V O L U M E 2 6 䡠 N U M B E R 4 䡠 F E B R U A R Y 1 2 0 0 8
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Phase I and Pharmacokinetic Study of Imatinib Mesylate in
`Patients With Advanced Malignancies and Varying Degrees
`of Renal Dysfunction: A Study by the National Cancer
`Institute Organ Dysfunction Working Group
`Joseph Gibbons, Merrill J. Egorin, Ramesh K. Ramanathan, Pingfu Fu, Daniel L. Mulkerin, Stephen Shibata,
`Chris H.M. Takimoto, Sridhar Mani, Patricia A. LoRusso, Jean L. Grem, Anna Pavlick, Heinz-Josef Lenz,
`Susan M. Flick, Sherrie Reynolds, Theodore F. Lagattuta, Robert A. Parise, Yanfeng Wang, Anthony J. Murgo,
`S. Percy Ivy, and Scot C. Remick
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-
`tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment
`and to develop dosing guidelines for imatinib in such patients.
`Patients and Methods
`Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine
`clearance [CrCL] ⱖ 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction,
`CrCL 20 to 39 mL/min; and severe dysfunction, CrCL ⬍ 20 mL/min) received daily imatinib doses
`of 100 to 800 mg. Treatment cycles were 28 days long.
`Results
`The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800
`mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were
`more common in the renal dysfunction groups than in the normal group (P ⫽ .0096). There was
`no correlation between dose and SAEs in any group. No responses were observed. Several
`patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib
`area under the curve, was significantly greater in the mild and moderate groups than in the normal
`group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concen-
`tration and plasma imatinib, and an inverse correlation between plasma AGP concentration and
`imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose.
`Conclusion
`Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate
`renal dysfunction, respectively, despite their having increased imatinib exposure.
`
`J Clin Oncol 26:570-576. © 2008 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Imatinib mesylate (Gleevec; Novartis Pharmaceuti-
`cals, Florham Park, NJ), is an orally administered,
`highly selective inhibitor of the tyrosine kinase fam-
`ily containing ABL, the platelet-derived growth fac-
`tor receptor (PDGFR), c-KIT, and the receptor for
`stem-cell factor.1-4 Imatinib has become standard
`treatment for chronic myeloid leukemia and other
`hematologic malignancies that express a constitu-
`tively active form of the BCR-ABL fusion gene.5,6
`Imatinib has also become standard treatment for
`gastrointestinal stromal tumors and other less com-
`mon malignancies that have rearrangement of the
`
`PDGFR␣ and PDGFR␤ genes.7-18 The daily ima-
`tinib dose ranges from 400 to 800 mg.
`Although safety and pharmacokinetic data for
`imatinib are available for healthy volunteers and
`patients with cancer who have acceptable renal func-
`tion, there are currently no data regarding the safety
`and disposition of imatinib in patients with renal
`dysfunction. Characterizing the safety and pharma-
`cokinetics of imatinib in patients with impaired re-
`nal function is important because renal dysfunction
`is regularly encountered among patients with
`cancer, and fluid retention and electrolyte abnor-
`malities occur in patients receiving imatinib. There-
`fore, this study and one in patients with liver
`
`From the Developmental Therapeutics
`Program, Case Comprehensive Cancer
`Center, Ireland Cancer Center at
`University Hospitals of Case Medical
`Center and Case Western Reserve
`University School of Medicine, Cleve-
`land, OH; University of Pittsburgh
`Cancer Institute, Pittsburgh, PA; Univer-
`sity of Wisconsin Comprehensive
`Cancer Center, Madison, WI; City of
`Hope National Medical Center, Duarte;
`University of Southern California/Norris
`Comprehensive Cancer Center, Los
`Angeles, CA; University of Texas Health
`Science Center, San Antonio, TX; Albert
`Einstein College of Medicine, Bronx;
`Kaplan Comprehensive Cancer Center,
`New York University, New York, NY;
`Wayne State University, Detroit, MI;
`National Cancer Institute, Medicine
`Branch, National Naval Medical Center,
`Bethesda; Center for Treatment and
`Evaluation Program, Division of Cancer
`Diagnosis and Treatment, National
`Cancer Institute, Rockville, MD; and
`Novartis Pharmaceuticals, Florham
`Park, NJ.
`
`Submitted July 23, 2007; accepted
`September 27, 2007.
`
`Supported by National Institutes of
`Health Grants No. U01 CA62502, M01
`RR-000080, P30 CA43703, U01
`CA099168, 5M01 RR-00056, P30
`CA47904, 5 U01 CA62505, U01
`CA062491, and 5U01CA069853 and
`Translational Research Initiative
`Contract No. 22XS041A.
`
`Presented in part at the 39th Annual
`Meeting of the American Society of
`Clinical Oncology, May 31-June 3, 2003
`Chicago, IL.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Corresponding author: Scot C. Remick,
`MD, Mary Babb Randolph Cancer
`Center, West Virginia University, 1801
`Health Sciences South, PO Box 9300,
`Morgantown, WV 26506; e-mail:
`sremick@hsc.wvu.edu.
`
`© 2008 by American Society of Clinical
`Oncology
`
`0732-183X/08/2604-570/$20.00
`
`DOI: 10.1200/JCO.2007.13.3819
`
`570
`
`Downloaded from jco.ascopubs.org on March 7, 2016. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`Boehringer Ex. 2025
`Mylan v. Boehringer Ingelheim
`IPR2016-01565
`Page 1
`
`

`
`Imatinib Dosing in Patients With Renal Dysfunction
`
`dysfunction19 were conducted by the National Cancer Institute Organ
`Dysfunction Working Group.
`
`PATIENTS AND METHODS
`
`Patient Eligibility
`Eligible patients were required to meet the following criteria: pathologi-
`cally confirmed malignancy that was no longer curable by standard surgical or
`medical therapy, age ⱖ16 years; Eastern Cooperative Oncology Group perfor-
`mance status ⱕ 2; life expectancy ⱖ 3 months; leukocytes ⱖ 3,000/␮L or
`absolute granulocytes ⱖ 1,500/␮L; platelets ⱖ 100,000/␮L; total bilirubin
`within institutional normal limits; and AST/ALT ⱕ 1.5 ⫻ the institutional
`upper limit of normal. Because imatinib is metabolized by CYP3A, patients
`requiring therapeutic anticoagulation with warfarin were excluded. The
`institutional review board at each participating institution approved the
`protocol. Written informed consent was obtained from all patients before
`study treatment.
`Study Design
`Ten institutions enrolled patients into four groups on the basis of mea-
`sured creatinine clearance (CrCL). Group A (normal renal function) had
`CrCL ⱖ 60 mL/min; group B (mild dysfunction) had CrCL 40 to 59 mL/min;
`group C (moderate dysfunction) had CrCL 20 to 39 mL/min; and group D
`(severe dysfunction) had CrCL less than 20 mL/min. Two separately measured
`24-hour urine CrCL determinations, not deviating from each other by more
`than 25%, were required, with the most recent performed within 1 week of
`treatment. Stratification was based on the most recent measurement. Labora-
`tories at each institution performed CrCL measurements, and no cross-site
`standardization was performed. Patients were seen for safety evaluations and
`examination weekly during cycle 1, biweekly during cycle 2, and every 4 weeks
`thereafter. CBCs and serum chemistries were performed weekly for the first 12
`weeks and biweekly thereafter.
`Drug Formulation and Administration
`Imatinib was supplied as hard gelatin capsules of 100-mg dosage strength
`by the Cancer Therapy and Evaluation Program, National Cancer Institute
`(Rockville, MD), under a Collaborative Research and Development Agree-
`ment with Novartis Pharmaceuticals. Imatinib was ingested with 8 ounces of
`water. Doses ⱕ 600 mg were given as a single dose. The 800-mg dose was
`administered as 400 mg bid to avoid local irritant effects on the gastric mucosa,
`except on day 1, when an 800-mg single dose was given to facilitate pharma-
`cokinetic studies (Table 1). To permit single-dose pharmacokinetic profiling,
`therapy was started on day 1, held on days 2 and 3, and resumed on day 4.
`Imatinib was ingested daily without interruption thereafter.
`A cycle of therapy consisted of uninterrupted daily dosing for 28 days
`(except for the first cycle). Participants who completed one cycle of therapy
`and had pharmacokinetic studies completed were considered assessable. Re-
`sponse was evaluated using Response Evaluation Criteria in Solid Tumors
`Group criteria after every two cycles.20 Doses were escalated separately in each
`
`group (Table 1). Intrapatient dose escalation by one level was permitted for
`patients who failed to respond or who experienced disease progression at their
`starting dose level, provided they did not experience any dose-limiting toxicity
`(DLT). Dose modifications were prescribed in the protocol. For grade 3 or
`worse toxicity, imatinib was reduced by one dose level on recovery.
`Four patients with normal renal function and three in each renal dys-
`function group could accrue to each dose level. If a patient’s second CrCL
`indicated that patient qualified for a different group than indicated by the first
`CrCL, then the eligible patient was added to the safest known level in the
`appropriate group.
`Assessment of DLT was limited to the first cycle of therapy, which was
`defined as any drug-related grade 3 or 4 nonhematologic toxicity or worse
`(excluding alopecia and renal abnormalities); grade 4 neutropenia; occurrence
`of fever with absolute neutrophil count less than 1,500/␮L; grade 4 thrombo-
`cytopenia; grade 3 or worse nausea and/or vomiting occurring despite anti-
`emetic therapy and requiring hydration for more than 24 hours; grade 3 or
`worse diarrhea occurring despite loperamide therapy; or treatment delay last-
`ing more than 4 weeks. Elevation of ␥-glutamyltransferase was not considered
`a DLT. Assessment of renal toxicity was conducted per previously published
`guidelines.21 Elevations in creatinine or decreases in CrCL that moved a
`patient to a more advanced renal dysfunction group were considered DLT. If
`CrCL worsened by ⱖ 30%, the patient was removed from the study. No dosing
`changes were made for improvements in renal function. The National Cancer
`Institute Common Toxicity Criteria, Version 2.0, were used to assess all toxic-
`ities.22 The maximum-tolerated dose (MTD) for each group was defined as the
`highest dose tested in which one patient or fewer experienced DLT when at
`least six patients had been treated at that dose.
`
`Pharmacokinetic Studies
`On day 1, 7-mL heparinized venous blood samples were obtained before
`and at 0.5, 1, 2, 3, 4, 8, 12, 24, 36, 48, and 72 hours after imatinib ingestion. On
`day 15, blood samples were obtained just before and at 0.5, 1, 2, 3, 4, 8, 10, 12,
`13, 16, and 24 hours after imatinib ingestion. Plasma was prepared by centrif-
`ugation and stored at ⫺20°C until analyzed for drug content. Imatinib protein
`binding on the day 15, 24-hour sample was determined by equilibrium dialy-
`sis.23 Alpha-1 acid glycoprotein (AGP) concentrations in serum obtained
`before therapy and on day 15 were measured by immunonephelometry (Dade
`Behring nephelometer; Covance CLS, Indianapolis, IN). On day 1, urine was
`collected for 24 hours after imatinib ingestion, and an aliquot was stored at
`⫺20°C until analyzed for drug content.
`Plasma and urinary concentrations of imatinib and its active metabolite
`N-desmethyl-imatinib (CGP74588) were determined by a validated liquid
`chromatography/mass spectrometry assay.24 Concentration versus time data
`for imatinib and CGP74588 were modeled noncompartmentally using the
`Lagrange function as implemented by the LAGRAN computer program.25,26
`
`Statistical Methods
`Statistical methods are described in detail in the Appendix (on-
`line only).27
`
`Table 1. Imatinib Dose Administration and Dose-Escalation Schema
`
`Group A
`
`Group B
`
`Group C
`
`Group D
`
`Dose Level
`
`Dose (mg)
`
`No. of Patients
`
`Dose (mg)
`
`No. of Patients
`
`Dose (mg)
`
`No. of Patients
`
`Dose (mg)
`
`No. of Patients
`
`1
`2
`3
`4
`5
`Total patients
`
`400
`600
`800ⴱ
`—
`—
`
`4
`4
`6
`
`14
`
`400
`600
`800ⴱ
`—
`—
`
`4
`9
`9
`
`22
`
`200
`400
`600
`800ⴱ
`
`8
`4
`10
`0
`
`22
`
`100
`200
`400
`600
`800ⴱ
`
`2
`0
`0
`0
`0
`2
`
`NOTE. Imatinib dose is shown in milligrams per day administered orally in 28-day cycles.
`ⴱGiven in divided daily dose (400 mg bid) except for day 1, when given as a single dose.
`
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`
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`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`571
`
`Boehringer Ex. 2025
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`IPR2016-01565
`Page 2
`
`

`
`Gibbons et al
`
`RESULTS
`
`Table 3. Cumulative Toxicity Experience for All 60 Patients During Cycle 1
`
`Patient Demographics
`Sixty patients were enrolled between September 2001 and Febru-
`ary 2005 (Table 2). Fourteen patients were entered in group A, 22
`patients were entered in group B; 22 patients were entered in group C,
`and two patients were entered in group D. One group B patient had
`incomplete data; only registration and safety data were analyzed. No
`patients requiring dialysis were enrolled, and it was deemed expedi-
`tious not to delay closure of the study for purposes of recruiting only
`this cohort. Causes of renal insufficiency (groups B through D) were
`identified retrospectively for 34 (74%) of the 46 patients.
`Safety Profile
`A total of 182 imatinib cycles were administered. The cumulative
`experience of clinical toxicity occurring in all 60 patients during the
`first cycle of therapy is summarized in Table 3. The MTD of imatinib
`was not reached for any group. Group A had a higher proportion of
`
`Table 2. Patient Demographics and Causes of Renal Insufficiency
`
`Characteristic
`
`No. of
`Patients
`
`63
`16-84
`
`Sex
`Male
`Female
`Age, years
`Median
`Range
`Race/ethnicity
`White
`African American
`Unknown
`ECOG performance status
`0
`1
`2
`Tumor type
`c-kit (CD117), status unknown
`Renal
`Colorectal
`Lung
`Ovarian cancer
`Sarcoma
`Melanoma
`Other
`c-kit (CD117)-positive
`GIST
`Endometrial stromal tumor
`Other (thymus, Ewing’s sarcoma, colon, pancreas)
`Normal renal function
`Cause of renal insufficiency, retrospectively
`identified in 34 (74%) of 46 patients
`Multi-factorial
`Age-related
`Atherosclerotic cardiovascular disease
`Prior chemotherapy
`Cisplatin based
`Non–cisplatin based
`Other
`
`29
`31
`
`54
`5
`1
`
`17
`36
`7
`
`53
`10
`5
`4
`4
`5
`3
`22
`7
`2
`1
`4
`14
`
`20
`5
`3
`3
`2
`1
`3
`
`%
`
`48
`52
`
`90
`8
`2
`
`28
`60
`12
`
`88
`
`12
`
`59
`15
`9
`9
`
`9
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; GIST, gastroin-
`testinal stromal tumor.
`
`Toxicity
`
`Nausea
`Vomiting
`Fatigue
`Hemoglobin
`Creatinine
`Edema
`Hyperglycemia
`Anorexia
`Diarrhea
`Hypoalbuminemia
`Lymphopenia
`Abdominal pain
`Rash/desquamation
`Dyspnea
`Hypocalcemia
`Alkaline phosphatase
`Constipation
`Headache
`Hyponatremia
`Hypophosphatemia
`
`1
`
`30
`16
`17
`11
`9
`16
`11
`12
`14
`8
`0
`11
`11
`0
`9
`8
`7
`10
`9
`2
`
`Gradeⴱ
`
`3
`
`4
`3
`2
`7
`5
`0
`2
`0
`1
`4
`6
`1
`0
`3
`2
`0
`2
`1
`2
`4
`
`2
`
`7
`8
`7
`6
`8
`6
`3
`4
`1
`4
`10
`3
`4
`9
`1
`3
`2
`0
`0
`3
`
`4
`
`0
`0
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`5
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`Total
`
`41
`27
`26
`24
`22
`22
`17
`16
`16
`16
`16
`15
`15
`12
`12
`11
`11
`11
`11
`9
`
`ⴱDose-limiting toxicity was assessed during this cycle. Toxicity was graded
`according to the National Cancer Institute Common Toxicity Criteria (version
`2.0).22 Baseline abnormalities such as anemia and renal dysfunction were not
`ascribed relation to study drug at study entry; change in these or any other
`abnormalities or toxicity are captured in Table 3.
`
`assessable patients (13 of 14 patients) than did group B (14 of 22
`patients) or group C (14 of 22 patients). Both group D patients
`were assessable.
`DLT occurred in two patients with mild renal dysfunction and
`two patients with moderate dysfunction (Table 4). A patient with mild
`renal dysfunction having grade 3 dyspnea (not treatment-related) had
`the dose reduced from 800 mg/d to 600 mg/d per protocol beginning
`on day 5 of cycle 1. After receiving 600 mg/d from days 5 through 15,
`the patient experienced drug-related grade 3 hypophosphatemia. An-
`other patient with mild renal dysfunction at the 800-mg/d dose level
`experienced grade 3 dyspnea owing to imatinib-related fluid reten-
`tion. One patient with moderate renal dysfunction at the 200-mg/d
`dose level had a DLT of grade 3 vomiting that resulted in Mallory-
`Weiss tears, and another, at the 600-mg/d dose level, experienced
`dose-limiting grade 3 hypophosphatemia and fatigue.
`Imatinib was generally well tolerated (Table 3). The most fre-
`quently reported adverse events over the course of the entire study
`across all cohorts and dose levels were primarily mild to moderate in
`
`Table 4. Summary of Dose-Limiting Toxicity Encountered in the Study
`
`Group
`
`Dose (mg)
`
`No. of
`Patients
`
`Description
`
`B
`B
`C
`
`C
`
`600
`800
`200
`
`600
`
`9
`9
`8
`
`10
`
`Grade 3 hypophosphatemia
`Grade 3 dyspnea
`Grade 3 nausea and vomiting with
`Mallory-Weiss tears
`Grade 3 hypophosphatemia and
`fatigue
`
`572
`
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`Boehringer Ex. 2025
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`IPR2016-01565
`Page 3
`
`

`
`Imatinib Dosing in Patients With Renal Dysfunction
`
`severity, and the majority were toxicities known to be associated with
`imatinib (see Appendix).
`There was a significant difference in cycle 1, day 1 (baseline)
`albumin among the four patient groups (P ⫽ .025; Appendix Table
`A1, online only). The pair-wise comparison showed no significant
`difference in baseline albumin between groups A and B, groups B and
`C, groups B and D, and groups C and D. However, there were signif-
`icant differences in baseline albumin between groups A and C
`(P ⫽ .0009) and groups A and D (P ⫽ .0126). Edema was considerably
`more frequent among patients with normal renal function (64%) than
`among those patients with mild (27%) or moderate (27%) dysfunc-
`tion over the course of study treatment. There was no significant
`association between renal function group and edema grade or the
`presence or absence of edema when the analysis was restricted to cycle
`1 (data not shown). Similarly, there was no significant association
`between edema grade and dose level during the first cycle (data not
`shown). However, when edema was classified as absent or present,
`logistic regression indicated that dose level was significantly related to
`edema (P ⫽ .033). Specifically, with every 200-mg increase in imatinib
`dose, the odds of having edema at any time during the study increased
`1.87-fold (Appendix Table A2, online only).
`Serious adverse events (SAEs) were more common in patients
`with renal impairment than in patients with normal renal function.
`SAEs were reported in two (14%) of 14 patients with normal renal
`function, 13 (59%) of 22 patients with mild dysfunction, nine (43%)
`of 21 patients with moderate dysfunction, and two (100%) of two
`patients with severe dysfunction (P⫽ .0096). There was no correlation
`between imatinib dose and SAEs in any group. All 13 patient deaths
`that occurred on this study were related to disease progression; none
`were considered to be treatment-related.
`
`Time on Study and Efficacy Evaluation
`The median duration of treatment was 52 days (range, 8 to 588
`days; 95% CI, 43 to 59 days). No objective responses were observed.
`Fourteen patients had stable disease, several of which were longstand-
`ing: a group A patient with gastrointestinal stromal tumor (c-kit⫹)
`treated with 600 mg/d (511 days), a group C patient with liposarcoma
`treated with 200 mg/d (224 days), a group C patient with invasive
`thymoma (c-kit⫹) treated with 600 mg/d (203⫹ days), and a group D
`patient with non–small-cell lung cancer treated with 100 mg/d (143
`days). The median duration of treatment of patients with c-kit⫹
`tumors (n ⫽ 7) was 105 days, whereas that of patients with c-kit status
`unknown tumors was 50.5 days (P ⫽ .108). Group A patients re-
`mained on the study longer than did those in groups B and C
`(P ⫽ .025; Appendix Fig A1, online only).
`Pharmacokinetics
`Pharmacokinetic data after the first dose of imatinib (day 1) and
`at steady-state (day 15) were available for 51 and 47 patients, respec-
`tively (Table 5). The rate of imatinib absorption, as reflected by time to
`maximum serum concentration, was similar in all groups, although
`there was considerable interpatient variability. After the first imatinib
`dose, the imatinib elimination half-lives were similar among the four
`groups, with mean values of approximately 19 hours on day 1 and 28
`hours on day 15. On days 1 and 15, the dose-normalized maximum
`serum concentration (Cmax) was approximately 1.6- and 2.2-fold
`greater in the mild and moderate renal dysfunction groups, respec-
`tively, than in the normal group; however, there was large variability
`within each group. As with Cmax, imatinib exposure, as expressed by
`dose-normalized AUC0-⬁ (area under the curve from 0 to infinity)
`on day 1 and AUC0-24 (AUC from 0 to 24 hours) on day 15, was
`
`Table 5. Pharmacokinetic Parameters of Imatinib and CGP74588 and Summary of AGP Levels
`
`Normal
`
`Mild Renal Dysfunction
`
`Moderate Renal Dysfunction
`
`Severe Renal Dysfunction
`
`Day 1 (n⫽ 13)
`
`Day 15 (n ⫽ 12)
`
`Day 1 (n ⫽ 20)
`
`Day 15 (n ⫽ 18)
`
`Day 1 (n ⫽ 16)
`
`Day 15 (n ⫽ 15)
`
`Day 1 (n ⫽ 2)
`
`Day 15 (n ⫽ 2)
`
`Plasma pharmacokinetics
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`Imatinib
`Tmax, hours
`Cmax, ng/mL/mg
`AUC, (ng/mL ⫻ h)/mg
`CL/F, L/h
`t1/2, hours
`V/F, L
`Percentage free
`
`4.4
`5.13
`108
`10.1
`17.2
`234
`
`3.1
`1.98
`35ⴱ†
`2.7
`6.6
`62.4
`
`3.3
`4.7
`2.11
`6.52
`42‡
`114
`5.5
`10.3
`10.7
`26.8
`137.1
`355.7
`2.4
`6.2
`(n ⫽ 10)
`
`3.0
`8.29
`213
`6.5
`19.3
`164.4
`
`1.5
`3.42
`119†
`4.6
`6.7
`93.0
`
`3.2
`11.42
`269
`4.8
`20.7
`139.0
`
`1.6
`5.79
`166†
`2.1
`6.7
`71.2
`
`1.6
`3.3
`4.77
`10.59
`77‡
`173
`4.7
`7.5
`24.1
`30.5
`290.1
`308.0
`4.1
`6.1
`(n ⫽ 12)
`
`1.1
`3.0
`8.08
`14.62
`119‡
`229
`2.8
`5.6
`17.8
`25.2
`235.7
`229.2
`3.0
`4.7
`(n ⫽ 5)
`
`3.5
`6.91
`124
`10.6
`21.3
`366.7
`
`0.7
`6.49
`86†
`7.3
`7.9
`345.0
`
`2.5
`13.32
`190
`5.8
`40.1
`290.0
`
`0.7
`6.10
`70‡
`2.1
`23.8
`73.3
`
`4.2
`0.72
`24.6
`
`2.8
`0.37
`14.8
`
`5.0
`1.39
`25.7
`
`3.1
`0.44
`9.2
`
`3.9
`1.35
`53.4
`
`2.3
`0.71
`32.2
`
`4.0
`2.68
`45.2
`
`2.4
`1.44
`24.2
`
`4.4
`1.56
`55.7
`
`2.7
`1.31
`40.9
`
`3.9
`3.2
`54.5
`
`1.8
`2.14
`37.6
`
`3.0
`5.71
`26.3
`
`1.4
`6.39
`11.7
`
`CGP 74,588
`Tmax, hours
`Cmax, ng/mL/mg
`AUC, (ng/mL ⫻ h)/mg
`
`t1/2, hours
`
`29.5
`
`12.2
`
`48.3
`
`64.7§
`
`35.2
`
`16.4
`
`39.3
`
`52.7
`
`41.7
`
`26.6
`
`36.6
`
`24.4
`
`2.8
`6.0
`0.015
`0.45
`Could not
`calculate
`Could not
`calculate
`Could not
`calculate
`(n ⫽ 2)
`2
`
`2
`
`33.6
`
`3.3
`
`0.136
`
`0.011
`
`—
`—
`
`CGP74599/imatinib AUC
`ratio
`Urinary excretion
`% of dose excreted as
`imatinib and CGP74588
`AGP, mg/dL
`
`0.238
`
`0.162
`
`0.242
`
`0.090
`
`0.261
`
`0.102
`
`0.255
`
`0.055
`
`0.212
`
`0.062
`
`0.230
`
`0.048
`
`(n ⫽ 7)
`2
`
`4
`
`—
`—
`
`(n ⫽ 13)
`2
`
`3
`
`—
`—
`
`(n ⫽ 9)
`1
`
`3
`
`—
`—
`
`99.5
`
`53.0
`
`112.4
`
`46.5
`
`87.4
`170.9
`(n ⫽ 18)
`
`91.5
`183.9
`(n ⫽ 16)
`
`71.4
`162.0
`(n ⫽ 13
`
`163.5
`
`70.9
`
`132.0
`
`73.5
`
`147.8
`
`52.0
`
`Abbreviations: AGP, ␣1-acid glycoprotein; Tmax, time to maximum serum concentration; Cmax, maximum concentration; AUC, area under the curve; CL/F, apparent
`clearance; t1/2, terminal half-life; V/F, apparent volume.
`ⴱMean ⫾ SD.
`†Dose-normalized area under the plasma concentration versus time curve from time 0 to ⬁.
`‡Dose-normalized area under the plasma concentration versus time curve from time 0 to 24 hours.
`§Precision of estimated t1/2 was compromised by daily dosing, which limited pharmacokinetic sampling to 24 hours after day 15 dose.
`
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`
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`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`573
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`

`
`Gibbons et al
`
`50
`
`100
`150
`200
`250
`300
`α-1 Acid Glycoprotein (mg/dL)
`
`350
`
`400
`
`50
`
`100
`150
`200
`250
`300
`α-1 Acid Glycoprotein (mg/dL)
`
`350
`
`400
`
`50
`
`100
`150
`Creatinine Clearance (mL/min)
`
`200
`
`250
`
`450
`
`400
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`20
`
`18
`
`16
`
`14
`
`12
`
`10
`
`68
`
`4 2 0
`
`400
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`A
`
`Dose-Normalized Imatinib AUC ([ng/mL • h]/mg)
`
`B
`
` Imitinib CL/F (L/h)
`
`C
`
`α-1 Acid Glycoprotein (mg/dL)
`
`Fig 1. Relationship between creatinine clearance and imatinib apparent clearance.
`Points represent individual patients. (A) Alpha-1 acid glycoprotein (AGP) concentration
`and dose-normalized imatinib area under the curve (AUC); (B) AGP concentration and
`imatinib clearance (CL/F); (C) AGP concentration and creatinine clearance.
`
`dysfunction. Although Pappas et al33 reported that imatinib pharma-
`cokinetics parameters in a patient on hemodialysis were not differ-
`ent than those in patients with normal renal function, the imatinib
`
`significantly greater in patients with mild or moderate dysfunction
`than in those with normal renal function. In that apparent clearance is
`defined as dose/area under the curve (AUC), there was a corre-
`sponding significant decrease in imatinib clearance as renal func-
`tion worsened (Table 5 and Fig 1). The apparent volume of
`distribution on days 1 and 15 was significantly lower for patients with
`mild and moderate dysfunction than for patients with normal renal
`function. The percentage of unbound imatinib ranged between 2.1%
`and 14.5% (Table 5).
`In all groups, the half-life of CGP74588 was longer than that of
`imatinib and, although there was great interpatient variability, there
`was a trend for the CGP74588 half-life assessed after the day 1 dose to
`increase as renal function worsened (Table 5). The limit of pharma-
`cokinetic sampling to 24 hours after the day 15 dose precluded accu-
`rate assessment of the half-life after that dose. The day 1 and 15
`dose-normalized CGP74588 Cmax was approximately 1.9-fold and
`2.2-fold greater in the mild and moderate dysfunction groups, respec-
`tively, than in the normal group. As with Cmax, CGP74588 exposure,
`expressed by dose-normalized AUC0-⬁ on day 1 and AUC0-24 on day
`15, was approximately two-fold greater in patients with mild or mod-
`erate renal dysfunction than in those with normal renal function. The
`CGP74588/imatinib AUC ratio was comparable in patients with renal
`dysfunctions and normal controls, with the mean value ranging be-
`tween 0.21 and 0.26, except for the two patients in the severe renal
`dysfunction group averaging 0.14 (Table 5).
`There was a positive correlation between AGP concentration and
`dose-normalized imatinib AUC0-⬁ on day 1 and AUC0-24 on day 15,
`inverse correlation between AGP concentration and imatinib appar-
`ent clearance, and an inverse relationship between AGP concentra-
`tions and CrCL (Fig 1, Table 5). Urinary excretion of imatinib and
`CGP74588 accounted for less than 10% of the imatinib dose and was
`not significantly different among the various groups (Table 5).
`
`DISCUSSION
`
`This study is the first systematic, prospective investigation of the safety
`and pharmacokinetics of imatinib in patients with renal dysfunction.
`Initial pharmacokinetic studies of imatinib were done primarily in
`patients with chronic myeloid leukemia and demonstrated rapid ab-
`sorption; approximately 100% bioavailability; a plasma half-life of 10
`to 23 hours; a two- to three-fold accumulation at steady-state; no effect
`of food on pharmacokinetic parameters; mainly hepatic metabolism,
`primarily by CYP3A; binding to AGP; and ⱕ 10% renal excretion.28-32
`Earlier-phase studies of imatinib also identified electrolyte abnormal-
`ities, fluid retention and edema as toxicities, and the potential for
`significant drug-drug interactions, all of which provided the rationale
`to explore dosing in patients with renal dysfunction.5-10
`The overall safety, side effect profile, and tolerability of ima-
`tinib in patients with renal dysfunction are similar to those in
`patients with acceptable renal function. An MTD was not reached
`in either the minimal or moderate renal dysfunction groups. Only
`two patients with severe renal dysfunction and no patients on renal
`dialysis were treated, which precludes any firm conclusion on
`dosing of such patients.
`Despite comparable toxicity across normal, mild, and moderate
`renal dysfunction groups, an unexpected observation was that ima-
`tinib pharmacokinetics were altered significantly in patients with renal
`
`574
`
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`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
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`
`

`
`Imatinib Dosing in Patients With Renal Dysfunction
`
`clearance in that patient was 4.2 L/h, which is approximately the same
`as the mean imatinib clearance in our moderate and severe renal
`dysfunction groups and significantly less than the mean imatinib
`clearance in our patients with normal renal function. Altered imatinib
`pharmacokinetics were not expected in patients with decreased renal
`function because the major route of imatinib clearance is through
`CYP3A-mediated metabolism to CGP74588, and ⱕ 13% of an ima-
`tinib dose is excreted in the urine.30-32,34 In retrospect, however, de-
`creased imatinib clearance might have been expected in patients with
`renal dysfunction because of the recognized decreased in vivo activity
`of hepatic CYPs in chronic renal failure.35-38 Another likely explana-
`tion for the decreased apparent clearance is the increased AGP con-
`centrations in patients with renal dysfunction, which would result in
`increased total plasma imatinib but decreased free fraction or un-
`changed free drug level. This implies the need to monitor free as well as
`total imatinib concentrations. Regardless of the mechanism for the
`observed increase in imatinib AUC in patients with renal dysfunction,
`the metabolite CGP74588 to imatinib AUC ratio seemed to be un-
`changed, except for the two patients in the severe renal dysfunction
`group. These results suggest that the metabolism of imatinib is prob-
`ably not affected in patients with moderate renal dysfunction.
`The finding that edema was more common over the course of
`study in patients with normal renal function was also unexpected.
`Edema and fluid retention are commonly encountered side effects of
`imatinib, and the cautionary emergence of congestive heart failure as a
`late toxicity of imatinib treatment raises concern about this clinical
`sign and toxicity.39-43 It is difficult to ascertain the significance of
`edema over the course of a phase I trial treating patients with refractory
`solid tumors as well as renal dysfunction. However, patients with
`normal renal function remained on study longer than did patients
`with mild or moderate dysfunction, which may be related to why
`normal patients were more prone to develop edema over the course of
`therapy. Nonetheless, there was no apparent increased risk of edema
`during the critical evaluative first cycle for safety across the renal
`function cohorts, and there may have been a dose-response effect
`when we analyzed dose level and grouped patients by absence or
`presence of edema. In a large phase II sarcoma study, edema, particu-
`larly periorbital edema, was seen in 84% of patients studied, which
`tended to occur within the first 8 weeks of therapy.44 Esmaeli et al45
`reported that edema from imatinib may result from inhibition of
`c-kit in dermal dendrocytes, and our results suggest that this may
`be dose-dependent.
`In summary, although there was an unanticipated increase in
`drug exposure in patients with mild or moderate renal dysfunction,
`this was not associated with any increased clinically meaningful toxic-
`ity or drug-related adverse events. Too few patients with CrCL less
`than 20 mL/min were evaluated to draw any conclusions about the
`behavior of imatinib in such patients. Given our results, there is no
`
`requirement for modification of initial imatinib doses given to pa-
`tients with mild or moderate renal dysfunction who can tolerate daily
`imatinib doses up to 800 mg and 600 mg, respectively. It may be
`prudent to reduce the initial dose of imatinib given to patients with
`severe renal dysfunction until more experience is gained in this subset
`of patients.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated a financial or other interest that is relevant to the subject
`matter under consideration in this article. Certain relationships marked
`with a “U” are those for which no compensation was received; those
`relationships marked with a “C” were compensated. For a detailed
`description of the disclosure categories, or