Review Article
`
`Pharmacokinetics, dynamics and toxicity of
`docetaxel: Why the Japanese dose differs from the
`Western dose
`
`Hirotsugu Kenmotsu1,2 and Yusuke Tanigawara1
`
`1Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo; 2Division of Thoracic Oncology, Shizuoka
`Cancer Center, Shizuoka, Japan
`
`Key words
`Docetaxel, ethnic difference, pharmacodynamics, pharma-
`cokinetics, toxicity
`
`Correspondence
`Yusuke Tanigawara, Department of Clinical Pharmacoki-
`netics and Pharmacodynamics, Keio University School of
`Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,
`Japan.
`Tel: +81-3-5363-3847; Fax: +81-3-5269-4576;
`E-mail: tanigawara-yusuke@umin.ac.jp
`
`Funding Information
`No sources of funding were declared for this study.
`
`Received January 6, 2015; Revised February 18, 2015;
`Accepted February 21, 2015
`
`Cancer Sci 106 (2015) 497–504
`
`doi: 10.1111/cas.12647
`
`â
`Docetaxel (Taxotere
`) has been one of the most important chemotherapeutic
`drugs for cancer treatment since 1996. Although a large number of clinical stud-
`ies have been conducted in various cancer fields, there is a discrepancy in the
`standard dose between Japan and Western countries. This article reviews the
`pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and
`explains why there exists an ethnic difference in dose, and further discusses
`which direction we should go forward to solve this problem. The original recom-
`mended dose was 100 mg ⁄ m2 every 3 weeks in US and European populations,
`while a Japanese phase I study suggested the recommended dose as 60 mg ⁄ m2
`every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel
`conducted in both the USA ⁄ Europe and Japan, indicated an absence of ethnic dif-
`ference in the pharmacokinetics. Both analyses demonstrated that docetaxel
`clearance is related to a1-acid glycoprotein level, hepatic function, age and body
`surface area. The relationship was observed between increasing docetaxel dose
`and increased tumor response rates across the dose range of 60 to 100 mg ⁄ m2.
`The area under the serum concentration time curve (AUC) of docetaxel at the first
`cycle was significantly related to time to progression. Hematological toxicities
`were well correlated with the AUC of docetaxel, and severe hematological toxici-
`ties were more frequently observed in Japanese patients treated with 60 mg ⁄ m2,
`compared to the US ⁄ European patients treated with 75–100 mg ⁄ m2 dose. The
`Japanese population seems more susceptible to the toxicity of docetaxel. A do-
`cetaxel dose of 75 mg ⁄ m2 is now standard not only in global trials but also in
`recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we
`need to continue to seek the appropriate dose of docetaxel depending on patient
`status and the goals of chemotherapy.
`
`Background and Aims of This Article
`
`D ocetaxel, a more potent semisynthetic derivative of pac-
`
`litaxel, derived from extracts of the leaves of the Euro-
`pean yew tree (Taxus baccata), was discovered in the 1980s.(1)
`â
`Docetaxel (Taxotere
`) was first approved for use by the US
`Food and Drug Administration in 1996 for locally advanced or
`metastatic breast cancer after failure of prior chemotherapy,
`with a dose of 60 to 100 mg ⁄ m2 administered intravenously
`over 1 hour every 3 weeks. Thereafter, additional indications
`were approved at a dose of 75 mg ⁄ m2. In contrast, docetaxel
`was approved in Japan in 1996 with the recommended dose of
`60 mg ⁄ m2 every 3 weeks, based on a Japanese phase I
`study.(2) Currently, docetaxel is widely used for treatment of
`breast, non-small cell
`lung, gastric, head and neck, ovary,
`
`© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd
`on behalf of Japanese Cancer Association.
`This is an open access article under the terms of the Creative Commons
`Attribution-NonCommercial
`License, which permits use, distribution and
`reproduction in any medium, provided the original work is properly cited and is
`not used for commercial purposes.
`
`esophageal, uterus body and prostate cancers, and the Japanese
`approved dose has been extended to 60 to 75 mg ⁄ m2. How-
`ever,
`there is still discrepancy between Japan and Western
`countries in the standard doses for pretreated non-small cell
`lung cancer, with docetaxel typically administered at a dose of
`60 mg ⁄ m2 every 3 weeks in both clinical practice and clinical
`trials of Japan.
`Docetaxel
`is one of the most important chemotherapeutic
`drugs and a number of clinical studies have been conducted to
`extend its clinical applications. When global or multi-national
`collaborative studies used the dose of 100 mg ⁄ m2, Japan was
`not able to join these studies because the 100 mg ⁄ m2 dose
`exceeded the Japanese approved dose. Recently, some Japa-
`nese patients were treated at a dose of 75 mg ⁄ m2 when they
`
`Cancer Sci
`
`| May 2015 | vol. 106 | no. 5 | 497–504
`
`OSI EXHIBIT 2002
`APOTEX V. OSI
`IPR2016-01284
`
`

`
`Review Article
`Pharmacokinetics ⁄ pharmacodynamics and toxicity of docetaxel
`
`www.wileyonlinelibrary.com/journal/cas
`
`participated in global clinical trials of docetaxel(67). With this
`unique history of docetaxel dose discrepancy, Japanese oncolo-
`gists still feel uncertain about the optimal dose selection.
`Needless to say, it is important to determine the optimal
`dose of docetaxel for Japanese patients in routine clinical set-
`tings. However, the central question is why the Japanese stan-
`dard dose of docetaxel differs from the Western dose. The
`present article focuses on reviewing pharmacokinetic (PK),
`pharmacodynamic (PD) and toxicological profiles of docetaxel,
`and discussing whether there is any evidence showing that a
`lower dose is more appropriate in the Japanese population. We
`also discuss which direction we should go forward to solve the
`current clinical problem.
`
`Pharmacokinetics
`
`Standard pharmacokinetics. Docetaxel PK parameters are
`summarized in Table 1.(2–8) In a phase I trial, the PK of docet-
`axel was linear, determined by 23 patients receiving 20–
`115 mg ⁄ m2. At high doses of docetaxel (85–115 mg ⁄ m2), a
`three-compartment model was found to provide a better fit
`than a two-compartment model with a terminal half-life of
`
`13.5  7.5 h (mean  SD), a plasma clearance of 21.1
` 5.3 L ⁄ h ⁄ m2 and a distribution volume of 72  40 L
`⁄ m2.(3,9) A PK analysis suggested the presence of nonlinear
`pathways,(10) whereas PK parameters remained linear up to
`175 mg ⁄ m2 in a phase I and PK study of docetaxel adminis-
`tered with granulocyte colony-stimulating factor.(11) Docetaxel
`exposure as measured by the area under the plasma concentra-
`tion time curve (AUC) was the only significant predictor of
`severe toxicity during the first course of chemotherapy.(12) It
`was also reported that docetaxel PK were similar for weekly
`and 3-weekly regimens.(13)
`Large interindividual variability in docetaxel PK was
`reported despite intravenous infusion dosing (coefficient of
`variation 30–40%), and the variability was related to both tox-
`icity and efficacy.(5,14,15) Therefore, unique clinical trials were
`conducted to attempt to optimize drug exposure in individual
`patients. Engels et al. reported a randomized trial to evaluate
`the effect of PK-guided individualized dosing of docetaxel in
`cancer patients. The interindividual variability was decreased
`by 35% after 1 PK-guided course, and PK-guided dosing also
`decreased the interindividual variability of
`the percentage
`decrease in white blood cell and absolute neutrophil counts by
`50%.(16) Yamamoto et al. also performed a randomized trial to
`assess individualized doses of docetaxel calculated from the
`estimated clearance and the target AUC of 2.66 lg h ⁄ mL, and
`reported that the standard deviation of AUC was significantly
`smaller in the individualized dosing arm than in the body
`
`surface area-based dosing arm.(17) Although individualized
`docetaxel dosing was feasible in both trials, they were not able
`to evaluate the efficacy of this dosing method due to the small
`sample size.
`It should be noted that docetaxel was the first drug whose
`population PK were evaluated in a prospective manner from
`phase I through to phase III clinical
`trials. The population
`PK analysis performed in the Western countries found that
`related to a1-acid glycoprotein
`docetaxel clearance was
`(AAG) level, hepatic function, age and body surface area.(18)
`The population PK analysis conducted in Japan analyzed
`data from 102 Japanese patients with solid tumors who par-
`ticipated into phase I and II clinical
`trials. Clearance was
`described by a similar equation to that in the Western popu-
`lation (Table 2). The mean values and covariate effects of
`docetaxel clearance in Japanese patients were comparable to
`those obtained in the European and US population, suggest-
`ing no racial difference in the elimination of docetaxel
`(Fig. 1).(19)
`Metabolism and elimination. Docetaxel is metabolized by the
`hepatic cytochrome P450 (CYP) 3A isoforms CYP3A4 and
`CYP3A5, and the predominant route of elimination of parent
`drug and metabolites is via biliary and intestinal excre-
`tion.(20,21) CYP3A4 activity was found to be the most signifi-
`cant
`independent variable for predicting the clearance of
`docetaxel.(15) Docetaxel
`is excreted mainly in the feces as
`metabolites. A study of 14C-docetaxel suggested that 6% and
`75% of the administered radioactivity is excreted in urine and
`â
`package insert).
`feces (Taxotere
`Distribution. Lipoproteins, AAG and albumin were the main
`carriers of docetaxel in plasma, and owing to the high interin-
`dividual variability of AAG plasma concentration,
`it was
`reported that AAG should be the main determinant of docet-
`axel plasma binding variability.(22)
`The fraction of unbound docetaxel was reported to range
`from 4% to 10% in the plasma of patients treated with docet-
`axel, and AAG was found to be correlated with fraction
`unbound and clearance of total docetaxel.(23) In a PD analysis
`of docetaxel monotherapy, greater maximum concentration
`(Cmax) and AUC of unbound docetaxel, but not total docet-
`axel, in plasma were associated with greater risk of grade 4
`neutropenia.(8) These
`results may reveal
`that primarily
`unbound drugs are pharmacologically active because they can
`distribute into tissues or cells to bind their targets. Also in a
`clinical study evaluating unbound docetaxel PK, AUC of
`unbound docetaxel was better associated with severe neutrope-
`nia than AUC of total (unbound + bound) docetaxel.(24)
`Drug interactions. Docetaxel
`is subject
`to extensive meta-
`bolic conversion by CYP3A isoenzymes, which results in
`
`Table 1. Pharmacokinetic features of docetaxel
`
`Authors
`
`Patients
`
`N Dose range (mg ⁄ m2)
`
`Cmax (lg ⁄ mL)
`
`AUC (lg h ⁄ mL)
`
`CL (L ⁄ h ⁄ m2)
`
`Ethnicity
`
`Extra et al.(3)
`Burris et al.(4)
`Taguchi et al.(2)
`Yamamoto et al.(5)
`Rosing et al.(6)
`ten Tije et al.(7)
`
`5.93†
`2.41†
`5–115
`65
`Solid tumor (Phase 1)
`18.3  5.4†
`5.9  1.9†
`5–115
`58
`Solid tumor (Phase 1)
`2.44  0.83‡
`1.61  0.59‡
`10–90
`27
`Solid tumor (Phase 1)
`24.5  6.4
`2.66  0.91
`1.30―3.82
`60
`29
`NSCLC
`34.8  9.3
`3.1  0.9
`2.6  0.5
`100
`24
`Solid tumor
`15.4  6.94
`5.69  2.27
`4.06  1.38
`Solid tumor (<65 years)
`75
`20
`16.6  10.0
`6.01  3.23
`3.54  1.58
`Solid tumor (≥65 years)
`75
`20
`29.4 L ⁄ h
`Minami et al.(8)
`Japanese
`2.68
`1.588
`60
`69
`Solid tumor
`†Pharmacokinetic parameters obtained at 100 mg ⁄ m2 dose. ‡Pharmacokinetic parameters obtained at 60 mg ⁄ m2 dose. AUC, area under the
`curve; CL, total body clearance; Cmax, maximum plasma concentration; NA, not available; NSCLC, non-small cell lung cancer.
`
`NA
`NA
`Japanese
`Japanese
`NA
`White ⁄ Black
`
`© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd
`on behalf of Japanese Cancer Association.
`
`Cancer Sci
`
`| May 2015 | vol. 106 | no. 5 | 498
`
`

`
`www.wileyonlinelibrary.com/journal/cas
`
`Review Article
`Kenmotsu and Tanigawara
`
`Table 2. Equations predicting docetaxel clearance for European ⁄ American and Japanese populations
`
`Authors
`
`Equations predicting docetaxel clearance
`CL = BSA (22.1 3.55 AAG 0.095 AGE + 0.225 ALB) (1 0.334 HEP)
`Bruno et al.(18)
`33
`CL = BSA (37.6 6.41 AAG 0.191 AGE + 0.0436 ALB) (1 0.209 HEP)
`Tanigawara et al.(19)
`25
`AAG, a1-acid glycoprotein level (g ⁄ L); ALB, albumin level (g ⁄ L); AGE (years); BSA, body surface area (m2); CL, total body clearance (L ⁄ h); HEP,
`complication of hepatic dysfunction indicated by HEP = 1 (presence) or HEP = 0 (absence).
`
`xCL (%)
`
`rs12762549 in ABCC2 (P = 0.00022) and rs11045585 in
`SLCO1B3 (P = 0.00017) with docetaxel-induced leukopenia
`⁄ neutropenia.(34)
`Regarding hepatic metabolism, influences of polymorphism
`in CYP3A4 and CYP3A5 on docetaxel PK were not demon-
`strated in several studies.(31,35) One study reported that simul-
`taneous presence of the CYP3A4*1B and CYP3A5*1A alleles
`was associated with a 64% increase in docetaxel clearance
`(P = 0.0015).(36)
`In addition,
`rs7761731 of CYP39A1 was
`found to be the only SNP significantly associated (P = 0.049,
`OR = 9.0) with the incidence of grade 4 neutropenia among
`28 SNP, which were associated with the AUC of docetaxel.(37)
`The pharmacogenomics of docetaxel have not yet been eluci-
`dated in a large clinical study. A genome-wide association
`study is expected to find genomic variants which relate to the
`efficacy or toxicity of docetaxel.(38,39)
`Special population: Hepatic dysfunction. In a population PK
`analysis, patients with concomitant elevations of transaminases
`(ALT or AST > 1.5 9 ULN)
`and
`alkaline
`phosphatase
`(>2.5 9 ULN) showed a 27% reduction in docetaxel clearance
`and are higher risk of toxicity.(14) However, in an observa-
`tional study of docetaxel for patients with metastatic breast
`cancer and liver dysfunction, PK results suggested that docet-
`axel at 25 mg ⁄ m2 for patients with more severe hepatic dys-
`function (serum total bilirubin 1.5–3 9 ULN, and ALT or
`ALT 2.5–5 9 ULN) may be underdosed compared with docet-
`axel at 100 mg ⁄ m2 for patients with normal hepatic func-
`tions.(40) Docetaxel unbound clearance was lower and more
`variable in patients with hepatic dysfunction compared to those
`without hepatic dysfunction.(41) Compared to patients with nor-
`mal liver function, patients with grade 2 and 3 elevations of
`transaminases at baseline in conjunction with elevation of alka-
`line phosphatase (grade ≥1) showed 22% and 38% lower clear-
`ances, respectively. Minami et al. proposed dose reduction by
`approximately 20% and 40% for patients with grade 2 and 3
`elevations of transaminases at baseline in conjunction with ele-
`vation of alkaline phosphatase, respectively.(42) Caution is war-
`ranted and appropriate dose reduction seems advisable for
`docetaxel when treating patients with liver dysfunction,
`although the correlation between serum drug exposure and tox-
`icity needs further investigation.
`Special population: Renal dysfunction. Preclinical PK studies
`show that hepatobiliary extraction is the major route of elimi-
`nation, with similar metabolic pathways in all species.(43) No
`apparent differences were seen in the plasma concentration
`time curves of docetaxel administered before or after dialy-
`sis.(44) Because docetaxel is excreted mainly in the feces as
`metabolites, docetaxel PK may not be altered in patients with
`renal dysfunction.
`Special population: Elderly. A population PK showed that age
`was one of
`factors affecting docetaxel clearance (6.7%
`decrease in mean clearance for a 71-year-old patient).(18) In a
`prospective PK study of 75 mg ⁄ m2 docetaxel every 3 weeks
`for patients with solid tumors, mean docetaxel clearance was
`not altered in elderly patients (≥65 years) versus younger
`
`Fig. 1. Comparison of clearance estimates predicted by European ⁄ US
`and Japanese population pharmacokinetic models of docetaxel. The
`model equations are described in Table 2, and a correlation analysis is
`provided: y = 1.178x 5.454 (R2 = 0.894, r = 0.945). CL, total body
`clearance (L ⁄ h). The solid line shows a unit line.
`
`several pharmacologically inactive oxidation products.(21) An-
`tiepileptic drugs,
`in particular phenytoin and phenobarbital,
`possess the potential to interact with docetaxel through induc-
`tion of the hepatic metabolic activity, and can greatly reduce
`the potential antitumor effects of docetaxel.(21) In contrast,
`potent
`inhibitors of CYP3A, such as ketoconazole, were
`reported to decrease docetaxel clearance (49% decrease in
`clearance of docetaxel).(21,25)
`Concomitant treatment with doxorubicin was associated with
`decreased docetaxel clearance (20% decrease in clearance),(26)
`probably because doxorubicin inhibited the CYP3A activity. In
`a PK and PD study for the combination of docetaxel and topo-
`tecan in patients with solid tumors, administration of topotecan
`on days 1–4 and docetaxel on day 4 resulted in an approximate
`50% decrease in docetaxel clearance and was associated with
`increased neutropenia.(27) In designing combination regimens
`of chemotherapeutic agents, attention should be paid to drug
`interactions.
`Pharmacogenomics. ABCB1 (P-glycoprotein, multidrug resis-
`tance 1), ABCC2 (MRP2) and SLCO1B3 (OATP1B3, OATP8)
`are considered as transporters to carry docetaxel. ABCB1 plays
`important and crucial roles in intestinal absorption and biliary
`excretion.(28,29) There was no statistically significant effect of
`genotype on the clearance of docetaxel for ABCB1 genetic
`variations.(30,31) However, the homozygous allele T of C1236T
`polymorphism in the ABCB1 gene (ABCB1*8) was signifi-
`cantly correlated with a decreased docetaxel clearance (25%;
`P = 0.0039).(32) Single nucleotide polymorphism (SNP)
`in
`ABCB1 may influence toxicity more than the PK of docetaxel.
`ABCC2 and SLCO1B3 have cooperative roles in the docet-
`axel transport process in the liver.(33) A Japanese case-control
`association study indicated a significant association of both
`
`Cancer Sci
`
`| May 2015 | vol. 106 | no. 5 | 499
`
`© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd
`on behalf of Japanese Cancer Association.
`
`

`
`Review Article
`Pharmacokinetics ⁄ pharmacodynamics and toxicity of docetaxel
`
`www.wileyonlinelibrary.com/journal/cas
`
`patients (<65 years). However, the percentage of patients expe-
`riencing grade 4 and febrile neutropenia was remarkably
`higher in elderly (63% and 16%, respectively) versus younger
`(30% and 0%, respectively) cohort.(7)
`In two phase II studies separately conducted in elderly
`(≥75 years) and non-elderly (<75 years) using non-small cell
`lung cancer patients treated with three weekly administration
`of docetaxel and cisplatin every 4 weeks, there was no differ-
`ence in the PK of docetaxel or cisplatin between the two
`groups with regard to clearance and volume of distribution. In
`the PD analysis, neutropenia was positively correlated with the
`AUC for docetaxel but not for cisplatin.(45) These results sug-
`gest that there is no significant difference in the PK of docet-
`axel between elderly and non-elderly patients, and that
`docetaxel is more toxic for elderly patients. In a PK study of
`paclitaxel, clearance of the unbound drug, the pharmacologi-
`cally active fraction, was
`significantly different between
`elderly (≥70 years) and younger (<70 years) patients.(46) How-
`ever,
`there is no data on the difference in clearance of
`unbound docetaxel between elderly and non-elderly patients.
`Inter-ethnic difference. There are some reports discussing
`inter-ethnic difference for PK and toxicity of docetaxel. In a
`prospective study of 106 patients with non-hematologic malig-
`nancy, there was no difference in geometric mean docetaxel
`(40.3 L ⁄ h) and White
`clearance between Black patients
`patients (41.8 L ⁄ h, P = 0.6). There was also no difference
`between Black and White patients in the percentage decrease
`in absolute neutrophil count nor docetaxel PK parameters
`related to the genotypes of CYP3A4, CYP3A5 and ABCB1.(47)
`By using published data of phase II and III clinical trials to
`investigate single agent docetaxel every 3 weeks, docetaxel-
`induced grade 3 ⁄ 4 neutropenia was frequently observed in
`Asian clinical studies compared to non-Asian studies (odds
`ratio 19.0). However, a major limitation of this study was not
`evaluating PK and serum AAG level.(48) According to results
`of population PK studies, there may be no significant differ-
`ence in docetaxel clearance between Japanese and White
`patients. (Fig. 1).(18,19) In PK analyses of docetaxel for Asian
`patients with breast cancer,
`including Chinese, Malays and
`Indians, no ethnic difference was observed.(49) Therefore, there
`seems present an inter-ethnic difference in toxicities, but ethnic
`difference in the PK of docetaxel has not been demonstrated.
`
`Pharmacodynamics
`
`response. In phase III studies for breast cancer
`Clinical
`patients previously treated with anthracycline, docetaxel
`100 mg ⁄ m2 produced significantly higher response rates than
`other regimens (response rate: 30–36%).(50,51) In two random-
`ized phase III studies, docetaxel 100 mg ⁄ m2 was significantly
`superior in overall survival.(50,52)
`two large
`Regarding hormone-refractory prostate cancer,
`phase III trials demonstrated that docetaxel showed survival
`benefits.(53,54) Until now,
`there has been no randomized
`phase III study to show efficacy of docetaxel monotherapy for
`Japanese patients with metastatic breast cancer and prostate
`cancer.
`There was a phase III study of docetaxel monotherapy ver-
`sus best supportive care in patients with non-small cell lung
`cancer, previously treated with platinum-based chemotherapy.
`Survival in patients treated with docetaxel 75 mg ⁄ m2 was sig-
`nificantly better than in those treated with best supportive care
`(P = 0.01).(55) Table 3 summarizes data on the efficacy of do-
`cetaxel monotherapy every 3 weeks for pretreated non-small
`
`lung cancer patients.(55–72) Response rates varied from
`cell
`2.7% to 17.9% for non-small cell lung cancer patients in sec-
`ond-line settings.
`Exposure-Response relationships. In a phase III trial compar-
`ing three doses of docetaxel
`for second-line treatment of
`advanced breast cancer, 527 patients were randomly assigned
`to docetaxel 60, 75 or 100 mg ⁄ m2
`intravenously every
`3 weeks.(51) A relationship between an increasing dose of do-
`cetaxel and increased tumor response was observed across the
`dose range of 60 to 100 mg ⁄ m2 (response rate: 22.1%, 23.3%
`and 36.0%, respectively) and toxicities were also related to
`increasing dose. However, there was no statistically significant
`relationship between the objective response rate and docetaxel
`exposure. In a population PK analysis, the AUC of docetaxel
`in the first cycles was significantly related to time to progres-
`sion.(14) A Japanese population PK study showed that the effi-
`cacy of docetaxel was not correlated with the AUC.(19)
`A large scale population PK ⁄ PD analysis was successfully
`implemented during the clinical development of docetaxel.(73)
`Cumulative dose and baseline AAG were significant indepen-
`dent prognostic factors for survival in patients with non-small
`cell lung cancer. In six phase II studies of docetaxel mono-
`therapy at a dose of 100 mg ⁄ m2 for non-small cell lung can-
`cer, baseline AAG was a significant predictor of response and
`survival.(12) A population PK study also showed that AAG
`was a significant predictor of response.(14) However, a predic-
`tive biomarker for the efficacy of docetaxel has not yet been
`established.
`
`Toxicity
`
`Toxicity profiles. The dose-limiting toxicity in phase I studies
`was neutropenia.(2–4) Neutropenia,
`leukopenia, neurological
`toxic effects, diarrhea, alopecia, asthenia and nausea were
`common adverse effects of docetaxel monotherapy every
`3 weeks. Toxicities of docetaxel monotherapy every 3 weeks
`for non-small
`cell
`lung cancer patients
`are
`shown in
`Table 3.(55–72) Despite Japanese patients being treated with
`lower 60 mg ⁄ m2 docetaxel,
`incidence of severe neutropenia
`and febrile neutropenia was higher in Japanese trials compared
`with patients treated with 75 mg ⁄ m2 docetaxel
`in Western
`country trials. In addition,
`it was reported that docetaxel-
`induced grade 3 ⁄ 4 neutropenia was more frequently observed
`in Asian clinical studies compared to non-Asian studies.(48)
`In a phase III study of docetaxel versus best supportive care
`in patients with non-small cell lung cancer previously treated
`with platinum-based chemotherapy,
`the docetaxel dose was
`reduced from 100 to 75 mg ⁄ m2 based on interim safety-data
`monitoring which identified a significantly higher toxic death
`rate in the chemotherapy arm of the study.(55) Based on this
`study, the standard dose of docetaxel for patients with pre-
`treated non-small cell
`lung cancer has been considered as
`75 mg ⁄ m2 every 3 weeks. It is also reported that docetaxel at
`a dose of 100 mg ⁄ m2 showed severe toxicities in heavily pre-
`treated breast cancer patients.(74) Therefore, an optimal dose
`of docetaxel potentially depends on treatment line and types
`of cancer.
`Exposure–toxicity relationship. Hematological toxicity of do-
`cetaxel correlated with the exposure to docetaxel.(14) Based
`upon a population PK ⁄ PD model describing factors responsible
`for the neutropenia caused by docetaxel, serum AAG levels,
`level of chemotherapy pretreatment and treatment center were
`identified as significant covariates of neutropenia.(75) In two
`randomized PK studies of docetaxel
`to compare PK-guided
`
`© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd
`on behalf of Japanese Cancer Association.
`
`Cancer Sci
`
`| May 2015 | vol. 106 | no. 5 | 500
`
`

`
`www.wileyonlinelibrary.com/journal/cas
`
`Review Article
`Kenmotsu and Tanigawara
`
`Table 3. Efficacies and toxicities of docetaxel monotherapy (phase III for previously treated non-small cell lung cancer patients)
`
`Authors
`
`Shepherd et al. 2000(55)
`
`Fossella et al. 2000(56)
`
`Hanna et al. 2004(57)
`Gridelli et al. 2004(58)
`Schuette et al. 2005(59)
`Camps et al. 2006(60)
`Ramlau et al. 2006(68)
`
`Kim et al. 2008(61)
`Maruyama et al. 2008(62)
`Paz-Ares et al. 2008(63)
`
`Takeda et al. 2009(64)
`Krzakowski et al. 2010(65)
`Lee et al. 2010(66)
`Herbst et al. 2010(67)
`
`Ramlau et al. 2012(69)
`Garassino et al. 2013(70)
`Kawaguchi et al. 2014(71)
`Reck et al. 2014(72)
`
`Dose
`(mg ⁄ m2)
`
`75
`100
`75
`100
`75
`75
`75
`75
`75
`
`75
`60
`75
`
`60
`75
`75
`75
`
`75
`75
`60
`75
`
`N
`
`55
`49
`121
`121
`276
`110
`103
`129
`415
`
`733
`239
`416
`
`65
`277
`79
`697
`
`457
`110
`151
`659
`
`Gr3-4
`ANC (%)
`
`Gr4 ANC
`(%)
`
`Gr3–4
`WBC (%)
`
`Gr4
`WBC (%)
`
`Gr3–4
`FN (%)
`
`ORR
`(%)
`
`Median
`PFS (mo)
`
`Median
`OS (mo)
`
`Ethnicity
`
`67.3
`85.7
`
`40.2
`18
`20.6
`9.3
`60
`
`73.6
`37
`
`85.9
`29.5
`
`24
`
`21.1
`21
`80.0
`29.9
`
`54
`77
`
`11
`
`36
`
`58.2
`
`18.8
`
`12
`
`21.2
`
`10
`27.5
`10.1
`41
`
`39.3
`2
`
`64.1
`21.3
`
`11
`
`64.0
`2.4
`
`3
`
`11
`
`4.8
`
`0.6
`
`1.8
`22.4
`8
`12
`12.7
`5
`2
`7.8
`3
`
`10.1
`7.1
`6
`
`25.0
`4.7
`
`6
`
`4.2
`4
`15.3
`4.7
`
`5.5
`6.3
`6.7
`10.8
`8.8
`2.7
`12.6
`9.3
`5
`
`7.6
`12.8
`12
`
`6.8
`5.5
`7.6
`10
`
`8.9
`15.5
`17.9
`3.3
`
`TTP 8.5w
`TTP 8.4w
`2.9
`
`TTP 3.4
`TTP 2.7
`TTP 13w
`
`2.7
`2.0
`TTP 2.6
`
`2.1
`2.3
`3.4
`4.2
`
`4.1
`2.9
`3.2
`2.7
`
`7.5
`5.9
`5.8
`6.0
`7.9
`7.3
`6.3
`6.6
`7.8
`
`8.0
`14.0
`6.9
`
`10.1
`7.2
`12.2
`10.0
`
`10.4
`8.2
`12.2
`9.1
`
`NA
`
`NA
`
`NA
`NA
`NA
`NA
`White ⁄ Oriental
`⁄ Black
`White ⁄ Asian ⁄ Black
`Japanese
`Caucasian ⁄ Black ⁄
`Asian ⁄ Hispanic
`Japanese
`NA
`Korean
`Caucasian ⁄ East
`Asian
`NA
`White ⁄ Asian
`Japanese
`White ⁄ Asian ⁄ Black
`⁄ Indian
`
`ANC, absolute neutrophil count; FN, febrile neutropenia; Gr, grade; NA, not available; mo, months; ORR, objective response rate; OS, overall sur-
`vival; PFS, progression-free survival; TTP, time to progression; w, weeks; WBC, white blood cell.
`
`individual dosing and dosing based on body surface area, the
`PK-guided individual dosing decreased interindividual variabil-
`ity in hematological toxicity.(16,17)
`Idiosyncratic toxicity. Popular idiosyncratic toxicities of do-
`cetaxel
`include fluid retention, nail changes,
`tearing and
`hypersensitivity reactions. Fluid retention was reported to
`occur in 53% of patients treated with docetaxel monotherapy
`at a dose of 75 or 100 mg ⁄ m2, and median time to onset
`was 85 days (95% CI 81–92 days). The cumulative dose
`of docetaxel was the most
`important predictor
`for fluid
`retention.(14)
`In two studies to evaluate nail change in patients treated
`with docetaxel, 26–58% developed nail changes.(76,77) These
`studies showed that the number of chemotherapy cycles and
`cumulative docetaxel doses were strongly associated with the
`development of nail changes.
`
`Clinical Trial Simulations
`
`Virtual computer simulations resembling clinical trials of do-
`cetaxel were performed to assess the benefit from dose intensi-
`fication in patients with high AAG levels, using PK ⁄ PD and
`death ⁄ drop-out models describing time to progression.(78–80)
`The simulated phase III trial showed slightly longer median
`in the 125 mg ⁄ m2 docetaxel group than in the
`survival
`100 mg ⁄ m2 group, but the results did not show a useful benefit
`of
`increasing the dose. Clinical
`trial simulation was also
`applied to design the most advantageous combination regimen.
`Based on modeling techniques using clinical data,
`the PD
`interaction was simulated between capecitabine and docetaxel
`in metastatic breast cancer.(79) Bruno et al. conducted simula-
`tions to determine how much of a decreased capecitabine dose
`
`would be non-inferior to the standard dose in a combination
`regimen with docetaxel for the second-line treatment of meta-
`static breast cancer.(80)
`
`What is the Optimal Dose?
`
`In a phase I study of docetaxel performed in the USA, neutro-
`penia was the dose-limiting toxicity and the maximum toler-
`ated dose for patients receiving two or fewer chemotherapy
`regimens was 100–115 mg ⁄ m2. This study concluded that the
`recommended doses for phase II trials were 100 mg ⁄ m2 for
`good-risk patients and 80 mg ⁄ m2 for poor-risk patients, respec-
`tively.(4) A European phase I study of docetaxel also reported
`that the tolerated dose was 115 mg ⁄ m2 and the recommended
`dose for a phase II study was 100 mg ⁄ m2.(3) In a Japanese
`phase I study of docetaxel, based on the observation of dose-
`limiting toxicities including leukopenia and neutropenia, the
`maximum tolerated dose was determined to be 70–90 mg ⁄ m2.
`The Japanese investigators concluded that a dosage regimen of
`60 mg ⁄ m2 at 3–4-week intervals was appropriate for the early
`phase II clinical trial.(2) This discrepancy in the Western and
`Japanese phase I trials created the important difference in the
`recommended dose of docetaxel between US ⁄ Europe and
`Japan. Prospective population PK analysis of docetaxel for
`Japanese patients showed similar clearance values to European
`and US populations, suggesting the absence of ethnic differ-
`ence in the PK.(18,19,73) Although hematological toxicity of do-
`cetaxel was reported to be well correlated with exposure to
`docetaxel, similar PK cannot explain the difference in the
`recommended dose of docetaxel between US ⁄ Europe and
`Japan.(14).However, based upon the toxicity profiles,
`the
`Japanese population seems more susceptible to the toxicity of
`
`Cancer Sci
`
`| May 2015 | vol. 106 | no. 5 | 501
`
`© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd
`on behalf of Japanese Cancer Association.
`
`

`
`Review Article
`Pharmacokinetics ⁄ pharmacodynamics and toxicity of docetaxel
`
`www.wileyonlinelibrary.com/journal/cas
`
`docetaxel. This difference in toxicity profiles was possibly
`caused by unknown genetic factors, and differences
`in
`unbound docetaxel concentrations or baseline counts of white
`blood cells. However, mechanistic insights are not yet eluci-
`dated for different sensitivity to docetaxel
`toxicity between
`Japanese and Western populations.
`Nowadays, a docetaxel dose of 75 mg ⁄ m2 is used in most of
`global clinical trials.(53–56) The approved recommended doses
`of docetaxel in Asian countries except Japan (China, Korea,
`Taiwan and Singapore) are 100 mg ⁄ m2 for breast cancer and
`75 mg ⁄ m2 for non-small lung cancer.(66) A docetaxel study in
`Singapore using doses of 75 or 100 mg ⁄ m2 showed similar PK
`but relatively higher incidence of febrile neutropenia compared
`to the Western population.(31) Recent Japanese clinical trials
`also used 75 mg ⁄ m2 dose for breast cancer and non-small cell
`lung cancer.(81,82) With an increasing number of medical
`oncologists in Japan with experiences and skills in toxicity
`management and with the significant progress in supportive
`care, a docetaxel dose of 75 mg ⁄ m2 is likely to become a che-
`motherapy treatment option with curative intent in Japan.
`
`Conclusion
`
`Oncologists have used docetaxel for almost 20 years, and it is
`now one of the most
`important cytotoxic drugs for cancer
`treatment. A prospective population PK analysis of docetaxel
`indicated the absence of ethnic difference in PK. However,
`although so far most Japanese patients have been treated with
`60 mg ⁄ m2 docetaxel, severe hematological toxicities are more
`frequently experienced in the Japanese compared to the US
`and European patients given 75–100 mg ⁄ m2 doses. Twenty
`years ag