Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

Masatomo Miura

doi:10.1248/bpb.b15-00103

Abstract

Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). According to European LeukemiaNet recommendations, the clinical response of CML patients receiving TKI therapy should be evaluated after 3, 6, and 12 months. For patients not achieving a satisfactory response within 3 months, the mean plasma concentration for the three months of TKI administration must be considered. In TKI therapy for CML patients, therapeutic drug monitoring is a new strategy for dosage optimization to obtain a faster and more effective clinical response. The imatinib plasma trough concentration (C₀) should be set above 1000 ng/mL to obtain a response and below 3000 ng/mL to avoid serious adverse events such as neutropenia. For patients with a UGT1A1*6/*6, *6/*28, or *28/*28 genotype initially administered 300–400 mg/d, a target nilotinib C₀ of 500 ng/mL is recommended to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1*1 allele initially administered 600 mg/d, a target nilotinib C₀ of 800 ng/mL is recommended. For dasatinib, it is recommended that a higher C_max or C₂ (above 50 ng/mL) to obtain a clinical response and a lower C₀ (less than 2.5 ng/mL) to avoid pleural effusion be maintained by once daily administration of dasatinib. Although at present clinicians consider the next pharmacotherapy from clinical responses (efficacy/toxicity) obtained by a fixed dosage of TKI, the TKI dosage should be adjusted based on target plasma concentrations to maximize the efficacy and to minimize the incidence of adverse events.

1. INTRODUCTION

Therapeutic drug monitoring (TDM) is carried out by evaluating the drug concentration in biological fluids to provide individual treatment through dose-adjustment to improve efficacy or avoid adverse events and to transition from an ineffective treatment to a clinical effect. However, to carry out TDM, therapeutic target ranges indicating exposure-response (efficacy/toxicity) relationships must be determined. For patients who do not achieve a CCyR or MMR at each time point, the plasma concentration of these TKIs must be adequately considered, and mutations in the BCR-ABL kinase domain should also be analyzed.⁶⁾ TDM is considered a dosing optimization tool to obtain faster clinical responses such as CCyR or MMR with TKIs. The aim of this paper is to review the exposure–response relationships of imatinib, nilotinib, and dasatinib from our previous studies and to describe new strategies for pharmacotherapy in CML treatment to avoid unnecessary complications and potentially achieve a cure.

2. IMATINIB TDM

After oral administration, imatinib is rapidly and completely absorbed with a bioavailability of 98.3%,⁷⁾ after which it is extensively metabolized to the N-desmethyl derivative CGP74588 (N-desmethylimatinib) by CYP 3A4,^8,9) and up to 80% of the administered dose is excreted in the feces as metabolites or unchanged drug by the agency of ATP-binding cassette (ABC) transporters, such as the breast cancer resistance protein (BCRP) or P-glycoprotein.¹⁰⁾ In addition to inter-patient variability of the activity of enzymes or transporters related to imatinib pharmacokinetics, factors such as age, gender, body size, liver, and renal function, drug interactions, and adherence to therapy are also causes of individual differences in imatinib plasma concentration.¹¹⁾ Consequently, the steady-state plasma trough concentration (C₀) of imatinib obtained 24 h after administration of a 400 mg standard daily dose ranged from 109 ng/mL to 4980 ng/mL,^11–20) and ranged from 140 ng/mL to 2457 ng/mL when limited to Japanese CML patients.^21–26) In Japanese CML patients, the inter-patient imatinib C₀ coefficient of variation (CV) ranged from 38.2% to 62.9%.^21–25) Several studies have investigated whether the imatinib C₀ reflects the clinical response of patients taking imatinib, namely exposure–response relationships.^{11,12,20–22,25–30)} In Japanese CML patients, we have reported that the imatinib C₀ was significantly higher in patients with a MMR than in those without a MMR; the mean values were 1107±594 ng/mL and 873±529 ng/mL, respectively (p=0.002).²¹⁾ Picard et al. first reported that a steady-state imatinib C₀ measured after at least 12 months of treatment with a standard imatinib dose correlated with the MMR, and the threshold for the imatinib C₀ should be set above 1002 ng/mL.¹²⁾ Several studies have also reported that patients with an imatinib C₀ less than 1000 ng/mL have a significantly lower rate of successfully achieving an improved MMR.^{13,18,21,26,31)} In the combined data set,^{12,13,18,21,26,31)} the rate of MMR achievement was significantly higher for patients with an imatinib C₀ above 1000 ng/mL than for patients with a C₀ less than 1000 ng/mL (odds ratio, 2.48; 95% CI, 1.82–3.38, p<0.0001) (Fig. 1). Thus, for CML patients, the target imatinib C₀ should be set above 1000 ng/mL.

Fig. 1. Meta-analysis for Correlation between Imatinib C₀ >1000 ng/mL and MMR

However, dose adjustment according to the target concentration should not be evaluated with an imatinib C₀ of only one point, for example only days 28 or 29 after beginning imatinib treatment, because variability of the intra-patient imatinib C₀ CV is quite large ranging from 8.4% to 49.3%.³²⁾ Therefore, a recommendation for the measurement of imatinib C₀ is each week for the first month after beginning treatment, then once a month to month three, and subsequently every three months up to one year with appropriate dosage adjustment. As provisionally defined by the ELN, simultaneous with an evaluation of clinical response according to transcript levels at each time point,⁵⁾ the mean imatinib C₀ for three months or using multiple points should also be assessed for each patient treated with imatinib³²⁾ (Fig. 2). After one year, the imatinib C₀ might be assessed at 6-month intervals, as well as each time a potentially interacting drug is introduced or withdrawn or if poor adherence to treatment is suspected.

Fig. 2. A Therapeutic Strategy for CML Patients Treated with Imatinib

Patients with a mean imatinib C₀ above 1000 ng/mL not exhibiting a positive effect (non-responders) might switch to a 2nd generation TKI therapy such as nilotinib or dasatinib (Fig. 3). On the other hand, non-responders with a mean imatinib C₀ less than 1000 ng/mL should be advised to increase the dosage from 400 mg to 600 mg (500 mg in Japanese patients because of their smaller body mass index) once daily after checking for compliance of imatinib usage,^32,33) and their imatinib C₀ should again be monitored (Fig. 3). Patients with a mean imatinib C₀ less than 1000 ng/mL that have intolerable toxicities such as edema and rash should also switch to a 2nd generation TKI, whereas patients with a mean imatinib C₀ above 1000 ng/mL with intolerable toxicities might suspend imatinib administration and then restart treatment at a 100 mg lower dose^24,32) (Fig. 3).

Fig. 3. A Proposed Therapeutic Strategy Using Imatinib TDM for CML Patients

According to results from the previous 14 reports, the mean steady-state imatinib C₀ obtained 24 h after taking a 400 mg standard daily dose was 1226 ng/mL, which is greater than the 1000 ng/mL target concentration.^{11–19,21–25,32)} However, patients obtaining an imatinib C₀ above 1000 ng/mL administered the lower dose of 200 mg were very rare.²¹⁾ The overall survival (OS) and event-free survival (EFS) was reported to be significantly inferior for patients taking an imatinib dose of 200 mg compared to patients taking 400 mg and 300 mg during the same period.²³⁾ In the same report, the estimated cumulative rate of CCyR or MMR during the first 18 months was significantly lower for patients taking the 200 mg daily dose than for patients in the 400 mg or 300 mg groups.²³⁾ Even for patients intolerant of the 300–400 mg dose of imatinib, excessive dose reductions to ≤200 mg imatinib should be avoided, and such patients should be switched to a 2nd generation TKI.²³⁾

A complete molecular response (CMR) is defined as ≤0.0032% of BCR-ABL 1 transcript levels. A duration of CMR more than 24 months indicates the feasibility of discontinuing imatinib therapy.^34,35) Although the imatinib C₀ was significantly higher in patients with MMR achievement than in patients without a MMR, there was no significant difference in the imatinib C₀ between patients achieving or not achieving a CMR (1243±660 ng/mL vs. 1372±654 ng/mL, respectively).³⁶⁾ Furthermore, it has also been reported that there was no significant difference in the imatinib C₀ between patients who achieved a MMR (976±385 ng/mL) and a CMR (1138±809 ng/mL).³⁰⁾ For CMR achievement, a higher imatinib C₀ was not necessary; however, the target imatinib C₀ should still be set above 1000 ng/mL.

BCRP, encoded by the ABCG2 gene, is a membrane efflux transporter normally expressed in the small intestine and biliary canalicular front of hepatocytes,^37,38) which is involved in the absorption, distribution, and excretion of a wide variety of clinically relevant drugs. The single-nucleotide polymorphism (SNP) 421C>A in the ABCG2 gene reduces BCRP function. The level and function of ABCG2 expressed from the 421 A allele are reduced compared with those of the 421C/C protein.³⁹⁾ We have reported that the dose-adjusted imatinib C₀ was significantly lower in Japanese patients with the ABCG2 421C/C genotype than in patients with the C/A+A/A genotypes.⁴⁰⁾ Petain et al. have also reported that imatinib clearance in patients carrying the ABCG2 421C/A genotype was significantly lower than in those subjects with the 421C/C genotype.⁴¹⁾ Patients with the ABCG2 421 A allele were associated with a higher imatinib C₀ than patients with the 421C/C genotype.^40,41) On the other hand, BCRP also contributes to the extracellular excretion of imatinib, and the drug efflux activity of BCRP is influenced by this SNP. Fifty-four percent of patients achieving CMR had the ABCG2 421 A allele, whereas 67% of patients not achieving CMR had the ABCG2 421C/C genotype.³⁶⁾ Thus, CML patients with the ABCG2 421 A allele were better able to achieve a CMR than patients with the 421C/C genotype. This result is believed to be associated with the intracellular concentration of imatinib and is in agreement with the findings reported by Kim et al.⁴²⁾ In addition, several studies have reported that the ABCG2 421 A allele is associated with a significantly higher rate of MMR.^42–44)

The involvement of multiple human transporters in imatinib pharmacokinetics makes the investigation of imatinib transport mechanisms difficult. However, among the various drug-transporters, BCRP appears to impart the strongest influence on imatinib exposure and clinical response. Knowledge of a patient’s ABCG2 421C>A genotype before initiating therapy could be useful when making dosing decisions aimed at achieving optimal imatinib exposure, and in conjunction with TDM could aid patient management.⁴⁵⁾

At the recommended dose of 400 mg/d, imatinib sometimes causes severe adverse events, such as neutropenia, edema, and skin rash, which in turn may lead to poor compliance, premature cessation of treatment, or failure of the therapy.⁵⁾ On the other hand, increased imatinib dosages above 400 mg/d have been associated with increased rates of some adverse events, and discontinuation rates of imatinib therapy were significantly greater for patients taking the higher dosage (71% vs. 44%).⁴⁶⁾ An imatinib C₀ above 3180 ng/mL is reported to be associated with a higher frequency of grade 3/4 adverse events such as neutropenia.¹⁵⁾ With an increase in imatinib C₀, the frequency of adverse events such as rash and edema is increased.^11,15) Therefore, an imatinib C₀ greater than 3000 ng/mL should be avoided.

The inter- and intra-individual variation of imatinib C₀ is very large. Therefore, a TDM should be routinely provided to CML patients taking imatinib. For CML patients that have an imatinib C₀ of 1000 ng/mL but lack a sufficient clinical response, switching to another tyrosine kinase inhibitor such as nilotinib or dasatinib is recommended.

3. NILOTINIB TDM

Nilotinib, which inhibits BCR-ABL1 with about 25-fold greater potency than imatinib, dosed at 150 mg twice daily and 200 mg twice daily gives a faster and more pronounced response compared with imatinib 400 mg once daily.³⁾ Nilotinib is absorbed with a bioavailability of approximately 30% and is metabolized by CYP3A4.⁴⁷⁾ Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), potentially increasing the concentrations of drugs eliminated by these enzymes.⁴⁷⁾ In particular, bilirubin is glucuronidated by UGT1A1⁴⁸⁾; however, nilotinib inhibits bilirubin metabolism via UGT1A1, thereby increasing bilirubin levels.^49,50) In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients (ENESTnd) study, a higher nilotinib exposure was reported to be significantly correlated with greater incidence of all-grade bilirubin elevation.⁵¹⁾ The same results were also obtained by another study in patients with imatinib-resistant or -intolerant CML.⁵²⁾

The most common promoter sequence for UGT1A1 contains the (TA)6TAA sequence, while the less frequent *28 allele contains an extended sequence of 7 TA repeats. The UGT1A1*28/*28 genotype is associated with unusually high bilirubin levels.^53,54) The UGT1A1*6 (211G>A) isoform has also been reported to cause a reduction in UGT1A1 enzyme activity.⁵⁵⁾ In the Japanese population, the UGT1A1*6/*6, *6/*28 and *28/*28 genotypes that include activity-reducing polymorphisms were detected in 1.3%, 3.2%, and 2.7% of the population, respectively.^56,57) In clinical studies, the inhibitory effect of UGT1A1 by nilotinib is particularly apparent in patients who are poor metabolizers (PMs) with the UGT1A1*6/*6, *6/*28, and *28/*28 genotypes. Singer et al. reported that patients with the UGT1A1*28/*28 genotype have an elevated risk of nilotinib-induced hyperbilirubinemia compared with patients with the extensive metabolizer (EM) genotypes such as UGT1A1*1/*1 and *1/*28, and the relative risk for grade 3 or greater hyperbilirubinemia in chronic phase CML patients with the UGT1A1*28/*28 genotype is 18 (95% CI: 4.1, 78.5).⁵⁸⁾ In Japanese CML patients, within the first 12 weeks of nilotinib administration, elevation of bilirubin levels in patients with UGT1A1 EM genotypes were slightly higher by 30%; however, the median time to elevation of bilirubin levels in patients with the UGT1A1 PM genotypes was 2.0 weeks (hazard ratio, 6.11; p=0.004).⁵⁹⁾ Thus, the influence of UGT1A1 inhibition by nilotinib appears within 1–3 weeks after initiating nilotinib administration. Therefore, patients with an increased risk of hyperbilirubinemia could be identified by prospective genotyping of UGT1A1 prior to initiation of nilotinib therapy.^52,59) For patients with the UGT1A1*6/*6, *6/*28, or *28/*28 genotypes, reduction of the initial dose of nilotinib to 150 mg twice daily or 200 mg twice daily is necessary to prevent elevation of bilirubin levels or alternatively choosing another tyrosine kinase inhibitor such as dasatinib might be recommended⁵⁹⁾ (Fig. 4).

In the ENESTnd study, patients with a higher nilotinib C₀ tended to have lower BCR-ABL ratios at 12 months compared to patients with a lower C₀, but the difference was not statistically significant.⁵¹⁾ Consequently, there was also no relationship between nilotinib C₀ and the MMR rate at 12 months after initiation of nilotinib therapy.⁵¹⁾ However, in the study of patients with imatinib-resistant or -intolerant CML, patients with a lower nilotinib C₀ had a significantly longer time to CCyR (p=0.010) and MMR (p=0.012).⁵²⁾ Patients with a nilotinib C₀ above 500 ng/mL required a significantly shorter time to achieve CCyR or MMR.⁵²⁾ Similar to imatinib, therapeutic drug monitoring to maintain a target plasma concentration would be beneficial during nilotinib therapy.

Fig. 4. A Proposed Therapeutic Strategy Using Nilotinib TDM for CML Patients

In the East Japan CML (EJCML) study of 30 Japanese patients with imatinib-resistant or-intolerant CML, we reported that the nilotinib C₀ was significantly higher in 21 patients with a MMR by 12 months than in 9 patients not achieving a MMR; the mean nilotinib C₀ values (median) were 1451±741 (1255) ng/mL and 534±409 (373) ng/mL, respectively (p=0.001). The threshold for nilotinib C₀ should be set above 761 ng/mL on a receiver operating characteristic (ROC) curve with a sensitivity of 76.2% and specificity of 77.8%.⁶⁰⁾ Afterwards, however, 10 patients during the first 12 months discontinued nilotinib treatment because of severe adverse events such as thrombocytopenia and hyperbilirubinemia.⁶¹⁾ Consequently, in the final analysis of the EJCML study, the nilotinib C₀ tended to increase in patients who achieved MMR at 12 months, but this result was not statistically significant; the median C₀ were 774 ng/mL and 490 ng/mL (less than 500 ng/mL), respectively (p=0.261).⁶¹⁾ Shibata et al. have reported that UGT1A1 SNPs are important determinants of severe toxicity from nilotinib in Japanese patients.⁶²⁾ In addition, Kim et al. suggested that decreased UGT1A1 function by nilotinib leading to decreased glucuronidation of UGT1A1 substrates might result in unexpected toxicity.⁶³⁾ In the EJCML study, we did not carry out genotyping of UGT1A1 prior to initiation of nilotinib therapy. If only UGT1A1 EM patients had been enrolled in this study, the relationship between nilotinib exposure and clinical response would be clearer.

In common practice, the daily dose of nilotinib during the maintenance phase after 3 months of nilotinib therapy for UGT1A1 PM patients was 300–400 mg/d, lower than the mean daily dose of 600 mg/d for UGT1A1 EM patients.⁵⁹⁾ For UGT1A1 PM patients who achieved MMR, the steady-state mean C₀ of nilotinib was 591 ng/mL.⁵⁹⁾ Therefore, for UGT1A1 PM CML patients, after administration of the initial 300–400 mg/d dose of nilotinib, the target nilotinib C₀ should be 500 ng/mL, although a longer time to achieve MMR might be needed (Fig. 4). Similar to our study, in a case study, Kim et al. also reported that the daily maintenance dose of nilotinib in UGT1A1 PM patients was reduced to 400 mg/d because of hyperbilirubinemia.⁶³⁾ Nilotinib should not be given above 600 mg daily for UGT1A1 PM patients. On the other hand, in UGT1A1 EM patients who achieved MMR at 12 months, the steady-state mean nilotinib C₀ was 934 ng/mL.⁵⁹⁾ Based on the EJCML study and the steady-state mean nilotinib C₀,^59,61) a target C₀ of 800 ng/mL is recommended for TDM after administration of the initial 600 mg/d dose of nilotinib (Fig. 4). In UGT1A1 PM patients, the incidence of grade 3/4 hyperbilirubinemia at a nilotinib C₀ of 800 ng/mL is approximately 50%.⁵²⁾ Therefore, continuous administration of the 600 mg/d dose of nilotinib for UGT1A1 PM patients should be avoided. If nilotinib is the initial therapy chosen for UGT1A1 PM patients, a target nilotinib C₀ of 500 ng/mL is recommended to balance efficacy and toxicity. Poor nilotinib exposure is considered to be the major contributing factor to therapeutic failure.

Similar to imatinib, dose-adjustment according to the target concentration should not be evaluated using only a single nilotinib C₀ data point, for example only day 8 after beginning treatment, because the intra-patient variability of the CV value of nilotinib C₀ is very large (mean value: 36.4%),³²⁾ and the bioavailability of nilotinib is increased when given with a meal.⁴⁷⁾ Therefore, the timing of nilotinib C₀ measurements should be the same as for imatinib after beginning treatment. Transitions of nilotinib C₀ of two patients with poor adherence to treatment are shown in Fig. 5. Thus, dose-adjustment based on the target concentration or evaluation of nilotinib C₀ for adherence to treatment requires multiple C₀ values before the evaluation time point. Therefore, it is recommended that the nilotinib C₀ be measured each week for the first month after beginning treatment, then monthly until month three, and subsequently once every three months. The periodic measurement of nilotinib C₀ might lead to the feasibility of discontinuing nilotinib in the future.

Fig. 5. Transition of Nilotinib C₀ for Two Patients with Poor Adherence to Treatment

4. DASATINIB TDM

The elimination half-life of dasatinib, an inhibitor of BCR-ABL1 with a potency 325-fold that of imatinib, is approximately 3–6 h.^64,65) In the Dasatinib versus Imatinib Study In Treatment-Naive Chronic Myeloid Leukemia (DASISION) trial, the rates of CCyR and MMR for dasatinib dosed 100 mg once daily were higher and showed both a faster and more pronounced response than imatinib 400 mg dosed once daily.^4,66) However, all grade pleural effusion occurred in 19% of patients receiving dasatinib within 36 months, and this side effect was linked to an overall discontinuation rate of 29%.⁶⁷⁾ Wang et al. have reported that the major cytogenetic response was significantly associated with the weighted average steady-state dasatinib plasma concentration, and pleural effusion was significantly associated with the dasatinib C₀ (hazard ratio 1.22) with the hazard ratio increasing 1.22-fold for every 1.0 ng/mL increase in dasatinib C₀.⁶⁴⁾ In the Phase I and Phase II studies, pleural effusion was reported to be less frequent with once daily dasatinib treatment than with twice daily treatment.⁶⁸⁾ In the Phase III study, the mean steady-state dasatinib C₀ after taking 100 mg once daily was 2.61 ng/mL (pleural effusion rate: 11.0%), whereas with dosing 140 mg twice daily the dasatinib C₀ was 6.71 ng/mL (pleural effusion rate: 22.0%).⁶⁴⁾ Yu et al. have reported that the dasatinib C₀ should not exceed 2.5 ng/mL, because of increased risk of cumulative incidences of pleural effusion.⁶⁹⁾ From these previous reports, the administration of dasatinib 100 mg once daily was found to be the best dosage to obtain sufficient efficacy with reduced side effects.^64,68,70) Thus, in contrast to imatinib and nilotinib, the main purpose of TDM of dasatinib is the avoidance of side effects (Fig. 6).

Fig. 6. Target Plasma Concentrations of Imatinib, Nilotinib, and Dasatinib for CML Patients

The frequencies of developing a T315I BCR-ABL1 mutation in patients receiving imatinib, nilotinib, and dasatinib therapy were 1.5% by 48 months, 3.3% by 48 months, and 7.1% by 36 months, respectively, and the frequency of the T315I mutation was highest in dasatinib therapy. In Philadelphia chromosome-positive acute lymphoid leukemia patients undergoing dasatinib monotherapy, we reported that the plasma concentration at 2 h (C₂), maximum plasma concentration (C_max), and area under the observed plasma concentration–time curve (AUC) of dasatinib were significantly lower in patients with the T315I mutation than those without this mutation.⁷¹⁾ Therefore, it is recommended that the dasatinib C₂ or C_max target concentration be set above 50 ng/mL to avoid a low exposure of dasatinib because of the risk of developing BCR-ABL point mutations⁷¹⁾ (Fig. 6). An effective transient dasatinib concentration of 100 nM (approximately 50 ng/mL) is sufficient to inhibit in vitro proliferation of most cell lines expressing imatinib-resistant BCR-ABL mutations, with the exception of T315I.⁷²⁾ In addition, Vainstein et al. have reported that a higher inhibitory potential at maximum concentration based on the IC₅₀ and C_max of dasatinib correlated with improved CCyR rates in CML patients treated with dasatinib.⁷³⁾ Although continuous dasatinib exposure for 24 h is not needed, a higher C_max of dasatinib is necessary (Fig. 6). Consequently, the therapeutic target of dasatinib is recommended to maintain a higher C_max or C₂ (above 50 ng/mL) and lower C₀ (less than 2.5 ng/mL) by administration of dasatinib 100 mg once daily (Fig. 6). Dose-adjustment up or down in 20 mg increments based on the target concentration or clinical response may be carried out, using once daily administration as a general rule.

In the prospective OPTIM dasatinib trial with patients newly diagnosed with CP-CML that began therapy with dasatinib 100 mg once daily, Rousselot et al. reported that when patients with a dasatinib C₀ ≥3 nM (1.5 ng/mL) at day 15 were randomized into either a no dose-adjustment group or a dose-adjustment group to obtain a C₀ of <3 nM (median C₀ from 5.1 nM to 2.1 nM), discontinuation rates of dasatinib therapy were 27% and 13%, respectively, and the overall rates of pleural effusion by 36 months were 48.9% and 11.3%, respectively (p=0.008).⁷⁴⁾ In the same report, they also reported that the dasatinib C_max was found to be associated with clinical response and that the C₀ was associated with fluid retention and pleural effusion.⁷⁴⁾ Thus, a dasatinib C₀ not detectable in analysis by LC-MS/MS or HPLC with a limit of quantification (LOQ) of 1.0 ng/mL may signify a better clinical outcome.

Although AUC is the best pharmacokinetic parameter to characterize dasatinib exposure, many blood collection time-points are required to accurately calculate AUC values. The C₂ point of dasatinib was able to accurately predict the AUC of dasatinib in a shorter time frame and could be used to predict efficacy.⁷⁵⁾ In addition, the C₂ point of dasatinib could also be used to predict drug-interactions between dasatinib and a proton pump inhibitor (PPI) or histamine-2 (H2) receptor antagonist.^75,76) H2-Receptor antagonists and PPIs are known to decrease the dasatinib AUC by 61% and 43% and the C_max by 63% and 42%, respectively.⁷⁷⁾ The combination of dasatinib and acid suppressants requires monitoring of the dasatinib C₂ to ensure efficacy of dasatinib.

CV values for the C₀ and C_max of dasatinib with the 100 mg once-daily dose were 26% and 56%, respectively.⁶⁴⁾ Thus, the inter-individual variation of dasatinib C_max is large. However, using the C₂ point after dasatinib administration, whether a high enough C_max will be obtained can be predicted. Therefore, it is recommended that TDM service be routinely provided to patients taking dasatinib.

5. CONCLUSION

In TKI therapy for CML patients, TDM is a new strategy that provides a method for optimizing the drug dosage to obtain faster and more pronounced clinical responses. The target imatinib C₀ should be set above 1000 ng/mL and less than 3000 ng/mL. BCRP appears to impart the strongest influence on imatinib exposure and clinical response. Knowledge of the ABCG2 421C>A genotype before initiating imatinib therapy would be useful for making dosing decisions aimed at achieving optimal imatinib exposure. The nilotinib C₀ after administration of an initial 300–400 mg/d dose for patients with the UGT1A1*6/*6, *6/*28, or *28/*28 genotypes would be a target C₀ of 500 ng/mL to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1*1 allele, the nilotinib C₀ after administration of an initial 600 mg/d dose is recommended to give a target C₀ of 800 ng/mL. For dasatinib, it is recommended that a higher C_max or C₂ (above 50 ng/mL) and lower C₀ (less than 2.5 ng/mL) be maintained by administration of dasatinib 100 mg once daily. Although at present clinicians consider the next pharmacotherapy from clinical responses such as efficacy or adverse events obtained from a fixed dosage of TKI, we suggest that the drug dosage be adjusted based on target concentration to maximize efficacy and minimize the incidence of adverse events. Consequently, TKI therapy could be continued for a longer time, and faster and more pronounced clinical responses could be obtained.

Acknowledgments

I would like to express my thanks to Dr. Mitsuhiro Takeshita (presently at Tokiwa Hospital, Fukushima, Japan, previously professor of Tohoku Pharmaceutical University), Dr. Tadashi Ohkubo (presently at Shichifuku Pharmacy, Aomori, Japan; previously assistant professor of Hirosaki University Hospital), Dr. Naoto Takahashi (Professor of the Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine) and Dr. Kenichi Sawada (Akita University, previously professor of the Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine) for their valuable guidance and suggestions. I would also like to thank the late Dr. Takanori Hishinuma (previously professor of the Division of Pharmacotherapy, Tohoku University Graduate School of Pharmaceutical Sciences) for leading me into the field of pharmaceutical sciences. This work was supported by Grant Nos. 26460188, 26461414, and 23590168 from the Japan Society for the Promotion of Science, Tokyo, Japan.

Conflict of Interest

The author declares no conflict of interest.

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