Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors: focus on the pharmacokinetic targets.

Clin Pharmacokinet DOI 10.1007/s40262-014-0137-2

REVIEW ARTICLE

Practical Guidelines for Therapeutic Drug Monitoring of Anticancer Tyrosine Kinase Inhibitors: Focus on the Pharmacokinetic Targets Huixin Yu • Neeltje Steeghs • Cynthia M. Nijenhuis Jan H. M. Schellens • Jos H. Beijnen • Alwin D. R. Huitema

•

Ó Springer International Publishing Switzerland 2014

Abstract There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and response (efficacy/ toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations (Ctrough) of [1,000, [50 and [20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of

H. Yu (&) C. M. Nijenhuis J. H. Beijnen A. D. R. Huitema Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, PO Box 90440, 1006 BK Amsterdam, The Netherlands e-mail: [email protected] N. Steeghs J. H. M. Schellens Department of Medical Oncology, Netherlands Cancer InstituteAntoni van Leeuwenhoek, Amsterdam, The Netherlands N. Steeghs J. H. M. Schellens J. H. Beijnen A. D. R. Huitema Department of Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands J. H. M. Schellens J. H. Beijnen Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

TKIs with proposed pharmacokinetic targets, mainly Ctrough, and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.

1 Introduction Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that is involved in the measurement and interpretation of drug concentrations in biological fluids to improve individual patient care, e.g. by dose adaptation. Many factors that impact plasma concentrations need to be considered in TDM, such as food effect, patient adherence and interacting co-medication [1]. Some important requirements for drugs to be suitable candidates for TDM include the absence of an easily measurable biomarker for drug effects; long-term therapy; availability of a validated sensitive bioanalytical method; significant inter-individual and relatively low intra-individual variability; a narrow therapeutic range; a defined and consistent exposure–response (efficacy/toxicity) relationships, in which the exposure can be interpreted as trough plasma concentration (Ctrough), maximum plasma concentration (Cmax) or area under the plasma concentration–time curve (AUC); and a feasible dose-adaptation strategy [2]. TDM has shown its benefits in many drug classes (e.g. anticonvulsants, antibacterials, antipsychotics, antidepressives, immunosuppressants and antiretrovirals). However, in cancer treatment, TDM is still limitedly applied [3–5]. One of the key constraints for TDM of most anticancer agents is the lack of well-established exposure–response relationships [6]. Over the past decade, as the molecular signalling that drives cancer progression is being gradually deciphered,

H. Yu et al.

the introduction of tyrosine kinase inhibitors (TKIs) as targeted therapy of cancer has revealed its importance. These TKIs are most often oral drugs that inhibit the adenosine triphosphate (ATP)-binding site of tyrosine kinase receptors in malignant cells, thereby inhibiting the autophosphorylation of the tyrosine residues, and thus prohibit activation of proteins involved in the angiogenesis and tumour proliferation signalling [7]. By the end of 2013, 20 TKIs had been (conditionally) approved by the European Medicines Agency (EMA) and 22 by the US FDA (ponatinib included) for different cancer treatments [8, 9]. Our review focuses on the TKIs approved by both the EMA and FDA as at 28 February 2013. General information on these TKIs is provided in Table 1. The initial dose regimens of these anticancer drugs are fixed, which has been postulated to be (partially) responsible for variable treatment responses [10, 11]. In clinical practice, the necessities and evidence applying TDM of TKIs attract increasing attention. We previously reported that 73.2, 11.1 and 48.6 % of outpatients treated with imatinib, erlotinib and sunitinib, respectively, do not meet established pharmacokinetic targets (Ctrough) [12]. Besides, most of the TKIs meet the requirements that are listed above for TDM. The key factor for performing TDM, i.e. the exposure–response relationship, has been identified for several TKIs for several therapeutic indications. Very recently, Josephs et al. [13] briefly suggested pharmacokinetic targets of TKIs in a review focusing on clinical pharmacokinetics of TKIs. In this review, we elaborate the current knowledge on exposure–response relationships, explain the reasons and/or pitfalls of proposed pharmacokinetic targets, and further offer guidance on dose adaptation of TKIs based on pharmacokinetic parameters.

2 Practical Guidelines for Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors This section provides an overview of exposure–response relationships and related dose adjustments for the TKIs listed in Table 1. Table 2 summarises the mean/median values of main pharmacokinetic parameters with coefficient of variation for the different TKIs. Exposure– response relationships studied for the different TKIs are presented in Table 3. Finally, in Table 4 the recommended dosing algorithms are summarised. The different TKIs are discussed in more detail in the following sections. 2.1 Axitinib It has been shown that the AUC and Cmax of axitinib increased proportionally to the dose [14]. There have been

studies exploring the exposure–response relationship of axitinib (Table 3). One recent report retrospectively correlated the 5-year efficacy with cycle 1 day 1 post-dose (1–2 h) concentration in 52 patients with metastatic renal cell cancer (mRCC) [15]. By scaling the first-dose concentration in four quartiles, the authors found that the median progression-free survival (PFS) and overall survival (OS) in quartile 3 [n = 11; concentration range 45.2–56.4 ng/mL; AUC from time zero to 12 h (AUC12) range 154–620 ngh/ mL] was numerically longer than the other quartiles. The patients in quartile 4 (n = 13) with highest first-dose concentrations showed the highest incidence of grade C3 adverse events. This report indicated an exposure–response relationship of axitinib, albeit that the power of the analysis was very limited. Another study reported that patients with mean steady-state AUC (AUCss) at the end of cycle 1 above the median (median AUCss 605 ngh/mL) showed longer median OS than that in patients with an AUC below the median (n = 109), yet the difference did not reach statistical significance (OS: 88 vs. 69 weeks, p [ 0.05) [16]. In addition, daily AUC estimated by pharmacokinetic model at the end of 4 weeks of treatment was found to correlate significantly with the probability of response in mRCC patients, evaluated by logistic regression (n = 173, p \ 0.0001) [17]. Patients with an AUC C300 ngh/mL showed significantly longer median PFS and median OS than that in patients with an AUC \300 ngh/mL (PFS 13.8 vs. 7.4 months, p = 0.003; OS 37.4 vs. 15.8 months, p \ 0.001). However, further studies are still needed to confirm a pharmacokinetic target, and TDM based on AUC for axitinib may not be feasible in the clinic. One well-established biomarker for axitinib efficacy is diastolic blood pressure (DBP). Rini et al. [18] retrospectively evaluated the correlation between DBP C90 mmHg and efficacy in five phase II studies including four different tumour types [mRCC, non-small cell lung cancer (NSCLC), melanoma and thyroid cancer] (n = 230). The patients were separated into a DBP \90 or C90 mmHg group using the maximum DBP achieved by week 8. The authors concluded that the DBP C90 mmHg group was associated with a longer median OS (p \ 0.001), a longer median PFS (p = 0.107) and a higher objective response rate (ORR) (p \ 0.001) than that of the DBP \90 mmHg group throughout therapy. Besides, they also discussed that upwards dose adjustment among patients with DBP \90 mmHg and without grade 3/4 toxicities may improve clinical outcomes. Recently, a prospective controlled study of axitinib dosing according to the DBP target has been completed [19, 20]. In total, 112 mRCC patients with 2 consecutive weeks of blood pressure B150/90 mmHg, with no grade [2 axitinib-related toxicities, and with B2 antihypertensive medications were randomised to active (dose titration according to DBP) and control (fixed dosing)

TKIs: Which Levels to Target? Table 1 Overview of tyrosine kinase inhibitors approved by both the European Medicines Agency and US FDA by 28 February 2013, including fed/fasted condition required during administration of tyrosine kinase inhibitors Common name

Brand name

First approvala

Main indication(s)

Approved dose regimen

Approved coadministration

Fed/fasted

Axitinib

InlytaÒ

2012

RCC

5 mg bid (cdd)

–

NI [14]

Crizotinib

XalkoriÒ

2012

ALK? NSCLC

250 mg bid (cdd)

–

NI [27, 126]

Dasatinib

SprycelÒ

2006

CP CML AP, MB or LB CML; Ph? ALL

100 mg od (cdd) 140 mg od (cdd)

– –

NI [11]

Erlotinib

TarcevaÒ

2005

NSCLC

150 mg od (cdd)

–

F [127]

PC

100 mg od (cdd)

Gemcitabine

Gefitinib

IressaTM

2009

EGFR mutation? NSCLC

250 mg od (cdd)

–

NI [128]

Imatinib

Ò

Glivec or GleevecÒ

2001

Ph? CP CML; KIT? GIST

400 mg od (cdd)

–

WM [129]

Ph? AP CML; Ph? ALL

600 mg od (cdd)

(Chemotherapy)b

TykerbÒ

2008

HER2? BC

1,250 mg od (cdd)

Capecitabine

HER2? and HR- BC

1,000 mg od (cdd)

Trastuzumab

Lapatinib

Ò

F [130, 131]

HER2? and HR? BC

1,500 mg od (cdd)

Aromatase inhibitor

2007

CP Ph? CML

300 mg bid (cdd)

–

F [132, 133]

Nilotinib

Tasigna

Pazopanib Sorafenib

VotrientÒ NexavarÒ

2010 2006

RCC; STS RCC; HCC

800 mg od (cdd) 400 mg bid (cdd)

– –

F [94] CO [11]

Sunitinib

SutentÒ

2006

RCC; GIST

50 mg od (4/2)

–

NI [11]

pNET

37.5 mg od (cdd)

–

Vandetanib

CaprelsaÒ

2012

MTC

300 mg od (cdd)

–

NI [134]

Vemurafenib

ZelborafTM

2012

BRAF V600? melanoma

960 mg bid (cdd)

–

NI [135]

4/2 4-week dosing, followed by 2-week rest, ALK? anaplastic lymphoma receptor tyrosine kinase positive, ALL acute lymphocytic leukaemia, AP accelerated phase, BC breast cancer, bid twice daily, BRAF V600? BRAF V600 positive, cdd continuous daily dosing, CML chronic myeloid leukaemia, CO conflicting opinion, CP chronic phase, EGFR mutation? epidermal growth factor receptor mutation positive, F fasted, GIST gastrointestinal stromal tumour, HCC hepatocellular carcinoma, HER2? human epidermal growth factor receptor type 2 positive, HR- hormone receptor negative, HR? hormone receptor positive, KIT? proto-oncogene tyrosine-protein kinase positive, LB lymphoid blast, MB myeloid blast, MTC medullary thyroid cancer, NI not important, NSCLC non-small cell lung cancer, od once daily, PC pancreatic cancer, Ph? Philadelphia chromosome positive, pNET pancreatic neuroendocrine tumours, RCC renal cell cancer, STS soft-tissue sarcoma, WM with meal a

Information from the European Medicines Agency

b

In newly diagnosed Ph? ALL patients

arms. Significantly improved ORR was found in the active titration arm and control arm (54 vs. 34 %, p = 0.019); however, the median PFS showed no difference between these two arms (14.5 vs. 15.7 months, p = 0.244). These studies suggested that there might be a basis for dose titration according to DBP (see Table 4) [17–19, 21]. A study found that the linear correlation between AUC and DBP was poor (r2 \ 0.10), and AUC and DBP were independent predictors for efficacy [17]. As the measured DBP may show considerable intrapatient variability, dosing based on DBP may not be the most optimal dosing strategy. However, the possibility of dose titration based on exposure has not been confirmed. Therefore, dosing based on DBP is currently the best dose–individualisation strategy in axitinib-treated renal cell cancer (RCC) patients. Nevertheless, the application of TDM based on exposure is not ruled out.

2.2 Crizotinib Pharmacokinetic parameters of crizotinib have been reported to be linear from 100 mg once daily to 300 mg twice daily [22]. In vitro, crizotinib inhibited phosphorylation of nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) in Karpas299 (cells with the presence of a t(2;5) chromosomal translocation and expression of the NPM–ALK fusion protein) with a concentration producing 50 % inhibition (IC50) of 10.8 ng/mL (24 nmol/L) [23]. Another study found that the IC50 of NSCLC cells with EML4-ALK-E13A20 translocation (NCI-H3122) was 108 ng/mL (0.24 lmol/L) [24]. In a preclinical study (in mice), both Karpas299 ALK and H3122 NSCLC cells were implanted in mice [25]. By pharmacokinetic–pharmacodynamic modelling, the authors found that the plasma concentration of the drug producing 50 % of the maximal

[46, 49, 57]

Ctrough: 820a (105) ng/mL

60–64

[31, 32, 38, 144]

[22, 126, 142, 143]

[162–165] [120, 135]

50

Cmax: 42,000a (37) (26,000–58,000) ng/mL

1.2

[106, 108, 109, 160, 161] 100

Total Ctrough : 62.8 , 62.4–84.9 , 64.8–86.3 , 68 , 101 (51) ng/mL

[107, 116, 159]

[97, 98, 102, 103, 105, 157, 158]

[90, 91, 156]

[87, 88, 155]

[87, 133]

Ctrough: *1,000a, 1,497a (43) ng/mL

13.2

34–62

8.13

25.3

27.7

[65, 69, 73] [151–154]

f

e

d

c

b

a

A range of concentrations from different cycles at steady-state in the same study

Combined Ctrough of sunitinib and SU12662

Result from repeated dosing of dasatinib 70 mg

Median value of PK parameter observed at standard dose level

Mean value of PK parameter estimated at standard dose level

Mean value of PK parameter observed at standard dose level

%CV percentage coefficient of variation, AUC24 area under the plasma concentration–time curve from time zero to 24 h, bid twice daily, CL/F apparent total oral clearance, Cmax maximum plasma concentration, Ctrough trough plasma concentration, od once daily, PK pharmacokinetic, t half-life

960 mg bid

Vemurafenib

50 mg od

300 mg od

Vandetanib

a

40–60 c

Total Ctroughe: 45–62.8a,f (26–57), *50c ng/mL

37.5 mg od

Sunitinib c,f

Ctrough: 2,920a (32), 3,750a (104), 4,100a (74), 4,200c (2,800–5,600), 4,300c (±3,400) ng/mL

400 mg bid

Sorafenib c,f

25–48

Ctrough: 24,000a (67), 28,100a (11), 28,700c (24,600–30,900), 29,800c (10,300–75,000) ng/mL

800 mg od

Pazopanib

a

0.9

31

Ctrough: 900a, 998c, 1,165c, 1,190c, 1,239a (52) ng/mL

400 mg bid

e

29.3

Ctrough: 1,123 (64) ng/mL

300 mg bid

Nilotinib

17

24

Lapatinib a

Ctrough: 1,300c (600–3,500), 1,444a (49), 1,752a (45) ng/mL Ctrough: 780a (22), 780a (42) ng/mL

600 mg od 1500 mg od

[11, 12, 65–67, 69, 73, 149, 150]

18

Ctrough: 900c (400–1,600), 979a (54), 1,058a (53), 1,400a (41), 1,530a (44) ng/mL

400 mg od

Imatinib

11.8

[40, 46, 49, 57, 146] [58, 124, 128, 147, 148]

41

Ctrough: 130a (96), 266a (41), 291.2a (66), 406a (104–1,846) ng/mL

250 mg od

Gefitinib

150 mg od

Ctrough: 890a (29.2–3,470), 1,050a (49), 1,059a (52), 1,200a (52) ng/mL

[145] 30

4.47

578d

Cmax: 1,760 (26) ng/mL

a

36.2

Ctrough: 3.72b (28) ng/mL

140 mg od

100 mg od

Ctrough: 1a, 2.61b (26) ng/mL

100 mg od

Dasatinib

Erlotinib

[32, 38]

42 3–5

Ctrough: 256c, 274a ng/mL

[14, 17, 136, 137–141]

250 mg bid

Cmax: 21.4a (84), 27a (36), 27.0a (56), 27.8a (79), 31a (49), 39a (40), 41a (81), 41.9a (60), 44.6a (101), 63a (57), 63a (66), 68.0a (58) ng/mL

37.8

Crizotinib

4.09

AUC24: 154a (19), 258a (39), 265a (77), 276a (78), 300a (67), 375c (32.8–1,728), 380a (56), 404a (68), 416a (63), 416a (108), 451a (94), 466a (85), 781a (69) ngh/mL

References

5 mg bid

CL/F (L/h)

Axitinib

t (h)

Standard dose level

Common name

Steady-state meana,b (%CV or range) or medianc (range or ±median absolute deviation) PK parameters

Table 2 Pharmacokinetic parameters and pharmacokinetic variability for the different tyrosine kinase inhibitors

H. Yu et al.

Erlotinib

Dasatinib

Crizotinib

– 46

–

NSCLC

191

CP CML

–

H3122 NSCLC 567

–

Karpas299 ALCL

CP CML

–

56

mRCC

–

230

DBP C90 mmHg

176

mRCC, NSCLC, TC, melanoma

AUC C300 ngh/mL

173

mRCC

p = 0.351 (Cox hazard model) p = 0,127 (Cox hazard model)

Cumulative pleural effusion (17.4 vs. 6.9 %) Inhibition of EGFR OS PFS

Ctrough [1.5 ng/mL (3 nmol/L) at day 15

Preclinical target: Ctrough [about 500 ng/mL Serum Ctrough C1,810 ng/mL (4.60 lmol/L) after day 7

–

p = 0.021

p \ 0.01 (Cox proportional hazards model) Grade C1 pleural effusion

[56]

[49]

[39]

[32, 38]

p \ 0.01 (logistic regression model)

Ctrough

[25]

[25]

[27–30]

[19]

[18]

–

– MCR

EC50

EC50

–

p = 0.019 NG

ORR (54 vs. 34 %)

p \ 0.001 ORR (43.9 vs. 12.0 %)

p = 0.244

p = 0.107

Median PFS (10.2 vs. 7.1 months)


p \ 0.001

Median OS (25.8 vs. 14.9 months)

p = 0.006


wCavg,ss

233 ng/mL (in mice plasma)

666 ng/mL (in mice plasma)

Preclinical target: 120 ng/mL

Dose titration when BP B150/90 mmHg in 2 consecutive weeks, no grade [2 toxicity, no dose reduction, B2 antihypertensive medications

DBP C90 mmHg

p = 0.024


[17]

p \ 0.001 p = 0.003

[16]

[15]

References

p [ 0.05

Best response

Best response

Evaluation methods/indexes for PD (unless mentioned otherwise)



Median OS (88 vs. 69 weeks)

AUC [605 ngh/mL

109

Median PFS (28.3 vs. 7.5–11.8 months)

AUC12: 154–620 ngh/mL

mRCC

Median OS (NG vs. 20.3–27.7 months)

PD (with vs. without PK marker)

C1D1PC: 45.2–56.4 ng/mL

52

mRCC

PK/surrogate marker

Axitinib

N

Indication

Common name

Table 3 Summary of clinical exposure–response relationships established for different tyrosine kinase inhibitors in patients

TKIs: Which Levels to Target?

Lapatinib

ST

GIST with wild-type KIT or exon 9 mutated 67 ? 81

Diarrhoea

Free Ctrough [20 ng/mL

Dose ranging from 500 to 1,600 mg

RECIST complete response

Ctrough [1,100 ng/mL

12 38

OOBR (100 vs. 67 %) OOBR (67 vs. 67 %)


GIST with KIT exon 11 mutated GIST with KIT exon 9 mutated

39

73

GIST

Median TTP (30.6–33.1 vs. 11.3 months)

40 103

CML CML Ctrough [1,100 ng/mL

84

CML

[74]

[84, 85]

p \ 0.03 (linear regression)

[73]

[73]

[73]

[70, 71] [72]

[69]

[68]

[67]

[66]

[65]

[64]

[59]

[58]

[58]

References

ROC

p=1

p = 0.001

p = 0.0029

ROC ROC

p = 0.02

Compare Ctrough with or without CCyR: p = 0.045

CCyR

Ctrough [1,000 ng/mL (Ctrough with or without CCyR: 1,078 vs. 827 ng/mL)

MMR MMR

191

CML

Compare Ctrough with or without MMR: p = 0.002

p = 0.0120

MMR (74 vs. 59 %)

Ctrough [1,002 ng/mL (Ctrough with or without MMR: 1,107.4 vs. 872.7 ng/mL)

Ctrough [560 ng/mL Serum Ctrough [2,158 ng/mL

254

CML

Compare Ctrough with or without CCyR: p = 0.01

CCyR

Ctrough [1,000 ng/mL (Ctrough with or without CCyR: 1,009 vs. 812 ng/mL)

MMR (83.2 vs. 60.1 %)

351

CML

ROC Compare Ctrough with or without MMR: p \ 0.001

MMR


p = 0.0103

p = 0.0158

p = 0.016

p = 0.009


(Ctrough with or without MMR: 1,452 vs. 869 ng/mL)

Response (PR, SD, PDi)

Ctrough with PR or SD vs. with PDi: 1,117 vs. 520 ng/mL


68

CML

Median PFS (NG)

D8/D3 \1.587

44 20

NSCLC

HNSCC

Imatinib


Presence of any grade of rash

30


NSCLC

Ctrough C200 ng/mL

30


NSCLC

PK/surrogate marker

Gefitinib

N

Indication

Common name

Table 3 continued

H. Yu et al.

Sorafenib

HCC

OS (12.0 vs. 6.5 months)

Grade C2 hypertension

Serum concentration [4,780 ng/mL

36 Serum Cmax C4,780 ng/mL

Grade C2 hand–foot skin reaction

RCC, HCC

Serum concentration [5,780 ng/mL

51a

NG

Grade C3 toxicity

Cumulative AUC [3,161 lgh/mL (cumulative AUC with or without grade C3 toxicity: 3,499 vs. 2,250 lgh/mL)

PFS (NG)


52

54

ST

SUVmax

Ctrough EC50 of 4,800 ng/mL

p = 0.0824

ROC

ROC

Compare Ctrough with or without grade 3 toxicity: p = 0.0083

Compare cumulative AUC with or without grade C3 toxicity: p = 0.034

ROC

p = 0.16

Sigmoidal Emax model

p = 1.7e-5

RR (45 vs. 18 %)

Grade 3 toxicity

41

p = 4.1e-3

Best response

C40 % decrease

–

p = 0.009

PFS (49.4 vs. 20.3 weeks)

PR

One patient (800 mg od) with Ctrough *30,000 ng/mL Ctrough C20,600 ng/mL

IAUGC

Response (83 vs. 0 %)

Mean TTP (23 vs. 28 vs. 31 vs. 27 months)

Ctrough C20,000 ng/mL

Ctrough C15,000 ng/mL

(Ctrough: \469.4 vs. 469.4 to \771 vs. 771 to \1,113 vs. C1,113 ng/mL)

(serum Ctrough: \829 vs. 829–1,569 vs. [1,569 ng/mL) Ctrough [469.4 ng/mL

p [ 0.05

MMR (46.9 vs. 48.6 vs. 51.5 %)

Serum Ctrough [829 ng/mL

ROC Compare Ctrough with or without MMR: p = 0.0012

MMR

Ctrough [761 ng/mL


(Ctrough with or without MMR: 1,255.1 vs. 372.8 ng/mL)


PK/surrogate marker

Mean Ctrough with or without grade 3 toxicity: 7,700 vs. 4,400 ng/mL

23

205

RCC

Sarcomas

28

HCC

ST

10

157

Imatinib pre-treated CML

RCC

455

Newly diagnosed CML

Pazopanib

30

Imatinib pre-treated CML

Nilotinib

N

Indication

Common name

Table 3 continued

[103]

[102]

[101]

[98]

[97]

[92]

[91]

[90]

[88]

[87]

[86]

References


219

28

GIST

ST

Total Ctroughb = 50–100 ng/mL

AUCss

AUCss

PK/surrogate marker

p = 3e-9 (logistic regression)

SD –

p = 0.001 (distribution model)

OS Response, DLT

p = 0.06 (logistic regression)

p = 0.002 (logistic regression)

SD

p = 0.001 (Weibull probability

p = 0.01 (distribution model)

OS

TPP

p = 0.001 (Weibull probability

PR or CR

p = 1e-5 (logistic regression)

TPP


PR or CR


[108]

[106]

[106]

References

b

a


Plasma sample number

ALCL anaplastic large-cell lymphoma, AUC area under the plasma concentration–time curve, AUC12 AUC from time zero to 12 h, BP blood pressure, C1D1PC cycle 1 day 1 1–2 h post-dose concentration, CCyR complete cytogenetic response, CML chronic myeloid leukaemia, CP chronic phase, CR complete response, Ctrough trough plasma concentration, D8/D3 Ctrough on day 8 vs. Ctrough on day 3, DBP diastolic blood pressure, DLT dose-limiting toxicity, EC50 concentration of the drug producing 50 % of the maximal effect, EGFR epidermal growth factor receptor, Emax maximum effect, GIST gastrointestinal stromal tumour, HCC hepatocellular carcinoma, HNSCC metastatic squamous cell cancer of the head and neck, IAUGC initial area under the tissue gadolinium concentration–time curve, KIT tyrosine-protein kinase, MCR major cytogenetic response, mHNSCC metastatic squamous cell cancer of the head and neck, MMR major molecular response, mRCC metastatic renal cell cancer, NG not given, NSCLC non-small cell lung cancer, OOBR overall objective benefit rate, ORR objective response rate, OS overall survival, PFS progression-free survival, PD pharmacodynamics, PDi progressive disease, PK pharmacokinetic, PR partial response, RCC renal cell cancer, RECIST response evaluation criteria in solid tumours, ROC receiver operating characteristics, SD steady disease, ST solid tumours, SUVmax maximum standardised uptake value, TC thyroid cancer, TTP time to progression, wCavg,ss weighted average steady-state plasma concentration

Relevant preclinical results were given for those tyrosine kinase inhibitors lacking clinical research. No data available for vandetanib and vemurafenib

146

mRCC

Sunitinib

N

Indication

Common name

Table 3 continued

H. Yu et al.

TKIs: Which Levels to Target? Table 4 Guidelines for therapeutic drug monitoring of tyrosine kinase inhibitors Common name

Indication of suggested target

Starting dose regimen

Axitinib

RCC

5 mg bid (cdd)

Recommended therapeutic target

Recommended dose adjustment

Type

Target

Efficacy

DBP C90 mmHg

DBP \90 mmHg without DLT for consecutive 2-week periods: : to 7 mg bid or to 10 mg bid

Safety

DBP \105 mmHg

DBP [100 mmHg: antihypertensive treatment DBP[105 mmHg: ; to 3 mg bid or further to 2 mg bid

Crizotinib

NSCLC

250 mg bid (cdd)

Efficacy

Ctrough [233 ng/mLa

Ctrough \233 ng/mL: : to 400 mg bid

Dasatinib

CP CML

100 mg od (cdd)

Safety

Ctrough \2.5 ng/mL

Ctrough [2.5 ng/mL: ; 20 mg od/step

Erlotinib

NSCLC

150 mg od (cdd)

Efficacy

Ctrough [500 ng/mLa

Ctrough \500 ng/mL: : 25 mg od/step

PC

100 mg od (cdd) ? gemcitabine

Gefitinib

NSCLC

250 mg od (cdd)

Efficacy

Ctrough [200 ng/mL

Ctrough \200 ng/mL: : 250 mg od/step

Imatinib

CML

400 mg od (cdd)

Efficacy


Ctrough \target: : 200 mg od/step

600 mg od (cdd) Nilotinib

GIST

400 mg od (cdd)

Efficacy


Imatinib pretreated CML

400 mg bid (cdd)

Efficacy

Ctrough [761 ng/mL

Ctrough \761 ng/mL: : 150 mg bid/step

Pazopanib

RCC

800 mg od (cdd)

Efficacy


Ctrough \20,000 ng/mL: : 400 mg od/step

Sunitinib

RCC

50 mg od (4/2)

Efficacy

Total Ctroughb [50 ng/mL

Total Ctroughb less than efficacy target: : 12.5 mg od/step

GIST

37.5 mg od (cdd)

Safety

Total Ctrough \100 ng/mL

Efficacy

Total Ctroughb [37.5–50 ng/ mL Total Ctroughb \75–100 ng/ mL

Total Ctroughb greater than safety target: ; 12.5 mg od/step

Steady-state concentration ranging from 26,000 to 58,000 ng/mL

Steady-state concentration out of range: : or ; 240 mg bid/step

Safety Vemurafenib

BRAF V600? melanoma

960 mg bid (cdd)

b

Efficacy

No data available for lapatinib, vandetanib and sorafenib 4/2 4-week dosing, followed by 2-week rest, bid twice daily, BRAF V600? BRAF V600 positive, cdd continuous daily dosing, Ctrough trough plasma concentration, CML chronic myeloid leukaemia, CP chronic phase, DBP diastolic blood pressure, DLT dose-limiting toxicities, GIST gastrointestinal stromal tumour, NSCLC non-small cell lung cancer, od once daily, PC pancreatic cancer, RCC renal cell cancer, : increase, ; decrease a

Result based on preclinical data

b


effect (EC50) values to inhibit ALK in these models were 666 and 233 ng/mL, respectively, and to inhibit tumour growth were 875 and 255 ng/mL, respectively. The EC50 value for ALK inhibition was suggested as clinical pharmacokinetic target. The same group later translated this inhibition of ALK in tumour xenograft models to tumour inhibition in patients by pharmacokinetic–pharmacodynamic modelling and simulation, which revealed that (based on the simulations) dosages of 200 mg twice daily or 250 mg once daily were sufficient in patients since these dosage will cause sufficient inhibition of the phosphorylation of ALK in [70 % and hepatocyte growth factor

receptor (MET) in [90 % of the patients [26]. However, the assumptions involved in this quantitative translation (e.g. similar drug distribution or the difference established in tumour growth between xenograft model and in patients) still need to be validated. A target concentration of 120 ng/mL has been widely referred to as the preclinically defined target efficacious concentration for crizotinib [27–30]; however, no studies have been found to support this target. Compared with the mean Ctrough of *274 ng/mL (Table 2), this concentration is relatively low. Considering the mean Ctrough, widely referred to preclinical target (120 ng/mL) and the reported

H. Yu et al.

variability, we recommend 233 ng/mL (the EC50 value for ALK inhibition in H3122 NSCLC xenografts) of crizotinib as a target to start with TDM in NSCLC patients. However, further studies are needed to validate this proposed target concentration. 2.3 Dasatinib One report showed that the mean Ctrough of dasatinib was 1 ng/mL. From a single centre, more than 40 % of 645 Ctrough samples tested were found to be \1 ng/mL [31]. By population pharmacokinetic modelling, the mean Ctrough was estimated to be 2–3 ng/mL in a large population (100 mg once daily, n = 146; 140 mg once daily, n = 141) and was estimated for each dose regimen shown in Table 2 [32]. However, another study reported a small group of patients (n = 14) with a mean Ctrough of 78 ng/ mL, which was very high compared with other studies [33]. Dasatinib was proved to be a very potent inhibitor of breakpoint cluster region-Abl (Bcr-Abl). In an in vitro study, Deng et al. [34] found that dasatinib induces cell apoptosis with an IC50 \48.8 ng/mL (100 nmol/L) in 8/15 myeloma cell lines. This concentration was confirmed in another study in which the authors observed that transient exposure of three chronic myeloid leukaemia (CML) cell lines to 48.8 ng/mL (100 nmol/L) of dasatinib resulted in apoptosis in the majority of cells [35]. In a preclinical animal study employing pharmacokinetic/biomarker modelling, it was predicted that plasma concentrations of *15 ng/mL would inhibit 90 % of phospho-Bcr-Abl in vivo for humans [36]. No significant correlation between dasatinib Ctrough and response (efficacy or toxicity) could be identified in CML and acute lymphocytic leukaemia (ALL) patients from four phase II studies [37]. However, in another study including 567 patients with chronic phase (CP) CML, the dasatinib weighted average steady-state plasma concentration (wCavg,ss; calculated as Cavg,ss multiplied by the daily dose averaged over the duration of uninterrupted treatment expressed in percentage of nominal dose) was found to be correlated with efficacy and steady-state Ctrough was correlated with safety [32, 38]. Described by a logistic regression model, the probability of achieving major cytogenetic response (MCR) in CP CML was significantly higher (p \ 0.01) with increasing wCavg,ss. Described by a Cox proportional hazards model, grade C1 pleural effusion was significantly predicted by increased Ctrough (p \ 0.01) [32]. However, Ctrough was not associated with MCR [38]. By separating the patients by Ctrough into three quartiles of \2.5, 2.5–5 and [5 ng/mL, in each quartile, the rate of pleural effusion were 4 vs. 14 vs. 25 %, rate of dose reduction was 26 vs. 45 vs. 59 %, rate of dose interruption was 51 vs. 64 vs. 75 %, while the MCR was 69 vs. 63 vs.

62 %, respectively [38]. If we define a rate of dose interruption of about 50 % as a non-acceptable cut-off, then the Ctrough should not exceed 2.5 ng/mL in CP CML patients. Nevertheless, this cut-off should be cautiously interpreted in the clinic as it was derived from a mixed dosing regimen. Another study has also suggested a correlation between Ctrough and toxicity [39]. In 191 patients with CP CML, Ctrough [1.5 ng/mL (3 nmol/L) at day 15 was significantly associated with increased risk of cumulative incidence of pleural effusion by 24 months (17.4 vs. 6.9 %, p = 0.021). Although wCavg,ss was suggested to predict efficacy [32, 38], TDM based on wCavg,ss is not feasible clinically. Besides, Ctrough should not exceed 2.5 ng/mL in CP CML patients [38]. 2.4 Erlotinib Thus far, no studies have shown a significant correlation between erlotinib drug exposure and response (Table 3). Mita et al. [40–43] (n = 42) and Pe´rez-Soler et al. [40–43] (n = 57) in patients with NSCLC, and Thomas et al. [40– 43] (n = 42) and Calvo et al. [40–43] (n = 25) in patients with head and neck cancer could not find a significant relationship between erlotinib plasma concentrations and response to treatment. In a phase II study in patients with recurrent or metastatic squamous cell cancer of the head and neck (HNSCC) (n = 115), Soulieres et al. [44] found that the median Ctrough of erlotinib (about 950 ng/mL) seemed to predict improved OS, although this did not reach statistical significance (p = 0.09). In preclinical studies, Yeo et al. [45] reported that erlotinib-inhibited epidermal growth factor receptor (EGFR) mutation NSCLC cell lines displayed activity and sensitivity at concentrations of 215 ng/mL (0.5 lmol/L). By using a human NSCLC tumour xenograft model, an erlotinib concentration of 1,100 ng/mL was expected to induce 80 % inhibition of tumour growth, but this threshold has not been evaluated in humans and it is very high compared with the observed therapeutic concentration range of erlotinib (Table 2) [46]. Moyer et al. [47] proved that 393 ng/mL (1 lmol/L) of erlotinib completely blocked DiFi human colon tumour cell proliferation, and led to apoptosis and cell cycle arrest. Besides, the EC50 in plasma to inhibit EGFR was estimated at 3,100 ng/mL (8 lmol/L) by orally administrated erlotinib in EGFR-associated phosphotyrosine of the HN5 xenografts mice model [48]. Later on, Hidalgo et al. [49] summarised the preclinical studies and suggested that a target Ctrough of approximately 500 ng/mL in humans was adequate to reach EGFR inhibition at a relevant degree of anti-proliferative activity after correction by interspecies differences. This target was widely referred to later in other studies [50–53].


What is worth noticing is that there is a large number of studies indicating a positive correlation between skin toxicity and clinical benefit in NSCLC patients [40, 44, 54– 56]. For example, Soulieres et al. [44] compared patients who developed grade C2 skin rash with those who did not, and found that OS was longer in patients with grade C2 rash (p = 0.045, n = 115). The median Ctrough in patients with grade C2 rash compared with those with grade \2 rash was not significantly different (803 vs. 1,097–1,126 ng/mL, p = 0.49). One study used dosing based on the occurrence of grade 2 rash in 42 NSCLC patients [40]. However, grade 2 rash was present already in the majority of patients (79 %) at the starting dose (150 mg) and dose escalation (with an additional 25 mg/ day) of erlotinib to reach grade 2 rash did not result in an increased response rate (RR). Some studies showed an association between the plasma concentrations and skin toxicity [49, 57], but without clearly establishing a cut-off. Very recently, Tiseo et al. [56] reported an exposure–toxicity receiver operating characteristics (ROC) curve analysis in NSCLC patients, in which a best erlotinib Ctrough before the eighth dose in predicting skin toxicity (grade 0–2 vs. grade 3) was 1,810 ng/mL (4.60 lmol/L) with a sensitivity of 70 % and a specificity of 70 %. However, this cut-off was not proved to predict response by Cox’s hazard model (PFS: p = 0.127; OS: p = 0.351). Therefore, currently, no definitive pharmacokinetic target for erlotinib has been established. Considering the observed concentration range in clinical practice and the preclinical knowledge of inhibition of EGFR, a Ctrough of 500 ng/mL seems justified to be the target concentration to start with TDM. 2.5 Gefitinib A few studies explored the exposure–response relationship for gefitinib (Table 3). Zhao et al. [58] showed that in patients with advanced NSCLC, 10 % with mutated EGFR and 90 % with wild type EGFR (total n = 30, mean Ctrough 266 ng/mL), a Ctrough C200 ng/mL was associated with significantly longer median OS (14.6 vs. 4.7 months, p = 0.009) and a higher incidence of rash (85.7 vs. 42.9 %, p = 0.043) than in patients with a Ctrough \200 ng/mL. In patients with wild-type EGFR (n = 27), a Ctrough C200 ng/mL predicted higher median OS (16.8 vs. 4.1 months, p = 0.002). The presence of an exposure–response correlation was also shown in patients with EGFR-mutated and wild-type NSCLC (n = 44, median Ctrough on day 3 was 662 ng/mL and on day 8 was 1,064 ng/mL) by Nakamura et al. [59]. The authors used a ratio D8/D3, which was defined as Ctrough on day 8 over Ctrough on day 3, as a pharmacokinetic marker. High D8/D3 (D8/D3 [1.587) was significantly associated

with better median PFS compared with that of low D8/ D3 (D8/D3 \1.587) (p = 0.0158). However, the hypothesis of applying the aforementioned pharmacokinetic marker is not very clear, and this approach is not very feasible for TDM. In addition, in a preclinical study, Yeo et al. [45] found that, similar to erlotinib, gefitinib concentrations of 223 ng/mL (0.5 lmol/L) can actively inhibit mutated EGFR NSCLC cell lines. However, this concentration has not been tested as a target concentration in humans. Similar to erlotinib, it has been suggested that the occurrence of skin rash is a predictor of gefitinib efficacy in patients with advanced NSCLC, which has been confirmed in numerous studies [41, 60–63]. Toxicity-guided dosing has been tested by dose escalation of 250 mg per step up to 750 mg to target grade 2 rash in 44 patients with head and neck cancer [64]. However, no increased activity was observed. In this study, Ctrough levels were measured in 20 patients. It was found that patients with partial response (PR) or stable disease (SD) (n = 5) showed higher Ctrough levels than those with progressive disease (n = 15) (1,117 vs. 520 ng/mL, p = 0.0103). There is no definitive exposure–response relationship established for gefitinib in EGFR-mutated NSCLC (approved indication). However, based on the studies listed above, and reported mean Ctrough and its associated variability (Table 2), a Ctrough of 200 ng/mL may be used for TDM in patients with NSCLC. 2.6 Imatinib In 68 patients with CML, Picard et al. [65] reported an exposure–effect ROC curve analysis showing that the threshold for imatinib Ctrough should be set at 1,002 ng/mL since this threshold was associated with a major molecular response (MMR) with a sensitivity of 77 % and specificity of 71 %. In a 5-year follow-up report of the IRIS (International Randomized Study of Interferon and STI571) trial, which included 351 patients with CML, Larson et al. [66] retrospectively showed that on day 29 an imatinib Ctrough [1,000 ng/mL was predictive of a complete cytogenetic response (CCyR) and MMR. Besides, Takahashi et al. [67], by studying 254 Japanese patients with CML, confirmed that patients with a Ctrough [1,002 ng/mL showed a higher probability of achieving an MMR than those with a Ctrough \1,002 ng/mL (p = 0.0120). Similarly, Marin et al. [69] (n = 84) and Koren-Michowitz et al. [68] (n = 191) suggested that the probability of response with a Ctrough \1,000 mg/mL was significantly lower. In smaller studies [70, 71] or using serum trough concentration [72], other thresholds have been used (see Table 3); however, a plasma Ctrough of 1,000 ng/mL as the pharmacokinetic target for imatinib-treated CML is currently recommended.

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In 73 patients with gastrointestinal stromal tumour (GIST), Demetri et al. [73] reported that patients with a steady-state Ctrough [1,100 ng/mL had a significantly longer time to tumour progression (TTP) (p = 0.0029) and larger overall objective benefit rate (OOBR) (p = 0.001), in GIST patients with tyrosine-protein kinase (KIT) exon 11 mutation, than patients with a Ctrough \1,100 ng/mL. Besides, the authors found that non-significance differences in OOBR were reached for patients with KIT exon 9 mutation with same cut-off in Ctrough, suggesting that a higher pharmacokinetic target may be needed for patients with exon 9 mutation. However, this suggestion has not been confirmed yet. In another study, Widmer et al. [74] did not find a significant association between total drug Ctrough and response in 36 patients with GIST. However, a cut-off value for Ctrough of 20 ng/mL free drug was found to correlate with complete response (CR) with the best sensitivity (86 %) and specificity (100 %) in KIT exon 9mutated and wild-type proto-oncogene patients. Further, a modelling approach to predict the free imatinib concentrations was presented in a population of 49 patients [75]. The same group recently explained that free Ctrough of imatinib is to be preferred over total Ctrough in TDM in GIST patients [76], by explaining a previous report of significantly lowered total concentrations after 90 days of imatinib treatment (n = 50) [77], which was possibly due to decreased protein concentrations in plasma over time and, hence, a decreased plasma concentration of imatinib [76, 78]. However, a free Ctrough target has not been validated in larger populations. Therefore, a total Ctrough of 1,100 ng/mL is currently suggested to be used as the pharmacokinetic target for imatinib-treated GIST. Exposure–toxicity studies found that toxicities such as fluid retention, rash, myalgia and anaemia are related to high plasma concentrations, but not all toxicities correlated with plasma concentration [66, 68]. It was also found that toxicity had a significant negative influence on adherence, which may be the predominant reason for inability to obtain adequate response [69, 79]. However, there is no clear pharmacokinetic cut-off related to intolerable toxicities. For the patients with a Ctrough \target (1,000 or 1,100 ng/mL), a dose increment is advised to 600 or 800 mg once daily [68]. An alternative approach for CML patients with treatment resistance on imatinib (with adequate drug exposure) is to switch therapy to a secondgeneration TKI such as nilotinib and dasatinib, which is reported to be a better option than an imatinib dose increment for some patients [68, 80]. Recently, prospective trials have been initiated to evaluate whether TDM can improve long-term response in CML patients [e.g. the I-COME (Imatinib Concentration Monitoring Evaluation] trial started in Switzerland, and

OPTIM IMATINIB in France] [81–83]. In the I-COME trial (accrual completed), 300 patients with CML were expected to be enrolled with 1 year of follow-up. Dosage adjustment was performed in the intervention group when Ctrough was B750 and C1,500 ng/mL in order to reach the pharmacokinetic target of 1,000 ng/mL. In the control arm, monitoring services were only applied in case of poor efficacy or toxicity. For the OPTIM IMATINIB study (ongoing), 200 patients with CML were expected to be included with 1 year of follow-up. Patients with an imatinib Ctrough \1,000 ng/mL after 1 month of treatment with 400 mg once daily were randomised into two groups, one without dose adjustment and one with dose adjustment, until the optimum plasma concentration was reached. Patients with an imatinib Ctrough [1,000 ng/mL continued their treatment. The results of above-mentioned trials have not been published yet. 2.7 Lapatinib Exposure–response relationships for lapatinib have not been identified yet. Lapatinib was reported to be well-tolerated at doses ranging from 175 to 1,800 mg once daily or 500 to 900 mg twice daily [84, 85]. In one phase I study it has been reported that the majority of responders had Ctrough values in the range of 300–600 ng/mL (n = 67 metastatic solid tumour patients) [84]. However, the results are difficult to interpret due to limited response data and a heterogeneous population. As for the most common drugrelated toxicity, the occurrence of diarrhoea was positively related to dose (p \ 0.03) but not with serum concentration [84], which was in agreement with another phase I study (n = 81) [85], and presence of rash showed no apparent relationship with both dose and serum concentration [84]. Thus far, no Ctrough targets for efficacy or toxicity have been established. Therefore, the mean steady-state Ctrough of around 780 ng/mL at standard dose (1,500 mg) in the clinic is currently the only reference value available for TDM. TDM-based dose adaptations based on this target cannot be recommended yet. 2.8 Nilotinib In 30 Japanese patients with imatinib-resistant or -intolerant (CP or accelerated phase) CML without Bcr-Abl1, plasma Ctrough was found to be significantly higher in 21 patients with an MMR than in nine patients without an MMR (median Ctrough 1,255.1 vs. 372.8 ng/mL, p = 0.0012) [86]. A target plasma Ctrough was defined as 761 ng/mL, which was significantly associated with an MMR by 12 months on a ROC curve with a sensitivity of 76.2 % and specificity of 77.8 %. In a large study, the exposure–response relationship, in patients with newly


diagnosed CP Philadelphia chromosome positive (Ph?) CML, was explored with model-predicted steady-state serum AUC and Ctrough, which were used as exposure markers (n = 455) [87]. No significant relationships (p [ 0.05) were found between the nilotinib Ctrough and MMR rate at 12 months, although the MMR rate increased according to increased serum Ctrough (Ctrough \829 ng/mL: 46.9 %; Ctrough 829–1,569 ng/mL: 48.6 %; Ctrough [1,569 ng/mL: 51.5 %). For the exposure–toxicity relationship, the authors found a significant positive correlation between AUC and all-grade elevations in total bilirubin, and a correlation between AUC and all-grade toxicities related to haemoglobin reductions and lipase elevation. Besides, regarding cardiac toxicities, every 1,000 ng/mL increase in serum Ctrough showed a 6.9-ms increase in Fridericia-corrected QT interval (QTcF) on electrocardiograms from baseline. The same group later presented the first report on the exposure–response relationship in patients with imatinib-resistant or -intolerant CML [88]. It was shown that patients with a Ctrough [469.4 ng/mL presented significantly longer TTP than those with a Ctrough \469.4 ng/mL (p = 0.009, n = 157). Besides, no significant differences were found in CCyR and MMR when scaling patients by Ctrough, although a lower Ctrough tended to associate with lower CCyR and MMR rates at 12 and 24 months. Based on presented targets and the steady-state nilotinib mean Ctrough (Table 2), a target Ctrough of 761 ng/mL is recommended for TDM in clinical practice [86]. This target, established in imatinib pre-treated CML patients, could be lower than the suggested target in imatinib-naı¨ve patients. Therefore, it is proposed to use this target in imatinib pre-treated CML patients. 2.9 Pazopanib In preclinical studies, optimal inhibition of tumour angiogenesis was observed when a plasma pazopanib concentration [17,500 ng/mL (40 lmol/L) was maintained over the entire dosing interval [89]. A pharmacokinetic target in the same concentration range has been identified in clinical studies. In a phase I study (solid tumours, n = 63), Hurwitz et al. [90] showed that patients with a Ctrough C15,000 ng/mL had a markedly higher incidence of hypertension (77 vs. 39 %) than patients with a Ctrough \15,000 ng/mL, and a Ctrough C15,000 ng/mL was also suggested to correlate with clinical activity. As stated by the authors, 83 % (5/6) of RCC patients with responses achieved a Ctrough C15,000 ng/mL, and 100 % (4/4) of RCC patients with progressive disease had a Ctrough \15,000 ng/mL. In another phase I study in patients with hepatocellular carcinoma (HCC) (n = 28), Yau et al. [91] showed that a larger decrease in dynamic contrast-

enhanced magnetic resonance imaging (DCE-MRI) parameters [e.g. the initial area under the tissue gadolinium concentration–time curve (IAUGC)] was associated with a higher pazopanib Ctrough, with patients that presented above 40 % decrease in IAUGC having pazopanib Ctrough C20,000 ng/mL. Based on the data from a phase II study (pharmacokinetic data available for 205 patients), Suttle et al. [92] reported that RCC patients with a Ctrough C20,600 ng/mL at week 4 showed significantly longer PFS, higher RR and more extensive tumour shrinkage than those with a Ctrough \20,600 ng/mL (PFS 49.4 vs. 20.3 weeks, p \ 0.005; RR 45 vs. 18 %, p \ 0.00002). Exploring the same data, the authors studied the relationship between exposure and adverse events, whereby they found that certain adverse events, e.g. diarrhoea, increase of alanine aminotransferase, hand–foot syndrome and stomatitis, increased with Ctrough [93]. Based on the aforementioned targets found in clinical studies, in our opinion, the argument for TDM of pazopanib is sufficiently set, as is the target Ctrough of 20,000 ng/ mL. However, it was suggested that increasing dose levels above 800 mg is not likely to result in further increased plasma concentrations judged from the population mean [90, 94], which may complicate TDM. Nevertheless, individual patients may still benefit from dose increments above 800 mg once daily. A prospective study investigating the feasibility of TDM of pazopanib based on this target is ongoing [95]. 2.10 Sorafenib A significant relationship between exposure and antitumor activity for sorafenib has not been established yet (Table 3) [11, 96]. Correlation between steady-state Ctrough (day 28) and maximum standardised uptake value (SUVmax) relative to baseline [quantified from fluorodeoxyglucose positron emission tomography (FDG-PET)] was found in 23 Japanese patients with solid tumours by an sigmoidal maximum effect (Emax) model (Hill model) [97]. Increased Ctrough was associated with reduced SUVmax with an EC50 of 4,800 ng/mL. However, SUVmax has only been suggested as a possible surrogate marker of response. Besides, in a phase II study, Maki et al. [98] found no difference in PFS between patients with Ctrough above median (4,300 ng/mL) or below it (p = 0.16, n = 41). In a preclinical study, Kuckertz et al. [99] presented dose-dependent effects of sorafenib in freshly isolated chronic lymphocytic leukaemia cells, in which sorafenib was found to uniformly induce cell apoptosis with an IC50 of about 3,700 ng/mL (8 lmol/L). Furthermore, at the clinically relevant plasma concentration of 4,650 ng/mL (10 lmol/L) [100], sorafenib increased apoptosis of cells by more than 50 % compared with control [99]. One clinical study investigated an

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Fig. 1 Graphical representation of observed mean Ctrough values and suggested target Ctrough values for different tyrosine kinase inhibitors with well-established exposure response relationships. Solid lines indicate the mean weighted difference between observed and target Ctrough (%), calculated as (weighted Ctrough level - target level)/ target level 9 100. Circles represent the difference between observed

and target Ctrough for each study (%), calculated as (Ctrough level of each study - target level)/target level 9 100. The various colours differentiate the size of the studies: n = 1 to \10: black; n C10 to \50: red; n C50 to\100: green; n C100: blue. CML chronic myeloid leukaemia, Ctrough trough plasma concentration, GIST gastrointestinal stromal tumour, RCC renal cell cancer

exposure–toxicity relationship in 54 patients with advanced solid tumour [101]. The authors found that increased cumulative AUC was present in patients with grade C3 toxicity compared with patients without grade C3 toxicity (3,499 vs. 2,250 lgh/mL, p = 0.034). By using an ROC curve, the highest risk for developing any grade C3 toxicity was associated with the threshold cumulative AUC of 3,161 lgh/mL. Another study found that Ctrough in patients exhibiting grade 3 toxicity was significantly higher than that observed in control patients (7,700 ± 3,600 vs. 4,400 ± 2,400 ng/mL, p = 0.0083) (sample n = 51) [102]. In addition, Fukudo et al. [103] reported that a random point of sorafenib steady-state serum concentration was a predictor for grade C2 hand–foot skin reaction and hypertension in Japanese patients with RCC or HCC. It was found that the optimal cut-off concentrations predicting grade C2 hand–foot skin reaction and hypertension were estimated to be 5,780 and 4,780 ng/mL, respectively, by ROC analysis (n = 52). Besides, HCC patients with a Cmax C4,780 ng/mL presented a numerically longer OS than that in patients with a Cmax \4,780 ng/mL (12.0 vs. 6.5 months, n = 36, log-rank p = 0.0824). Exposure of sorafenib was found to decrease over time [103–105]. For example, it has been reported that the AUC of sorafenib significantly decreased from a median of 60.3 lgh/mL at 1 month of treatment to 43.0 lgh/mL at 3 months of treatment (decrease about 29 %) [104]. The median AUC further decreased to 33.2 lgh/mL at the time of disease progression in HCC patients receiving a fixed dose (200 mg twice daily or 400 mg twice daily) (n = 15). In

another study, AUC, Cmax and Ctrough were decreased about 16, 20 and 22 %, respectively, after 113 days compared with that at 29 days of treatment [105]. No target dose of sorafenib for efficacy has been defined yet. A Ctrough target of [3,750–4,300 ng/mL, which is the range of the means/medians of observed Ctrough (Table 2) [98], has been suggested to be efficacious, which is also supported by preclinical studies (about 3,700 ng/mL) [99]. However, dose adaptations based on this target cannot be recommended yet. 2.11 Sunitinib An exposure–response relationship was presented by Houk et al. [106] for sunitinib treatment in an extensive metaanalysis containing 443 matched pharmacokinetic–pharmacodynamic data in patients with mRCC, GIST or other solid tumours treated with sunitinib doses ranging from 25 to 150 mg given once daily or once every other day in three different treatment schedules [4-week dosing, followed by 2-week rest (4/2), 2-week dosing, followed by 2-week rest (2/2) and 2-week dosing, followed by 1-week rest (2/1)]. By using a Weibull probability distribution model, the authors found that in mRCC patients sunitinib AUCss significantly correlated with PR or CR (p = 1e-5), TTP (p = 0.001), OS (p = 0.01) and probability of SD (p = 0.002). In GIST patients, sunitinib AUCss significantly correlated with TTP (p = 0.001), OS (p = 0.001) and probability of SD (p = 3e-9) but not with PR or CR (p = 0.06).


AUC and Ctrough have proved to be proportional to dose levels ranging from 25 to 100 mg once daily [107, 108] and Ctrough was stated to highly correlate with AUC by linear regression (r2 = 0.8–0.9) [109, 110], indicating that the correlation of Ctrough with response could be similar to that of AUC; hence, a TDM service could be provided based on the Ctrough target. Concentrations of sunitinib and its active metabolite (SU12662) were normally considered together as a total active concentration in studies investigating the exposure–response relationship of sunitinib. A target of total Ctrough was deduced as 50–100 ng/mL from preclinical and retrospective clinical trials [106, 108, 111–114]. For example, one preclinical experiment performed by Mendel et al. [112] reported that the minimum plasma concentrations required to block Flk-1/KDR (fetal liver kinase 1–kinase insert domain receptor) and plateletderived growth factor receptor (PDGFR)-phosphorylation in vivo were obtained at concentrations at or above 50–100 ng/mL. Data from vascular endothelial growth factor (VEGF)-induced vascular permeability assays supported the identification of 50–100 ng/mL as the minimum plasma concentration required to inhibit Flk-1/ KDR function in vivo [112]. In a retrospective clinical study, Faivre et al. [108] demonstrated in 28 patients that most patients with an objective response had a total Ctrough value above 50 ng/mL and most patients with dose-limiting toxicity had a total Ctrough value above 100 ng/mL. By correlating the total Ctrough with DBP elevation by sigmoidal Emax model, an EC50 of 84 ng/mL was defined [106]. In an individual pharmacokineticguided sunitinib study that included 30 patients with solid tumours, the percentage of patients that reached total Ctrough of 50 ng/mL increased from 44 to 56 % by adjusting dosage, indicating the feasibility of TDM for sunitinib [115]. Based on these data, with a dosing regimen of 50 mg once daily (4/2), the total Ctrough (combined sunitinib with SU12662) of [50 and \100 ng/mL as pharmacokinetic target in RCC seems justified. In GIST patients, administration of 37.5 mg once daily continuously instead of 50 mg once daily (4/2) may be as effective with less toxicity [116, 117]. For this indication, it is logical to use a lower target than that for 50 mg once daily (4/2). However, a threshold has not been studied in GIST thus far. Considering the linearity of Ctrough with dose levels [108] and proved significant exposure–response correlation [106], we recommend an extrapolated target as total Ctrough of [37.5–50 ng/mL for efficacy and \75–100 ng/mL for safety in GIST patients administered 37.5 mg once daily continuously.

2.12 Vandetanib Thus far, no clear exposure–response relationship has been proposed for vandetanib. In preclinical studies, the IC50 for VEGF-2 was 19 ng/mL (40 nmol/L); for EGFR 238 ng/mL (500 nmol/L); for rearranged during transfection (RET)derived oncoproteins 48 ng/mL (100 nmol/L); for prevention of VEGF-induced proliferation in human primary endothelial cells 29 ng/mL (60 nmol/L); and for different tumour cell growth it ranged from 1,283 ng/mL (2.7 lmol/ L) (A549) to 6,417 ng/mL (13.5 lmol/L) (Calu-6) in vitro [118, 119]. Vandetanib completely inhibited the proliferation of RET/papillary thyroid carcinoma 3 (PTC3)-transformed cells at a concentration of 2,377 ng/mL (5 lmol/L) and strongly reduced RET/PTC3 mitogenic effect at a concentration of 238 ng/mL (0.5 lmol/L) [119]. Comparing the preclinical results with clinical pharmacokinetic parameters presented in Table 2, we noticed that the steady-state Ctrough of vandetanib (*1,000–1,497 ng/mL), at the current fixed dosing regimen, exceeded most of the preclinical targets for anti-tumour efficacy. However, further exposure–response studies are recommended. Considering the long half-life (approximately 100 h) and large pharmacokinetic variability, a sample for TDM of vandetanib can be taken at a random sampling time point. 2.13 Vemurafenib Thus far, no significant exposure–response relationship has been proposed for vemurafenib. In a phase I trial, vemurafenib was reported to be well-tolerated at 960 mg twice daily [120]. The steady-state Cmax in these patients (n = 32) ranged from 26,000 to 58,000 ng/mL. This Cmax is much higher than the IC50 value of 15.2 ng/mL (31 nmol/L) for the mutated BRAFV600E and 49.0 ng/mL (100 nmol/L) for wild-type BRAF [121]. No distinction was made between the responders and non-responders and the effect of food on the absorption was not taken into account. Drug-related toxicities such as arthralgia, rash, squamous-cell carcinoma, nausea, fatigue and photosensitivity reactions were all dose related. However, it is unknown whether these adverse effects are related to plasma concentrations. In the clinical trials conducted with vemurafenib monotherapy, the toxic effects were managed by interruption of treatment or dose reductions to 720 or 480 mg twice daily until improvement to grade 1 or to baseline status [120, 122, 123]. No Ctrough or Cmax targets for efficacy or toxicity have been established. Since the half-life of vemurafenib is very long (approximately 50 h) and the drug is given twice daily, we recommend a vemurafenib steady-state

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concentration in the range of 26,000–58,000 ng/mL as the pharmacokinetic target, based on the Cmax determined in a clinical trial in which high responses were achieved [120].

3 Discussion Although proposed as pharmacokinetic targets for TKIs (Table 4), most of the targets are still required to be validated by prospective studies in various clinical centres. When adopting this dose advice in the clinic, one should be aware that there are shortcomings of the clinical studies on which the pharmacokinetic targets were based, i.e. limited cohort of patients, relatively short observation time or mixed diagnosis, etc. It should be noted that clear target concentrations have not been established for all TKIs or all indications. Due to the fact that TKIs are used as a specific targeted therapy, it might be important to group the population by relevant mutation status or previous treatment. However, there are only few studies considering relevant mutation status or previous treatment when establishing exposure–response relationship [73, 74, 86, 88]. Besides, it is advocated that preclinical target concentrations can be further confirmed in early clinical trials, in which case TDM might be beneficial to a broader population at an earlier stage. Nevertheless, protein binding should be taken into consideration when extrapolating pharmacokinetic targets from preclinical studies into humans. In addition to a few suggestions regarding the application of TDM for TKIs, we compared previously reported mean/ median Ctrough concentrations in clinical trials and suggested Ctrough efficacy targets in relative percentages (Fig. 1). Weighted Ctrough (wCtrough) levels were introduced which represented the mean Ctrough levels for the whole population presented in Table 2 (studies with unknown population size were not included). On the basis of data presented (Fig. 1), we found that the mean observed Ctrough levels for the whole population (presented as wCtrough levels) were higher than all suggested Ctrough targets for different TKIs, which was also true for most individual studies. This fact indicated that patients with a Ctrough exceeding the population mean have sufficient exposure. There were only a few exceptions shown in Fig. 1. One study of gefitinib revealed a much lower mean Ctrough than the suggested target; however, the size of this study was very small (n = 6) [124]. For imatinib, the observed mean Ctrough is very close to the suggested targets. There are studies indicating that the target concentrations suggested for imatinib are relatively high [70, 71, 125]. From the data as presented in Fig. 1, it can be concluded that it is reasonable to expect that for most TKIs (including new drugs) a plasma concentration around the observed mean Ctrough could be sufficient to be used as a reference to start with in a TDM service.

4 Conclusion As presented in this review, even though TDM of TKIs is still in its infancy, evidence has been accumulated to suggest that dose adjustment based on pharmacokinetic targets might be beneficial for patients treated with most TKIs. For imatinib, sunitinib and pazopanib, cohort studies to evaluate the feasibility and efficacy of routine TDM are completed, ongoing or planned, based on the hypothesis that TDM will increase efficacy and/or decrease toxicity. Also for other TKIs, it is important to confirm proposed target values. Thereafter, TDM could be eventually be brought into daily practice. Funding and conflicts of interest No sources of funding were used to assist in the preparation of this manuscript. The authors declare no conflict of interest.

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