness-of-fit plots of the full covariate model including age with observed log-transformed paclitaxel concentrations versus, left panel: model predictions of log-transformed paclitaxel concentrations, and right panel: individual Bayesian predictions of log-transformed paclitaxel concentrations.

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Fig. 3
figure 3

Visual Predictive Check with n = 1000 of the full covariate model including age, (a) with observed concentrations, and (b) without observed concentrations plotted. Data concern log-transformed paclitaxel plasma concentrations, with the solid black line representing observed median concentrations, and dashed grey lines representing the observed 5th and 95th percentiles. Light grey areas indicate the 95% CIs of the 5th and 95th percentile of the predictions, and dark grey areas indicate the CI of the median. The dots in panel a are the observed concentrations.

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Fig. 4
figure 4

Age as a continuous variable plotted against maximal elimination capacity of paclitaxel, with the line representing maximal elimination capacity (VMEL) of paclitaxel and grey bars reflecting the patient distribution per 5-year age group in the total cohort.

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Fig. 5
figure 5

Data simulation of the effect of age in (a) female patients and (b) male patients on the time-above-threshold concentration of 0.05 μmol/L, with paclitaxel administered at 80 mg/m2 in a 1-h infusion.

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Discussion

In this extensive dataset including a considerable number of elderly patients, older age had a marginal but nevertheless statistically significant impact on the maximal elimination capacity of paclitaxel. Given the considerable interindividual variability of paclitaxel PK and minimal effect of age on this unexplained variability, the minor drop of paclitaxel elimination capacity in elderly patients is not considered clinically relevant.

In the current study we used the 3-compartment model that was previously developed by Joerger et al. (13), and the dataset of Joerger et al. was also included in the current analysis. We performed extensive model evaluation to assess whether the added datasets were indeed adequately described by this previous model, e.g. including stratification on study cohort, and regimen. We could not identify major differences in model fit and for consistency have ultimately chosen to use the Joerger model to evaluate the influence of age on paclitaxel PK. Results from the current study are in line with paclitaxel PK parameters reported in previous studies, especially considering paclitaxel’s broadly reported large interindividual variability (12,13,15). Older patients received the 3-weekly schedule less frequently than their younger peers. However, no large differences were observed between older and younger patients receiving either 3-weekly or weekly paclitaxel administrations. Although a difference in weekly-administered paclitaxel median dose of 3 mg/m2 between older and younger patients reached significance in this large cohort, the absolute difference was very small. All patients included in this analysis received paclitaxel administered as a short infusion, ranging from 1 to 5 h. A recent meta-analysis showed a non-linear paclitaxel PK profile after short infusions (≤6 h) (21). This meta-analysis also showed that infusions of >24 h followed linear PK which were not comparable to shorter infusions. With the introduction of corticosteroid and antihistamine premedication, the 24 h infusion schedule is rarely used in clinical practice today. Therefore, twelve patients from the NKI retrospective cohort who were treated with 24 h infusions of paclitaxel were excluded from the current analysis.

Previous studies have reported conflicting results regarding the impact of older age on paclitaxel PK, ranging from no effect of aging up to an approximately 20% lower total paclitaxel clearance in older patients compared to their younger counterparts (9,10,13,22,23). Our study clearly showed that there is no PK basis for the posed increased risk of developing paclitaxel-related neutropenia in older patients. Therefore, it is postulated that this difference can be ascribed to greater treatment sensitivity, regardless of paclitaxel exposure, which may be due to a deprivation of bone marrow reserve or a reduced capacity for recovery from hematological stress in elderly patients (24).

One may be concerned that patients included in clinical trials do not reflect the typical older cancer patient treated in routine clinical practice, due to e.g. strict inclusion criteria for trial participants. The current analysis combined patients from multiple clinical trials with a prospectively included heterogeneous population of older patients selected to receive paclitaxel treatment in routine clinical practice. To enable inclusion of all previously collected paclitaxel PK data, the current study described total paclitaxel plasma concentrations. Although it is acknowledged that the free concentration might be more predictive of its effect than the total concentration, to our knowledge, this improved correlation has not adequately and prospectively been confirmed for paclitaxel (25). Paclitaxel has been shown to bind to serum albumin, but in the current study serum albumin values were comparable between older and younger patients, and its effect on paclitaxel PK appeared minor. To our knowledge, this study included the largest number of patients thus far to evaluate the effect of older age on paclitaxel exposure. Findings are in line with the majority of previous studies, showing a clinically negligible effect of older age on paclitaxel pharmacokinetics.

Time-above-threshold-concentration of 0.05 μmol/L (Tc > 0.05μM) was shown to be related to paclitaxel treatment efficacy, neuropathy, and hematological toxicity (26,27,28,29,30). Preliminary data suggested that, after weekly-administered paclitaxel, Tc > 0.05μM was predictive of efficacy and neurotoxicity (14,26,27). In the current study, the majority of older patients received weekly-administered paclitaxel. For simulation purposes we used the commonly used weekly-administered dose of 80 mg/m2. This may explain why our simulations resulted in lower Tc > 0.05μM compared to several previous studies (28,29,30), although it appeared to be in line with reported Tc > 0.05μM in multiple other studies including both weekly-administered and the 3-weekly paclitaxel regimen (15,16,26,27). Nonetheless, the marginal impact of older age on time-above-threshold-concentration of paclitaxel was statistically significant but was not considered to have clinical relevance.

In the current study, age was evaluated both as a continuous variable and as a dichotomous variable using a cut-off value of 70 years. By assessing age as a continuous variable no data were discarded thus providing the most informative analysis. Additionally, we dichotomized data to facilitate a more forward interpretation and presentation on the influence of older age on paclitaxel PK. The hereto applied cut-off value of 70 years was used because multiple studies have shown that organ functions may rapidly decline while chemotherapy-induced hematological toxicities tend to increase steeply after the age of 70 (24). By design, this study included various paclitaxel dose regimens administered in monotherapy or concomitantly with other chemotherapeutic agents. Because previous studies showed no influence on the PK of paclitaxel with co-administration of cisplatin (31,32,33), carboplatin (34,35), or doxorubicin (36), these per protocol administered combination treatments were not excluded from the current analysis. As part of clinical practice, concomitantly administered medication was strictly monitored to prevent possible drug-drug interactions. However, this was not a strict exclusion criterion of the current study. Prospectively included older patients in this cohort generally received paclitaxel treatment as part of outpatient care, which led to shorter sampling times in the older patient group. This may introduce potential bias, although full PK curves from older patients included in previous clinical trials were available. Besides, the flexible sampling scheme was implemented in order to lower barriers to enrollment of frail older patients in the dataset. Furthermore, both the retrospectively included datasets and the prospectively included observational cohort contained missing covariate data. Because our main objective was to evaluate the influence of older age on the elimination capacity of paclitaxel, thorough evaluation of other covariates and estimation of missing covariates were not within the scope of this study. For missing values, multiple imputation or mixture models were not performed. However, by introducing a separate estimate for the covariate bilirubin that contained missing data, it was precluded that missing data introduced bias. Furthermore, we evaluated whether the impact of age on paclitaxel PK may be distorted by performance status, by separately evaluating this covariate. Performance status did not alter our conclusion regarding the impact of age on paclitaxel PK.

In this extensive dataset including a considerable number of older patients, older age had only minor impact on paclitaxel PK. This study showed that there is no PK basis for a potentially increased risk of developing paclitaxel-related neutropenia in elderly patients.