Original article
Introduction Docetaxel is a
semi-synthetic taxane derivate neoplastic agent which is used in the
treatment of breast and castration-resistant prostate carcinoma (CRPC),
and several other cancers.8 Pharmacokinetics of
docetaxel shows a high inter-individual variability in clearance, which
may result in under- or overdosing.1 In order to
reduce this variability, doses are currently based on body surface area
(BSA).2
Dosing of anticancer drugs based on BSA is common practice since the
1950’s.3 Dosing on BSA is the method for predicting a
safe starting dose in phase 1 human trials translated from animal
toxicology data.3,4 However, many argued whether this
approach results in an optimal dose for each individual. BSA-based
dosing has shown to result in high inter-individual variability in drug
exposure for most anticancer drugs leading to undesirably side effects
or insufficient tumour response. Therefore, BSA-based dosing is much
debated as the method of choice for dosing
chemotherapeutics.1,5 Pharmacokinetic parameters such
as clearance and area under the curve (AUC) are known markers for
predicting therapeutic responses.2 A study of Engels
et al showed that the application of therapeutic drug monitoring (TDM)
significantly decreased the inter-individual variability in docetaxel
exposure when compared to BSA based dosing.6 Although
TDM is an elegant way of dose optimisation, it is very labour intensive
and costly in the day-to-day clinical setting. Therefore, alternative
anthropometric parameters that correlate better with drug exposure may
be considered to optimize dosing of anticancer
drugs.7,8
Docetaxel doses vary from 75-100 mg/m2 given once
every three weeks during an one hour intravenous infusion. Docetaxel is
metabolised in the liver via oxidation by CYP3A4, CYP3A5 and is bound to
albumin for 95% without significant renal
clearance.9-11 The pharmacokinetics of docetaxel can
be best described by a three-compartment model with half-life times of
4.5 minutes, 38.3 minutes and 12.2 hours, respectively. The area under
the plasma concentration time curve (AUC) increases proportionally with
increasing doses. Docetaxel is distributed in tissues with a mean volume
of distribution (VD) of 74 L/m2.9Docetaxel is characterized by highly interindividual pharmacokinetic
variation, with up to 10-fold differences in drug clearance in patients
with normal hepatic function.12 Bruno et alfound a median clearance of 36.6 L/h (5th to 95th range 17.5 L/h to 59.3
L/h).13 This variability may lead to adverse effects
or to suboptimal treatment or even treatment failure. The major adverse
effect is neutropenia, which is dose-limiting most of the
times.9 Other frequently occurring side effects of
docetaxel are anaemia, alopecia, nausea, asthenia, peripheral
neuropathy, fluid retention and nail toxicity.10,11
Lean body mass (LBM) could be an alternative dosing parameter to BSA,
since LBM has shown to correlate better with drug clearance of
cisplatin, paclitaxel and troxacitabine when compared to BSA or total
body weight (TBW) in obese patients.14 LBM as a dosing
parameter has been investigated for several anticancer drugs.7,15-23
Patients with comparable BSA values showed a wide variety in liver
volume and LBM. Since liver volume is strongly correlated with LBM and
docetaxel is mainly metabolized by the liver, it is hypothesized that
individual dosing on LBM should be preferred over
BSA.24,25
In our study we examined which of the anthropometric and body
composition parameters BSA, LBM and TBW correlates best with docetaxel
clearance (CL) and exposure (AUC). In addition, LBM, TBW and a fixed
dose were compared to BSA as dosing parameters for dose
individualisation of docetaxel.
Methods Patients and study We performed a multi centred prospective study in patients using
docetaxel. Patients that received chemotherapy with docetaxel for breast
cancer or castration-resistant prostate carcinoma (CRPC) were included.
Docetaxel in breast cancer treatment is part of a combined therapy with
cyclophosphamide and doxorubicin. In patients with CRPC docetaxel was
given as monotherapy. Other criteria for inclusion were: absolute
neutrophile count: > 1.5x109 /L, serum
creatinine ≤ 2x ULN, total bilirubin < 1.5 ULN. Exclusion
criteria were docetaxel use in the last year, moderate or severe liver
impairment ([ALAT and/or ASAT ≥ 1.5 ULN] and [AF ≥ 2.5 ULN]),
current therapy with any drug, dietary supplements, or other compounds
known to inhibit or induce CYP3A4. Every patient received 75 or 100
mg/m2 docetaxel dissolved in a saline solution and
infused over one hour.
Estimation of the study population size, 36 participants, was derived
from studies by Gusella and Prado.7,15 The study was
conducted in accordance with the Declaration of Helsinki and all study
participants provided written informed consent before study entry.
Body composition measurements TBW was measured using a medical body weight scale in kg. A fixed
stadiometer was used to determine the patients height, standing barefoot
against a straight wall. LBM was measured by a DEXA-scanner. In the
Deventer Teaching Hospital patients were scanned by a GE Lunar Scanner
(GE healthcare, Little Chalfont; United Kingdom), while patients in
Radboud University Medical Centre were scanned with a Hologic Discovery
scanner (Hologic, Bedford, U.S.A.).
PK sampling and analysis Pharmacokinetic blood samples were obtained at t=0 (just prior to
infusion), t=30 minutes after start of infusion, t=55 minutes after
start of infusion (i.e. just prior to the end of infusion) and a last
sample was obtained at t=180 minutes after start of infusion, according
to a validated limited sampling strategy.26-28Docetaxel plasma concentrations were quantified using a HPLC-UV method.
First liquid-liquid extraction was performed with tert-butylmethylether
as extraction fluid/organic layer. The plasma layer is frozen on a cryo
bath and the organic layer is evaporated with compressed air. HPLC-UV
analysis was done with paclitaxel as internal standard.
Methanol/phosphate buffer (65:35 v:v) was used as mobile phase, flow:
1.0 mL/min, detection 230 nm. The method was validated in line with the
European Medicines Agency Guideline on bioanalytical
validation.29 NONMEM® software
(ICON, Ireland) was used to determine the individual clearance (CL) and
distribution volume (Vd) by Bayesian analysis using a population model
described by Engels et al.6 The area under the curve
(AUC) was calculated with the formula:
\begin{equation}
\mathrm{AUC=\ }\frac{\mathrm{Dose\ (D)}}{\mathrm{Clearance\ (CL)}}\nonumber \\
\end{equation}