Invest New Drugs DOI 10.1007/s10637-015-0214-x
REVIEW
Axitinib plasma pharmacokinetics and ethnic differences Ying Chen & Akiyuki Suzuki & Michael A. Tortorici & May Garrett & Robert R. LaBadie & Yoshiko Umeyama & Yazdi K. Pithavala
Received: 11 December 2014 / Accepted: 28 January 2015 # Springer Science+Business Media New York 2015
Summary Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its
Michael A. Tortorici was employed by Pfizer Inc at the time of studies presented in this review. Y. Chen : M. Garrett : Y. K. Pithavala (*) Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA 92121, USA e-mail: [email protected] A. Suzuki : Y. Umeyama Pfizer Japan Inc, 3-22-7, Yoyogi, Shibuya-ku, Tokyo 1518589, Japan M. A. Tortorici Clinical Pharmacology and Pharmacometrics, CSL Behring Biotherapies for Life, 1020 First Avenue, King of Prussia, PA 19406, USA R. R. LaBadie Pfizer Inc, 558 Eastern Point Road, Groton, CT 06340, USA
pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted.
Keywords Asian . Axitinib . Caucasian . Ethnic Factor . Pharmacokinetics
Introduction Axitinib, a substituted indazole derivative (N-Methyl2-[3-((E)-2-pyridin-2-yl-vinyl)-1H indazol-6-ylsulfanyl]benzamide) with a molecular weight of 386.47 Daltons, is a potent and selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 [1]. Axitinib inhibits VEGF receptor phosphorylation with a 50 % inhibitory concentration in a sub-nanomolar range, VEGFmediated endothelial cell survival, migration, tube formation and vascular permeability in vitro, and blocks tumor growth and angiogenesis in preclinical animal models [2]. The efficacy of axitinib was demonstrated in previously treated patients with metastatic renal cell carcinoma (mRCC) in Phase 2 and 3 studies [3–8]. Axitinib also showed antitumor activity in treatment-naïve patients with mRCC [9, 10]. The common adverse events (AE) associated with axitinib treatment include diarrhea, fatigue, and hypertension [3–10]. Axitinib is approved for treatment of patients with advanced RCC in the secondline setting in the United States [11] and more than 60 countries, including in Asia and the European Union, at a recommended starting dose of 5 mg twice daily (BID).
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The clinical development of axitinib has been covered in detail in recent reviews [12–15] and in-depth reviews of clinical pharmacology of axitinib have been published elsewhere [1, 16, 17]. In brief, axitinib pharmacokinetics is similar between healthy volunteers and patients with advanced solid tumors, and is dose-proportional within the clinical dose range [1]. Following oral administration, axitinib is absorbed rapidly, with maximum observed plasma concentration (Cmax) reached within 4 hours and effective plasma half-life ranging between 2.5 and 6.1 h. Axitinib has a mean absolute bioavailability of 58 % and >99 % protein-binding. Axitinib is metabolized primarily by cytochrome P 450 (CYP) 3A4/5, and to a lesser extent (60, RaceJapanese, and Smokeractive are 1 if applicable and 0 otherwise [34]. It should be noted that while the population pharmacokinetic analysis indicated that active smokers had a higher axitinib CL, potentially resulting in lower axitinib exposure, the smoking effect was not well defined in the model, as indicated by the high estimated standard error (44 %), likely due to the very small number of active smokers (~3 %) in the dataset. The result of Japanese ethnicity obtained in axitinib population pharmacokinetic analysis differs from that observed in the Phase 1 study of axitinib, in which axitinib pharmacokinetics in Caucasian and Japanese subjects enrolled at a single clinical site were compared [23]. In order to interpret the clinical relevance of these seemingly discrepant results, several factors need to be taken into account. First, the study design of the Phase 1 study allowed for a prospectively planned, controlled, head-to-head comparison of pharmacokinetics in healthy subjects (enrolled at the same site) between the two ethnicities, in contrast to the pooled population pharmacokinetic analysis across multiple studies that included both healthy subjects and cancer patients. Second, intensive pharmacokinetic samples were collected in healthy subjects in the Phase 1 study compared to sparse data collected in the Phase 2 studies of axitinib, which enrolled Japanese patients. Third,
Invest New Drugs 100
800
80
Cmax,ss (ng/mL)
1000
AUC0-24,ss (ng·h/mL)
Fig. 2 Axitinib pharmacokinetics at steady-state following multiple oral doses of 5 mg axitinib twice daily in Japanese versus non-Japanese patients with solid tumors. AUC0–24,ss area under the plasma concentration–time curve from zero to 24 h at steady-state, Cmax,ss maximum observed plasma concentration at steady-state
600
400
0
0 Japanese (n=11)
pharmacokinetic data from the Phase 1 study were analyzed using non-compartmental methods without any model assumptions. Fourth, in the population pharmacokinetic analysis, Japanese patients were older and had a lower body weight than others in the pooled dataset, whereas Japanese and Caucasian subjects in the Phase 1 study were more balanced with respect to age and body weight. The median weight was 57 and 61 kg in Japanese studies [5, 27] compared with 74 kg for the rest of the population. Likewise, median age was 63 years in Japanese studies [5, 27] compared with overall median age of 42 years for the pooled analysis dataset. In contrast, in the Phase 1 study, mean age was 27 and 31 years, and mean
100
Axitinib clearance (L/h)
80
60
40
20
0 Black
Asian, Japanese non-Japanese
Hispanic
40
20
200
Caucasian
60
Other
Fig. 3 Box-and-whisker plot depicting axitinib systemic clearance by ethnicity. Circles represent individual data points; horizontal bars represent median; and brackets are drawn to the nearest value not beyond a standard span from the quartiles (1.5×interquartile range). Three outlier subjects with axitinib clearance values >100 L/h have been excluded from the plot for better visual examination of data from remaining subjects. CL clearance
Non-Japanese (n=5)
Japanese (n=11)
Non-Japanese (n=5)
weight was 77 and 68 kg in Caucasian and Japanese subjects, respectively [23]. Therefore, the observed Japanese effect in the population pharmacokinetic analysis may have been confounded by demographic imbalance in the overall study dataset. However, the 25 % reduction in axitinib CL was less than the estimated typical inter-individual variability of 60 % for CL [34] and lower than the 40 % change associated with each step-wise dose modification as outlined in current approved axitinib label. Furthermore, Monte Carlo simulations (n=1000) [34], performed to predict axitinib steady-state concentrations under the two extreme covariate combinations (>60-year-old Japanese with a low [10th percentile] body weight versus ≤60-year-old non-Japanese with a high [90th percentile] body weight) revealed a substantial overlap in the axitinib concentration profiles between the two extreme cases, supporting the notion that axitinib plasma pharmacokinetics is not substantially different in Japanese subjects as compared to non-Japanese subjects, and any differences are unlikely of clinical concern. Therefore, no dose adjustment is recommended on the basis of Japanese ethnicity, judging from the results of axitinib pharmacokinetic analyses. Axitinib is now approved in several Asian countries, including Japan, Taiwan, and Korea, and in each case, the labeled dosing for axitinib is identical to that used in non-Asian countries.
Genetic polymorphisms in axitinib-metabolizing enzymes and transporters on axitinib pharmacokinetics Among the key enzymes that are involved in metabolism of axitinib, CYP3A5, CYP2C19 and UGT1A1 exhibit some genetic polymorphisms that lead to changes in expression and/or activity level, and allelic frequencies for these genes have been shown to differ among ethnic groups [18–20]. For instance,
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allelic frequencies of CYP3A5*3 gene that results in a truncated protein with no catalytic activity, are lower in subjects from Asian regions (range, 0.648–0.761) than those from European regions (range, 0.922–0.932) [20]. The frequencies of poor metabolizers (PMs) of drugs such as S-mephenytoin, caused mainly by deficient alleles (CYP2C19*2 and CYP2C19*3), range between 18 and 23 % in Asians (or 15 to 25 % in the Eastern Asians) compared with less than 5 % in Caucasians [18, 20]. The allelic frequencies of UGT1A1*28 genes with 7 TA repeats in the promoter, which leads to reduced transcription, are higher in Europeans (range, 0.318–0.344) than in Eastern and South-Eastern Asians (0.139 and 0.140, respectively) [20]. To examine potential influences of genetic polymorphisms in several metabolizing enzymes on axitinib exposure, a fixed effects meta-analysis was performed using AUC0-∞ data measured in healthy subjects from 11 axitinib clinical studies [35]. The results demonstrated no statistically significant association between gene polymorphisms tested, including CYP2C19, CYP3A4*1B, CYP3A5, and UGT1A1, and axitinib plasma exposures, and that none of them contributed >5 % to the overall pharmacokinetic variability of axitinib. The study additionally found that polymorphisms in transporter genes, ABCB1 and ABCG2 (coding for ATP-binding cassette, subfamily B, member 1 and subfamily G, member 2, respectively) and SLCO1B1 (coding for soluble carrier organic anion transporter family, member 1) were not significant predictors of axitinib pharmacokinetic variability. It should be pointed out that since the analysis was done using pooled subjects of various ethnicities, the effect of gene polymorphisms within individual ethnicity could not be ascertained. The lack of the pharmacogenetic effect of CYP3A5, CYP2C19 and UGT1A1*28 on axitinib pharmacokinetic variability was supported by the same conclusion from a separate analysis using a mixed effect modeling populationbased approach using a similar set of data in healthy subjects [36]. These results from the meta-analysis are in agreement with the findings from direct comparative study of axitinib pharmacokinetics in Asians versus Caucasians described in the previous sections.
Axitinib efficacy and safety versus ethnicity The effect of ethnicity on axitinib efficacy and safety was evaluated in Japanese patients with mRCC in Japan (n=25) with those in the overall population (n=361) [7], 77 % of whom were Caucasians, enrolled in the same Phase 3 AXIS trial [6]. In the Japanese subgroup, median progression-free survival (PFS), the primary endpoint of the study, was 12.1 months (95 % CI, 8.6 to not estimable) with axitinib compared with 4.9 months (95 % CI, 2.8–6.6) with sorafenib (n=29) (hazard ratio 0.390; stratified one-sided P=0.0401). In comparison, median PFS was 6.7 months (95 % CI 6.3–8.6)
with axitinib versus 4.7 months (95 % CI 4.6–5.6) with sorafenib (n = 362) (hazard ratio 0.665; stratified one-sided P
REVIEW
Axitinib plasma pharmacokinetics and ethnic differences Ying Chen & Akiyuki Suzuki & Michael A. Tortorici & May Garrett & Robert R. LaBadie & Yoshiko Umeyama & Yazdi K. Pithavala
Received: 11 December 2014 / Accepted: 28 January 2015 # Springer Science+Business Media New York 2015
Summary Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its
Michael A. Tortorici was employed by Pfizer Inc at the time of studies presented in this review. Y. Chen : M. Garrett : Y. K. Pithavala (*) Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA 92121, USA e-mail: [email protected] A. Suzuki : Y. Umeyama Pfizer Japan Inc, 3-22-7, Yoyogi, Shibuya-ku, Tokyo 1518589, Japan M. A. Tortorici Clinical Pharmacology and Pharmacometrics, CSL Behring Biotherapies for Life, 1020 First Avenue, King of Prussia, PA 19406, USA R. R. LaBadie Pfizer Inc, 558 Eastern Point Road, Groton, CT 06340, USA
pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted.
Keywords Asian . Axitinib . Caucasian . Ethnic Factor . Pharmacokinetics
Introduction Axitinib, a substituted indazole derivative (N-Methyl2-[3-((E)-2-pyridin-2-yl-vinyl)-1H indazol-6-ylsulfanyl]benzamide) with a molecular weight of 386.47 Daltons, is a potent and selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 [1]. Axitinib inhibits VEGF receptor phosphorylation with a 50 % inhibitory concentration in a sub-nanomolar range, VEGFmediated endothelial cell survival, migration, tube formation and vascular permeability in vitro, and blocks tumor growth and angiogenesis in preclinical animal models [2]. The efficacy of axitinib was demonstrated in previously treated patients with metastatic renal cell carcinoma (mRCC) in Phase 2 and 3 studies [3–8]. Axitinib also showed antitumor activity in treatment-naïve patients with mRCC [9, 10]. The common adverse events (AE) associated with axitinib treatment include diarrhea, fatigue, and hypertension [3–10]. Axitinib is approved for treatment of patients with advanced RCC in the secondline setting in the United States [11] and more than 60 countries, including in Asia and the European Union, at a recommended starting dose of 5 mg twice daily (BID).
Invest New Drugs
The clinical development of axitinib has been covered in detail in recent reviews [12–15] and in-depth reviews of clinical pharmacology of axitinib have been published elsewhere [1, 16, 17]. In brief, axitinib pharmacokinetics is similar between healthy volunteers and patients with advanced solid tumors, and is dose-proportional within the clinical dose range [1]. Following oral administration, axitinib is absorbed rapidly, with maximum observed plasma concentration (Cmax) reached within 4 hours and effective plasma half-life ranging between 2.5 and 6.1 h. Axitinib has a mean absolute bioavailability of 58 % and >99 % protein-binding. Axitinib is metabolized primarily by cytochrome P 450 (CYP) 3A4/5, and to a lesser extent (60, RaceJapanese, and Smokeractive are 1 if applicable and 0 otherwise [34]. It should be noted that while the population pharmacokinetic analysis indicated that active smokers had a higher axitinib CL, potentially resulting in lower axitinib exposure, the smoking effect was not well defined in the model, as indicated by the high estimated standard error (44 %), likely due to the very small number of active smokers (~3 %) in the dataset. The result of Japanese ethnicity obtained in axitinib population pharmacokinetic analysis differs from that observed in the Phase 1 study of axitinib, in which axitinib pharmacokinetics in Caucasian and Japanese subjects enrolled at a single clinical site were compared [23]. In order to interpret the clinical relevance of these seemingly discrepant results, several factors need to be taken into account. First, the study design of the Phase 1 study allowed for a prospectively planned, controlled, head-to-head comparison of pharmacokinetics in healthy subjects (enrolled at the same site) between the two ethnicities, in contrast to the pooled population pharmacokinetic analysis across multiple studies that included both healthy subjects and cancer patients. Second, intensive pharmacokinetic samples were collected in healthy subjects in the Phase 1 study compared to sparse data collected in the Phase 2 studies of axitinib, which enrolled Japanese patients. Third,
Invest New Drugs 100
800
80
Cmax,ss (ng/mL)
1000
AUC0-24,ss (ng·h/mL)
Fig. 2 Axitinib pharmacokinetics at steady-state following multiple oral doses of 5 mg axitinib twice daily in Japanese versus non-Japanese patients with solid tumors. AUC0–24,ss area under the plasma concentration–time curve from zero to 24 h at steady-state, Cmax,ss maximum observed plasma concentration at steady-state
600
400
0
0 Japanese (n=11)
pharmacokinetic data from the Phase 1 study were analyzed using non-compartmental methods without any model assumptions. Fourth, in the population pharmacokinetic analysis, Japanese patients were older and had a lower body weight than others in the pooled dataset, whereas Japanese and Caucasian subjects in the Phase 1 study were more balanced with respect to age and body weight. The median weight was 57 and 61 kg in Japanese studies [5, 27] compared with 74 kg for the rest of the population. Likewise, median age was 63 years in Japanese studies [5, 27] compared with overall median age of 42 years for the pooled analysis dataset. In contrast, in the Phase 1 study, mean age was 27 and 31 years, and mean
100
Axitinib clearance (L/h)
80
60
40
20
0 Black
Asian, Japanese non-Japanese
Hispanic
40
20
200
Caucasian
60
Other
Fig. 3 Box-and-whisker plot depicting axitinib systemic clearance by ethnicity. Circles represent individual data points; horizontal bars represent median; and brackets are drawn to the nearest value not beyond a standard span from the quartiles (1.5×interquartile range). Three outlier subjects with axitinib clearance values >100 L/h have been excluded from the plot for better visual examination of data from remaining subjects. CL clearance
Non-Japanese (n=5)
Japanese (n=11)
Non-Japanese (n=5)
weight was 77 and 68 kg in Caucasian and Japanese subjects, respectively [23]. Therefore, the observed Japanese effect in the population pharmacokinetic analysis may have been confounded by demographic imbalance in the overall study dataset. However, the 25 % reduction in axitinib CL was less than the estimated typical inter-individual variability of 60 % for CL [34] and lower than the 40 % change associated with each step-wise dose modification as outlined in current approved axitinib label. Furthermore, Monte Carlo simulations (n=1000) [34], performed to predict axitinib steady-state concentrations under the two extreme covariate combinations (>60-year-old Japanese with a low [10th percentile] body weight versus ≤60-year-old non-Japanese with a high [90th percentile] body weight) revealed a substantial overlap in the axitinib concentration profiles between the two extreme cases, supporting the notion that axitinib plasma pharmacokinetics is not substantially different in Japanese subjects as compared to non-Japanese subjects, and any differences are unlikely of clinical concern. Therefore, no dose adjustment is recommended on the basis of Japanese ethnicity, judging from the results of axitinib pharmacokinetic analyses. Axitinib is now approved in several Asian countries, including Japan, Taiwan, and Korea, and in each case, the labeled dosing for axitinib is identical to that used in non-Asian countries.
Genetic polymorphisms in axitinib-metabolizing enzymes and transporters on axitinib pharmacokinetics Among the key enzymes that are involved in metabolism of axitinib, CYP3A5, CYP2C19 and UGT1A1 exhibit some genetic polymorphisms that lead to changes in expression and/or activity level, and allelic frequencies for these genes have been shown to differ among ethnic groups [18–20]. For instance,
Invest New Drugs
allelic frequencies of CYP3A5*3 gene that results in a truncated protein with no catalytic activity, are lower in subjects from Asian regions (range, 0.648–0.761) than those from European regions (range, 0.922–0.932) [20]. The frequencies of poor metabolizers (PMs) of drugs such as S-mephenytoin, caused mainly by deficient alleles (CYP2C19*2 and CYP2C19*3), range between 18 and 23 % in Asians (or 15 to 25 % in the Eastern Asians) compared with less than 5 % in Caucasians [18, 20]. The allelic frequencies of UGT1A1*28 genes with 7 TA repeats in the promoter, which leads to reduced transcription, are higher in Europeans (range, 0.318–0.344) than in Eastern and South-Eastern Asians (0.139 and 0.140, respectively) [20]. To examine potential influences of genetic polymorphisms in several metabolizing enzymes on axitinib exposure, a fixed effects meta-analysis was performed using AUC0-∞ data measured in healthy subjects from 11 axitinib clinical studies [35]. The results demonstrated no statistically significant association between gene polymorphisms tested, including CYP2C19, CYP3A4*1B, CYP3A5, and UGT1A1, and axitinib plasma exposures, and that none of them contributed >5 % to the overall pharmacokinetic variability of axitinib. The study additionally found that polymorphisms in transporter genes, ABCB1 and ABCG2 (coding for ATP-binding cassette, subfamily B, member 1 and subfamily G, member 2, respectively) and SLCO1B1 (coding for soluble carrier organic anion transporter family, member 1) were not significant predictors of axitinib pharmacokinetic variability. It should be pointed out that since the analysis was done using pooled subjects of various ethnicities, the effect of gene polymorphisms within individual ethnicity could not be ascertained. The lack of the pharmacogenetic effect of CYP3A5, CYP2C19 and UGT1A1*28 on axitinib pharmacokinetic variability was supported by the same conclusion from a separate analysis using a mixed effect modeling populationbased approach using a similar set of data in healthy subjects [36]. These results from the meta-analysis are in agreement with the findings from direct comparative study of axitinib pharmacokinetics in Asians versus Caucasians described in the previous sections.
Axitinib efficacy and safety versus ethnicity The effect of ethnicity on axitinib efficacy and safety was evaluated in Japanese patients with mRCC in Japan (n=25) with those in the overall population (n=361) [7], 77 % of whom were Caucasians, enrolled in the same Phase 3 AXIS trial [6]. In the Japanese subgroup, median progression-free survival (PFS), the primary endpoint of the study, was 12.1 months (95 % CI, 8.6 to not estimable) with axitinib compared with 4.9 months (95 % CI, 2.8–6.6) with sorafenib (n=29) (hazard ratio 0.390; stratified one-sided P=0.0401). In comparison, median PFS was 6.7 months (95 % CI 6.3–8.6)
with axitinib versus 4.7 months (95 % CI 4.6–5.6) with sorafenib (n = 362) (hazard ratio 0.665; stratified one-sided P
