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\begin{document}

\title{Role of TDM-based dose adjustments for major taxane anticancer drugs}



\author[1]{Marsilla Muth}%
\author[2]{Francis Ojara}%
\author[2]{Charlotte Kloft}%
\author[1]{Markus Joerger}%
\affil[1]{Kantonsspital Sankt Gallen}%
\affil[2]{Free University of Berlin}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\selectlanguage{english}
\begin{abstract}
Purpose: The classical taxanes (paclitaxel, docetaxel), the newer taxane
cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most
widely used anticancer drugs. Still, the optimal use and the value of
pharmacological personalization of the taxanes is still controversial.
Methods: We give an overview on the pharmacological properties of the
taxanes, including metabolism, pharmacokinetics-pharmacodynamic
relations and aspects in the clinical use of taxanes. The latter
includes the ongoing debate on the most effective and safe regimen, the
recommended initial dose, and pharmacological dosing individualization.
Conclusions: The taxanes are among the most widely used anticancer drugs
in patients with solid malignancies. Despite their longtime use in
clinical routine, the optimal dosing strategy (weekly versus 3-weekly)
or optimal average dose (cabazitaxel, nab-paclitaxel) has not been fully
resolved, as it may differ per tumor entity and line of treatment. The
value of pharmacological individualization of the taxanes (TDM, TCI) has
partly been explored for 3-weekly paclitaxel and docetaxel, but remains
mostly unexplored for cabazitaxel and nab-paclitaxel at present.%
\end{abstract}%



\sloppy


\section*{Article type: Invited
review}

{\label{article-type-invited-review}}

\section*{}

{\label{section}}

Role of TDM-based dose adjustments for major taxane anticancer drugs

M. Muth\textsuperscript{1}, F.W. Ojara\textsuperscript{2}, C.
Kloft\textsuperscript{2}, M. Joerger\textsuperscript{1}

\textsuperscript{1}Department of Oncology \& Hematology, Cantonal
Hospital, St. Gallen, Switzerland, Rorschacherstrasse 95, .Gallen,
Switzerland

\textsuperscript{2}Department of Clinical Pharmacy and Biochemistry,
Institute of Pharmacy, Freie Universitaet Berlin, Germnay

\emph{Keywords:Therapeutic drug monitoring, Pharmcotherapy, Clinical
Pharmacy, Chemotherapy, Toxicity}

\emph{}

\textbf{Introduction:} The classical taxanes (paclitaxel, docetaxel),
the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel
are among the most widely used anticancer drugs. Despite years of
research, the optimal dosing regimen (weekly versus 3-weekly) and
optimal dose are still controversial, as is the value of pharmacological
personalization of taxane dosing.

\textbf{Areas covered:} We give an overview on the pharmacological
properties of the taxanes, including metabolism,
pharmacokinetics-pharmacodynamic relations and aspects in the clinical
use of taxanes. The latter includes the ongoing debate on the most
effective and safe regimen (paclitaxel, docetaxel, nab-paclitaxel), the
recommended initial dose (cabazitaxel), and pharmacological dosing
individualization.

\textbf{Expert opinion:} The taxanes share the characteristics of
extensive hepatic metabolism and biliary excretion, the need for dose
adaptation in patients with liver dysfunction, and a substantial
pharmacokinetic variability even after taking into account known patient
chareacteristics. Data from clinical studies suggest that optimal
scheduling of the taxanes is dependent not only on the specific taxane
compound, but also on the tumor type and line of treatment. Finally,
treating oncologists should be aware of the substantial risk for
drug-drug interactions that is a direct consequence of the complex
hepatic metabolism of the taxanes.

\section*{Introduction}

{\label{introduction}}

The taxanes represent the backbone of many systemic anticancer treatment
regimens for early and advanced solid tumors. Paclitaxel was the first
compound of this class and was discovered as part of the U.S. National
Cancer Institute program to detect new anticancer drugs. In 1963, a
crude extract form the bark of the Pacific Yew, Taxus brevifolia, a
scarce and slow-growing evergreen found in the forests of the Pacific
Northwest, was found in preclinical studies to have cytotoxic activity
against many tumors, and paclitaxel was identified as the active moiety
in 1971. Docetaxel was detected somewhat later, is also synthesized from
10-deacetylbaccatin III, and represents a more water-soluble and potent
taxane derivative. Cabazitaxel is a semi-synthetic
10-deacetylbaccatin-III derivative, selected for clinical testing due to
its poor affinity for the ATP-dependent, resistance-related drug efflux
pump P-glycoprotein (PgP, MDR1, ABCB1), and its improved blood-brain
barrier penetration. The application of nanotechnology in oncology has
enabled the development of nab-paclitaxel, a soluble form of paclitaxel
that is linked to albumin nanoparticles. This has resulted in improved
pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of
nab-paclitaxel compared to cremophor-bound paclitaxel or polysorbate
80-bound docetaxel, neutralizing the taxane's inherent hydrophobicity.
This review article will systematically approach pharmacological aspects
including invidualized dosing and therapeutic drug monitoring (TDM) of
these major taxane anticancer compounds.

\textbf{Paclitaxel}

Paclitaxel is an alkaloid ester consisting of a taxane ring system
linked to a four-member oxetan ring at positions C-4 and C-5. The drug
is approved for the treatment of solid tumor entities including
non-small cell lung cancer (NSCLC), breast and ovarian cancer as well as
upper gastrointestinal tumors.

\textbf{Paclitaxel metabolism}

Paclitaxel stabilizes microtubule polymerisation that results in mitotic
arrest and apoptotic cell death in sensitive cancer cells. Resistance
mechanisms to paclitaxel are complex and a result of different
mechanisms, including efflux mediated by PgP (MDR1, ABCB1) and other ABC
transporters (efflux systems), alteration of paclitaxel binding to
tubulin (overexpression or mutations of tubulin), modifications of
cellular apoptotic signals and paclitaxel detoxification by CYP3A4 and
CYP2C8. Among mechanisms of resistance to taxanes, those related to
microtubule-associated proteins (MAP) are of major importance
(summarized in {[}1{]}).

\textbf{Paclitaxel pharmacokinetics}

Paclitaxel biotransformation is mediated by cytochrome P450 enzymes
(CYP), most prominently CYP3A4 and CYP2C8. With a high affinity and
metabolic rate, CYP2C8 is involved in a stereoselective hydroxylation of
paclitaxel at the 6-position to the main metabolite
6\selectlanguage{greek}α-\selectlanguage{english}hydroxy-paclitaxel (M5 metabolite). Additionally, paclitaxel
undergoes hydroxylation at the C13 side-chain of the molecule to
3'-p-hydroxyphenyl-paclitaxel (M4). Hydroxylation of paclitaxel is
highly influenced by potential induction or inhibition of CYP3A4.

Paclitaxel exhibits non-linear pharmacokinetics that becomes obvious
when giving the drug at the conventional intravenous infusion over one
or three hours (as compared to 24-hour infusions). Nonlinear PK of
paclitaxel is caused by saturable transport {[}2{]}, saturable binding
{[}3{]} of the drug, but also by interaction with the micelle-forming
solvent Cremophor EL (CrEL) {[}4{]}. CrEL has been suggested to inhibit
PgP-mediated biliary secretion {[}5{]}, cause lipoprotein dissociation
that would alter protein binding {[}6{]}, and alterations in the
distribution of paclitaxel by entrapment in micelles {[}7{]}. As a
consequence, the free fraction of paclitaxel decreases with increasing
concentrations of CrEL {[}7{]}.

Paclitaxel has been shown to bind to both albumin and \selectlanguage{greek}α\selectlanguage{english}1-acid
glycoprotein {[}8{]}, resulting in a high distribution volume of
paclitaxel of roughly 60 L/m\textsuperscript{2}. The terminal half-life
of paclitaxel has been estimated to between 8 and 12 hours {[}9, 10{]},
while it's maximum elimination capacity when given at a dose of
175mg/m\textsuperscript{2} over a 3-hour infusion has been estimated to
36 \selectlanguage{greek}µ\selectlanguage{english}mol/L*h {[}11{]}. While drug \emph{clearance} describes the body's
capacity to eliminate a specific drug that exhibits linear
pharmacokinetics, \emph{maximum elimination capacity} is the preferred
parameter for drugs with non-linear PK. Finally, paclitaxel undergoes
biliary excretion, which is why patients with liver function impairment
or liver metastases have a slower elimination of the drug and are at
increased risk of toxicity {[}12, 13{]}. Accordingly, a 3-weekly
paclitaxel dose of 135 mg/m\textsuperscript{2} is recommended in
patients with increased liver function tests (LFT), 115
mg/m\textsuperscript{2} with a total bilirubin between 25 and 40 \selectlanguage{greek}μ\selectlanguage{english}mol/L
and 100 mg/m\textsuperscript{2} with a total bilirubin between 40 and
70\selectlanguage{greek}μ\selectlanguage{english}mol/L. Paclitaxel should not be used in patients with a total
bilirubin \textgreater{}70 \selectlanguage{greek}μ\selectlanguage{english}mol/L {[}14{]}.

\textbf{2.3.} \textbf{Pharmacokinetics/pharmacodynamics relationships}

The time above a paclitaxel plasma concentration of 0.05 \selectlanguage{greek}μ\selectlanguage{english}mol/L
(T\textsubscript{C\textgreater{}0.05}) emerged as a predictor of
neutropenia {[}15-17{]} and chemotherapy-induced polyneuropathy (CIPN),
as well as clinical outcome in some studies. Mielke and colleagues
showed a significant association between paclitaxel
T\textsubscript{C\textgreater{}0.05} and CIPN in 24 patients with
advanced solid tumors {[}18{]}. Overall, there is a fairly consistent
association between paclitaxel exposure and drug-associated toxicity,
mainly haematological and neurological adverse events. Two studies found
an association between exposure to paclitaxel and clinical outcome in
advanced NSCLC {[}19{]} and ovarian cancer {[}20{]}, respectively. In
the study by Huizing and colleagues, patients with a paclitaxel
T\textsubscript{C\textgreater{}0.10} [?]15 hours had a longer median
survival as compared to patients with a paclitaxel
T\textsubscript{C\textgreater{}0.10} \textless{}15 hours (8.2 versus 4.8
months, p = 0.06) {[}19{]}. In the study by Joerger and colleagues in
ovarian cancer patients receiving 3-weekly paclitaxel and carboplatin
for ovarian cancer after cytoreductive surgery, a paclitaxel
T\textsubscript{C\textgreater{}0.05} \textgreater{}61 hours had an
improved time to disease progression as compared to patients with a
paclitaxel T\textsubscript{C\textgreater{}0.05} \textless{}61 hours
(85.2 versus 63.3 weeks; P = 0.05) {[}20{]}.

\textbf{2.4. Paclitaxel therapeutic drug monitoring and target
concentration intervention}

Major paclitaxel-associated toxicities include bone marrow suppression
(neutropenia, anemia, thrombopenia), acute or chronic neurotoxicity
resulting in either arthralgia and myalgia or cumulative peripheral
paresthesias or hypesthesias, respectively, and less frequent but
potentially severe acute CrEL-associated hypersensitivity reactions
{[}21{]}. Weekly instead of 3-weekly scheduling of paclitaxel has become
popular in some clinics due to its relative ease, shorter infusion
times, convenient monitoring, favourable clinical activity and potential
for reduced toxicity {[}22{]}. For the treatment of advanced NSCLC,
carboplatin in combination with weekly paclitaxel 100
mg/m\textsuperscript{2} has been shown to be equally effective as
3-weekly dosing at 200 or 225 mg/m\textsuperscript{2}. In NSCLC, lower
incidences of CIPN were reported with weekly paclitaxel 100 mg/m2
compared to 3-weekly paclitaxel at 200 and 225 mg/m\textsuperscript{2},
however contrary findings have been shown in breast cancer patients with
higher incidences of CIPN with paclitaxel 80
mg/m\textsuperscript{2}weekly dosing compared to 175
mg/m\textsuperscript{2} 3-weekly dosing {[}23-25{]}. For breast cancer,
weekly regimens are superior in terms of efficacy to 3-weekly paclitaxel
schedules in both the adjuvant {[}25{]} and metastatic setting {[}24{]}.
In ovarian cancer, weekly paclitaxel has become of particular interest
since the publication of the JGOG 3016 data {[}26{]}.

At least four prospective clinical studies explored paclitaxel
therapeutic drug monitoring (TDM) and target concentration intervention
(TCI) using Bayesian dose adjustments {[}table 1; 27-30{]}. In the study
by Woo and colleagues, seven children with refractory acute leukemia
were enrolled {[}28{]}. During a 24-hour paclitaxel infusion, repeated
PK-samples were drawn within the first eight hours, paclitaxel clearance
was immediately calculated using a population model, and dose adjustment
was performed 12 hours after the start of paclitaxel infusion to target
a paclitaxel AUC of 31.5~ \selectlanguage{english}45 \selectlanguage{greek}µ\selectlanguage{english}M*h. Target concentration intervention
(TCI) resulted in significantly more courses being in the AUC target
(71\% versus 0\%, p = 0.02), and TCI resulted in a decrease of PK
variability {[}28{]}. In the study by de Jonge and colleagues, 25
patients with advanced NSCLC received paclitaxel 175
mg/m\textsuperscript{2} over 3 hours and carboplatin AUC 6 every 3
weeks, and patients underwent repeated TDM and TCI {[}27{]}. Paclitaxel
data were subjected to population modeling, and paclitaxel dose was
calculated to target a paclitaxel T\textsubscript{C0.1} of [?]15 hours.
Similarly to the study of Woo and colleagues, TDM and TCI resulted in
decreased PK variability and an increased proportion of patients
reaching the paclitaxel PK target (from 64\% to 88\%). A large
prospective phase 3 clinical trial randomized patients with advanced
NSCLC to receive first-line palliative 3-weekly paclitaxel 200
mg/m\textsuperscript{2} in combination with carboplatin AUC 6 either
adjusted on clinical symptoms or additionally receiving TDM and TCI to
target paclitaxel T\textsubscript{C0.05} of between 26 and \textless{}
31 hours {[}29{]}. Among 365 patients randomly assigned patients, grade
4 neutropenia was only numerically decreased in the TDM versus non-TDM
arm (19\% versus 16\%; p = 0.10), but CIPN grade [?]2 was significantly
improved by using TDM and TCI (38\% versus 23\%, p \textless{} 0.001) as
was CIPN grade [?]3 (9\% versus 2\%, p \textless{} 0.001). Paclitaxel TDM
and TCI resulted in a significantly lower final paclitaxel dose (199
versus 150 mg/m\textsuperscript{2}, p \textless{} 0.001), but this did
not result in worse clinical efficacy (radiological response was 31\%
versus 27\%, overall survival 10.1 versus 9.5 months) {[}29{]}. A
similar prospective phase 3 trial randomized Chinese patients with
advanced NSCLC to receive first-line palliative 3-weekly paclitaxel 175
mg/m\textsuperscript{2} in combination with carboplatin AUC 6 either
adjusted on clinical symptoms or additionally receiving TDM and TCI to
target paclitaxel T\textsubscript{C0.05} of between 26 and \textless{}
31 hours {[}30{]}. Among 275 patients randomly assigned patients, grade
4 neutropenia was significantly decreased in the TDM versus non-TDM arm
(24\% versus 15\%; p = 0.009), while CIPN grade [?]2 was significantly
improved by using TDM and TCI (21\% versus 8\%, p = 0.005). Similarly to
the CEPAC-TDM trial, paclitaxel TDM and TCI resulted in a significantly
lower final paclitaxel dose in the trial by Zhang and colleagues (161
versus 128 mg/m\textsuperscript{2}, p \textless{} 0.001), while clinical
efficacy was numerically improved by using TDM and TCI (radiological
response was 26\% versus 32\%, overall survival 21.0 versus 24.0
months); progression-free survival was significantly higher in the TDM
plus TCI arm (4.17 versus 4.67 months, p = 0.026) {[}30{]}. Overall,
current data suggest individual paclitaxel
T\textsubscript{C\textgreater{}0.05} of 26 to \textless{}31 hours to be
adequate. Paclitaxel T\textsubscript{C\textgreater{}0.05} data can be
calculated with a single 24-hour PK sample of paclitaxel using readily
available online tools {[}31{]}. Rigorous population modelling of the
CEPAC-TDM trial data has enabled further characterisation of the
relationship between paclitaxel/platinum drug exposure and the
occurrence of key treatment-associated toxicities (neutropenia and
CIPN). A physiologically-motivated PK-PD model was developed to
characterise the time course of neutropenia after multiple cycles of
chemotherapy. Applying this model enables long-term prediction of
neutropenia for dose adaptation in patients undergoing
paclitaxel/platinum drug combination chemotherapy {[}32{]}. Furthermore,
a parametric time-to-event model was developed to characterise the
time-course in risk of first occurrence of clincally relevant
paclitaxel-associated peripheral neuropathy (NCI-CTC grade [?]2) and
quantify the impact of time-dependent paclitaxel exposure and patient
characteristcs (age, sex and smoking status ) for better prediction of
the individual patients' risk of peripheral neuropathy for different
paclitaxel dosing schedules. In addition, population modelling should in
future also be leveraged to characterise key efficacy end points such as
overall survival, thus establishing a framework to jointly predict
treatment response and associated toxicities a priori for different
paclitaxel treatment schedules based on treatment exposure and patient
characteristics.

\textbf{Docetaxel}

Docetaxel also has a four-member oxetan ring with minor modifications of
the C13 side-chain. It is approved for the treatment of malignant tumors
of the breast, lung, prostate, upper gastrointestinal tract and head and
neck.

\textbf{Docetaxel metabolism}

Similar to paclitaxel, docetaxel undergoes extensive hepatic metabolism,
biliary excretion and almost exclusive fecal elimination.
Biotransformation of docetaxel is different from paclitaxel, in that it
undergoes CYP3A4/3A5-mediated hydroxylation of the tert-butyl group to
form the M2 primary alcohol metabolite. Subsequently, docetaxel is
undergoing ring closure via a putative aldehyde, resulting in two
diastereoisomers M1 and M3. This is followed by oxidation to the M4
ketone metabolite. Similar to paclitaxel, the metabolites of docetaxel
are substantially less active compared to the parent compound.
Resistance mechanisms to docetaxel include cellular efflux through PgP
(MDR1, ABCB1), ABCB4 and ABCC1, mutations in or altered expression of
\selectlanguage{greek}β-\selectlanguage{english}tubulin, overexpression of MAP or upregulation of anti-apoptotic
cellular signaling. The most extensively studied mechanism of acquired
or intrinsic resistance to taxanes is overexpression of ABCB1
(summarized in {[}1{]}).

\textbf{Docetaxel pharmacokinetics and pharmacodynamics}

Docetaxel exhibits linear PK, with a clearance being constant over a
dose range between 20 and 115 mg/m\textsuperscript{2}. Docetaxel
pharmaceutical formulations use polysorbate 80 instead of cremophor EL
as the solvent. Docetaxel has a protein binding of roughly 95\%,
resulting in a high volume of distribution of
74L/m\textsuperscript{2}after a 100mg/m\textsuperscript{2} dose
{[}33{]}. Similar to paclitaxel, the free fraction of docetaxel
decreases with increasing concentrations of polysorbate 80 {[}34{]}.
Docetaxel has a terminal half-life of 12 hours and a clearance of 22
L/h/m\textsuperscript{2} {[}33{]}. Docetaxel undergoes biliary
excretion, which is why patients with liver function impairment or liver
metastases have a slower elimination of the drug and are at increased
risk of toxicity. Docetaxel clearance is 50\% of normal in patients with
LFT [?] 2.5-times ULN and 25\% in patients with a total bilirubin [?]
1.5-times ULN. Docetaxel should be omitted in patients with a total
bilirubin above ULN {[}35{]}. Docetaxel AUC is a significant predictor
of febrile neutropenia, infection, severe mucositis, diarrhea or
asthenia. In practical terms, the risk of severe toxicity doubles when
docetaxel AUC increases from 4.2 to 6.5 \selectlanguage{greek}µ\selectlanguage{english}g*h/mL {[}36{]}, and the the
risk of febrile neutropenia triples when AUC doubles {[}37{]}.

\textbf{Docetaxel therapeutic drug monitoring and target concentration
intervention}

Major docetaxel-associated toxicities include (febrile) neutropenia,
diarrhea, mucositis, alopecia, nail toxicity, cumulative CIPN and
polysorbate 80-associated HSR. Weekly docetaxel has a more favourable
toxicity profile compared to 3-weekly docetaxel, and is equally active
in metastatic breast and lung cancer, but not in castration-resistant
prostate cancer (CRPC) and early-stage breast cancer (summarized in
{[}1{]}).

Crombag and colleagues studied docetaxel PK and clinical data from 157
patients, and found a significant impact of patient age on docetaxel
clearance, with a reduction in clearance of 17\% and 34\% for a 10-year
and 20-year increase of patient age {[}38{]}. According to a large
meta-analysis in 1'150 cancer patients from 26 clinical trials, patients
with CRPC have a significantly lower mean exposure (AUC) of docetaxel
compared to patients with other solid tumors (fold change: 1.8,
1.5-2.2), and a 2.2-fold lower odds of developing severe neutropenia
(odds ratio: 0.46, 0.31-0.90) {[}39{]}. This confirms older data from
Franke and colleagues, and suggests castration-dependent PK of docetaxel
{[}40{]}. At least one prospective, randomized clinical study explored
TDM followed by TCI of docetaxel in 15 patients with advanced solid
tumors using Bayesian dose adjustments compared to BSA-based dosing in
another 15 patients {[}41{]}. All patients received docetaxel at an
initial dose of 75 mg/m\textsuperscript{2} at 3-weekly intervals,
underwent limited docetaxel PK sampling and dose adaptation for the
following cycle to achieve a docetaxel AUC of 4.9 mg/L*h (experimental
arm) versus BSA-based dosing (standard arm). Docetaxel TDM and TCI
resulted in a decrease of docetaxel PK variability by 39\%, and a
decrease of the variability of neutropenia by 50\%. Hematological
toxicity however was similar in the adjusted and the unadjusted dosing
arm, suggesting no clear advantage of docetaxel TDM and TCI for clinical
outcome in this small study {[}41{]}. While more research is required to
evaluate docetaxel TDM and TCI, current data suggest that an individual
AUC target of 5 mg/L*h should be adequate with standard dosing of 75
mg/m\textsuperscript{2}.

\textbf{Cabazitaxel}

Cabazitaxel is a semi-synthetic taxane from a single diastereoisomer of
10-deacetyl-baccatin-III. The drug is approved for the treatment of
patients with CRPC progressing or relapsing after docetaxel. Cabazitaxel
was selected for clinical development based on preclinical features such
as activity in taxane-resistant models and its ability to cross the
blood-brain barrier.

\textbf{Cabazitaxel metabolism}

Cabazitaxel undergoes extensive hepatic metabolism, biliary excretion
and mostly fecal elimination. Oxidative pathways include O-demethylation
leading to 10-O-demethyl-cabazitaxel and 7-O-demethyl-cabazitaxel,
followed by ring closure leading to an oxazolidine-like derivative.
Cabazitaxel is mainly metabolized by CYP3A4 and CYP3A5 (the contribution
of CYP3A estimated to be in the range of 80\%--90\%), and to a lesser
extent by CYP2C8 {[}42{]}. Cabazitaxel is the major circulating
compound. Cabazitaxel has been shown to be active in cell lines
resistant to cytotoxic agents such as anthracyclines, vinca alkaloids
and the older taxanes docetaxel and paclitaxel, probably due to its
lower affinity for the P-glycoprotein efflux pump (ABCB1). Accordingly,
cabazitaxel retains activity in some in vivo tumor models with innate or
acquired resistance to taxanes and other chemotherapeutic agents
{[}43{]}.

\textbf{Cabazitaxel pharmacokinetics and pharmacodynamics}

Cabazitaxel exhibits linear PK with an average drug clearance of 26.4
L/h/m\textsuperscript{2} and a long terminal half-life of 95 hours
{[}44{]}. Cabazitaxel pharmaceutical formulations use polysorbate 80 as
solvent. A pooled analysis of PK data from several cabazitaxel phase 1
studies showed cabazitaxel clearance to be significantly associated with
body surface area (BSA) and tumor type. On the contrary, patient gender,
weight, age, ethnicity, renal function and coadministration of
CYP-inducing agents did not significantly impact cabazitaxel PK.
Cabazitaxel is contraindicated in patients with severe hepatic
impairment and should be dose-reduced in patients with moderate hepatic
impairment {[}45{]}. Cabazitaxel can safely be administered in patients
with mild to moderate renal impairment as this did not have meaningful
effects on cabazitaxel PK {[}44{]}.

\textbf{Pharmacological aspects in the clinical use of cabazitaxel}

Major cabazitaxel-associated toxicities include (febrile) neutropenia,
diarrhea, mucositis, alopecia, cumulative CIPN and polysorbate
80-associated HSR. The PK-PD relationship between cabazitaxel exposure
(AUC) and neutropenia follows a typical sigmoidal maximal effect
(E\textsubscript{max}) model, in which the value of AUC to obtain 50\%
of E\textsubscript{max} was a cabazitaxel plasma concentration of 158
ng*h/mL for neutrophils and 143 ng*h/mL for leucozytes, which
corresponds to a cabazitaxel relative dose of approximately 10 mg/m\selectlanguage{ngerman}²
{[}46, 47{]}. No significant association was found between cabazitaxel
PK and overall survival in a small subset of 67 evaluable patients from
the large randomized phase 3 \emph{TROPIC} study in patients with
metastatic CRPC {[}48{]}. In the \emph{TROPIC} study, patients with
metastatic CRPC progressing after docetaxel were randomized to receive
either 3-weekly cabazitaxel 25 mg/m\textsuperscript{2} or mitoxantrone
12 mg/m\textsuperscript{2}, both in combination with 10 mg oral
prednisone daily. As a consequence of substantial toxicity in the TROPIC
study, the approved dose of cabazitaxel 25 mg/m\textsuperscript{2} was
prospectively tested against cabazitaxel 20 mg/m\textsuperscript{2} in
1'200 patients with metastatic CRPC \emph{(PROSELICA)} {[}49{]}.
Cabazitaxel at 20 mg/m\textsuperscript{2} was confirmed non-inferior
compared to cabazitaxel 25 mg/m\textsuperscript{2}, but the approved
dose of cabazitaxel was numerically superior (overall survival 14.5
versus 13.4 months), and PSA response was significantly higher with the
approved dose of 25 mg/m\textsuperscript{2} versus 20
mg/m\textsuperscript{2} (42.9\% versus 29.5\%, p\textless{}0.001). Most
importantly, severe cabazitaxel-associated toxicity was less prominent
in post-marketing clinical routine compared to the registration
trial\emph{(TROPIC)} , potentially as a consequence of improved toxicity
management or less sensitive patient populations. A small prospective
series of 10 patients with metastatic CRPC suggests metabolic
phenotyping using midazolam to predict cabazitaxel PK {[}50{]}, but
there is no prospective data on cabazitaxel TDM/TCI or dose
individualization published so far. A randomized phase-II trial assessed
the impact of cabazitaxel TDM and TCI on the clinical outcome (toxicity
and activity) in patients with metastatic CRPC \emph{(EUDRACT
2013-005504-34) (CAINTA)} , and data are expected to be published in
2020.

\textbf{Nab-paclitaxel}

Nab-Paclitaxel has been developed in an attempt to reduce toxicity
associated with conventional taxane formulations (caused by the use of
cremophor EL and polysorbate 80, respectively), while potentially
increasing antitumor activity. Cremophor EL and polysorbate 80 are
associated with increased toxicity, most importantly acute
hypersensitivity reactions, that can be severe or even life-threatening,
and requires the use of premedication with steroids and antihistamines.
Conventional solvents may also hinder the ability of the circulating
taxane molecules to cross the endothelial barrier and accumulate in
tumors, reducing antitumor activity and increasing the risk of systemic
toxicity. The first attempt to overcome the limitations imposed by the
use of solvents was albumin-bound nab-paclitaxel.

\textbf{Nab-paclitaxel metabolism}

With nab-paclitaxel, reversible binding of albumin to paclitaxel permits
exploitation of endogenous albumin pathways to enhance absorption,
distribution and concentration of the drug at the tumor site. Albumin is
a natural carrier of hydrophobic molecules and binds to the gp60
receptor on endothelial cells, resulting in the formation of vesicles
(caveolae) in the membrane of target cells that carry the albumin
complex across the endothelial membrane (transcytosis) and into
surrounding tissues. The entry and retention of albumin complexes in
tumor tissue are facilitated by the enhanced permeation and retention
effect, i.e. the accumulation of albumin complexes and other
macromolecules in the tumor interstitium via leaky tumor vasculature.
Accumulation of albumin-bound paclitaxel is facilitated by the
albumin-binding activity of secreted protein acidic and rich in cysteine
(SPARC) in malignant tumors. The absence of cremophor EL or polysorbate
80 in the nanoparticle, albumin-bound formulation virtually eliminates
the risk of acute, infusion-related hypersensitivity reactions without
requiring steroid premedication that is mandatory with conventional
taxane formulations. Additionally, the absence of a specific solvent in
the nab-paclitaxel formulation allows rapid intravenous infusion of the
drug in 30 minutes (versus 3 hour for 3-weekly paclitaxel and 60 minutes
for weekly paclitaxel, docetaxel and cabazitaxel), and requires no
special tubing or in-line filters. Nab-paclitaxel is approved for the
treatment of tumors of the pancreas, breast and lung. The metabolism of
and resistance mechanisms to nab-paclitaxel are very comparable to
solvent-based paclitaxel.

\textbf{Nab-paclitaxel pharmacokinetics and pharmacodynamics}

Nab-paclitaxel at a dose of up to 300 mg/m\textsuperscript{2} is
characterized by a linear, biphasic PK profile with a direct
relationship between drug exposure and toxicity. Average total clearance
of nab-paclitaxel is 15 L/h/m\textsuperscript{2}, with a terminal
half-life of roughly 27 hours. The mean volume of distribution is large
(roughly 630 L/m\textsuperscript{2}), indicating extensive extravascular
distribution and/or tissue binding of paclitaxel. When comparing the
population PK of 150 patients from several clinical studies receiving a
30-minutes infusion of nab-paclitaxel at a dose between 80 and
375mg/m\textsuperscript{2} with previous data from solvent-based
paclitaxel given over mainly 3 hours, nab-paclitaxel PK is characterized
by fast transport-driven distribution to peripheral compartments, rapid
disappearance of the parent compound from systemic circulation, high
distribution volume and a maximum elimination rate that is roughly 25\%
of solvent-based paclitaxel (8.1 versus 31.9 mg/L) {[}15, 51{]}. The
fraction of free paclitaxel is significantly higher with nab-paclitaxel
(6.2\%) as compared to solvent-based paclitaxel (2.3\%), resulting in
significantly higher exposure to unbound paclitaxel with nab-paclitaxel
compared with solvent-based paclitaxel, even with total exposure being
comparable. The clearance of nab-paclitaxel decreases with liver
dysfunction, and the recocmmended 3-weekly dose for nab-paclitaxel is
260 mg/m\textsuperscript{2} in patients with a total bilirubin
\textgreater{} ULN to \selectlanguage{english}[?] 1.25-times ULN, 200 mg/m\textsuperscript{2} for
patients with a total bilirubin between 1.26 and 2-times ULN and 130
mg/m\textsuperscript{2} for patients with a total bilirubin between 2
and 5-times ULN {[}52{]}. No dose adjustment is needed in patients with
mild to moderate renal impairment {[}51{]}.

\textbf{Pharmacological aspects in the clinical use of nab-paclitaxel}

Major toxicities with nab-paclitaxel include (febrile) neutropenia,
alopecia, cumulative CIPN, but virtually no cases of acute,
infusion-related HSR. Chen and colleagues found a significant
association nab-paclitaxel exposure and neutropenia in 150 solid tumor
patients, with the probability of experiencing a \selectlanguage{english}[?] 50\% reduction in
neutrophils being highly associated with the time above a nab-paclitaxel
plasma concentration of \textgreater{} 720 ng/ml (0.84 \selectlanguage{greek}µ\selectlanguage{english}mol/L) {[}51{]}.
The simulated duration above 720 ng/mL per cycle was reduced by 31\%
with weekly dosing at 100 mg/m\textsuperscript{2} versus 3-weekly dosing
at 300 mg/m\textsuperscript{2}. Nab-paclitaxel-associated neutropenia
was positively correlated with advanced age, but was not significantly
influenced by hepatic function, tumor type, patient gender or dosing
schedule. In advanced breast cancer as well as NSCLC, randomized data
suggest weekly nab-paclitaxel to be the preferred regimen due to an
improved safety-activity profile compared to 3-weekly regimens of
nab-paclitaxel {[}53, 54{]}. Still, there are different dosing regimens
approved from the different authorities for malignant tumors of the
breast, pancreas and lung. Prospective studies exploring nab-paclitaxel
TDM and TCI would be highly desirable.

\textbf{Conclusion}

The taxanes are among the most widely used anticancer drugs in patients
with solid malignancies. Despite their longtime use in clinical routine,
the optimal dosing strategy (weekly versus 3-weekly) or optimal average
dose (cabazitaxel, nab-paclitaxel) has not been fully resolved, as it
may differ per tumor entity and line of treatment. The value of
pharmacological individualization of the taxanes (TDM, TCI) has partly
been explored for 3-weekly paclitaxel and docetaxel, but remains mostly
unexplored for cabazitaxel and nab-paclitaxel at present.

\textbf{Declaration of interest}

The authors have no relevant affiliations or financiel involvement with
any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript.

\textbf{TABLE(S)}



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