DEVELOPMENT OF A PHARMACOKINETIC (PK) MODEL AND ASSESSMENT OF PATIENT (PT)
`COVARIATE EFFECTS ON DOSE-DEPENDENT PK FOLLOWING DIFFERENT DOSING SCHEDULES IN
`TWO PHASE I TRIALS OF AP23573 (AP), AN mTOR INHIBITOR
`A.A. Desai1†, M. Mita2, G.J. Fetterly3, C. Chang3, M. Netsch4, H.L. Knowles5, C.L. Bedrosian5, E.Rowinsky2, A. Tolcher2, M.J. Ratain1
`1University of Chicago, Chicago, IL USA; 2Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX USA; 3Cognigen Corporation, Buffalo, NY USA;
`4Charles River Laboratories Discovery and Development Services, Worcester, MA USA; and 5ARIAD Pharmaceuticals, Inc., Cambridge, MA USA
`Abstract #: 3043
`AP23573 PK Model
`PK Modeling of AP23573 – Once Weekly and Daily
`Background
`Methods and Results
`Effects of Patient Covariates on AP23573 PK – Daily
`AP23573 is a novel non-prodrug rapamycin analog that potently inhibits
`Dosing
`mTOR (through bivalent binding to FKBP and mTOR), a downstream
`effector of PI3K/Akt and nutrient-sensing pathways. A PK model was
`developed to characterize the blood concentration-time profile of AP23573
`and evaluate patient covariate effects following different dosing schedules.
`Phase I Objectives
`Trial Designs
`• Two phase I trials: open label,
`• Determine safety, tolerability and MTD of
`sequential, accelerated titration
`single-agent AP23573 in pts with refractory
`• Flat-fixed dosing of AP23573 as a
`or recurrent malignancies that are
`30-minute IV infusion without
`advanced or metastatic, and not amenable
`premedication
`to standard therapy or surgery
`• One trial examining AP23573
`administered once weekly starting
`• To develop a compartmental PK model
`at 6.25 mg
`that can adequately characterize the
`• One trial examining AP23573
`pharmacokinetics of AP23573 and provide
`administered QDx5 (Daily) every
`reasonable estimates of PK parameters,
`other week (two courses of 5 days
`resulting in the ability to apply the PK
`of dosing followed by a 9 day rest
`per cycle) starting at 3 mg
`model to future clinical trials; and
`• To examine the effect of patient covariates
`on AP23573 PK parameters; AUC, CL,
`and Vss.
`Phase I Trials – Patient Population
`
`12
`
`10
`
`n=3
`
`n=1
`
`n=5
`
`8
`
`6
`
`4
`
`2
`
`Onset of Mucositis/Stomatitis(days)
`
`n=1
`
`n=4
`
`n=1
`
`21
`
`18
`
`15
`
`12
`
`0369
`
`Onset of Mucositis(days)
`
`3 6
`
`.25
`
`12.5
`15
`
`18.75
`
`28
`
`10
`
`20
`
`25
`
`30
`
`10
`
`20
`
`30
`
`40
`
`70
`
`80
`
`90
`
`100
`
`10
`
`0123456789
`
`AUC (mg*hr/mL)
`
`6.25
`12.5
`25
`50
`75
`100
`
`22
`20
`18
`16
`14
`12
`10
`
`AUC (mg*hr/mL)
`
`AP23573 Blood Concentration (ng/mL)
`
`160
`
`180
`
`1
`
`0
`
`20
`
`40
`
`60
`
`140
`
`160
`
`180
`
`IC50 < 6 ng/mL
`
`1
`
`0
`
`20
`
`40
`
`60
`
`AP23573 Blood Concentration (ng/mL)
`
`0
`
`10
`
`20
`
`30
`
`70
`
`80
`
`90
`
`100
`
`02468
`
`Vss (L)b
`
`Common Tumor types
`
`101 (N=46)
`
`102 (N = 33)
`
`8
`8
`12
`
`1
`7
`5
`
`50
`60
`Weekly Dose (mg)
`
`12
`
`14
`
`16
`
`18
`20
`Daily Dose (mg)
`
`22
`
`24
`
`26
`
`28
`
`• Severity and time to onset of mucositis related to dose
`• No relationship observed between Cmax and onset date of mucositis
`Summary and Conclusions
`
`• AP23573 PK are nonlinearly related with dose
`•
`Interpatient variability of model-predicted PK parameters was modest within each cohort
`• Dose, BSA, and RBC are significant patient factors that describe the interpatient variability in Vss and CL
`• The relationship between dose and AUC, Vss, and CL could be attributed to saturation of distibution sites, such as RBC, allowing for deeper
`penetration of AP23573 to other tissues
`• Based on a dose-toxicity relationship, onset of mucositis is faster with once daily dosing regimen of AP23573, which may be attributed to
`sustained blood levels above a threshold concentration indicative of triggering a DLT
`• Both QW and QD x 5 regimens provide therapeutic AP23573 concentrations that exceed the IC50, thus providing support for utility of both
`regimens in Phase 2 trials currently ongoing
`• AP23573 has a reproducible and predictable pharmacokinetic profile with limited interpatient variability. These features are supportive of its
`use in combination chemotherapy regimens where precise pharmacokinetic behavior is crucial.
`
`References
`
`• Raymond E, et al. J. Clin. Oncol. 22: 2336-2347, 2004.
`• Ferron G, et al. Clin. Pharmacol. Ther. 61: 416-428, 1997.
`• AP23573 Investigator’s Brochure
`
`Acknowledgements:
`• Cognigen Corporation project team
`• Charles River Laboratories
`• The patients participating in the trials
`
`This research was supported by ARIAD Pharmaceuticals, Inc.
`
`60
`50
`40
`Weekly Dose (mg)
`
`0
`
`5
`
`15
`Daily Dose (mg)
`
`Red line represents model fit.
`
`Steady State Volume of Distribution vs. Dose Following Once
`Weekly or Daily Dosing
`
`700
`
`450
`
`400
`
`350
`
`300
`
`36
`
`.25
`12.5
`15
`18.75
`28
`
`250
`
`200
`
`Vss(L)
`
`150
`
`100
`
`50
`
`0
`
`0
`
`5
`
`10
`
`15
`Daily Dose (mg)
`
`20
`
`25
`
`30
`
`6.25
`12.5
`25
`50
`75
`100
`
`10
`
`20
`
`30
`
`60
`50
`40
`Weekly Dose (mg)
`
`70
`
`80
`
`90
`
`100
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`0
`
`Vss(L)
`
`• AP23573 displays nonlinear pharmacokinetics
`– Cmax and AUC increase disproportionately with dose
`– Both Vss and CL increase with dose
`• T1/2 remains constant due to increases in both Vss and CL with dose
`• These findings suggest that the dose nonlinearity has to be accounted for prior to assessment of patient covariate effects on
`AP23573 PK parameters
`
`• Colorectal carcinoma
`• Renal cell carcinoma
`• Lung (NSCLC*)
`– NSCLC, large cell, Bronchoalveolar carcinoma
`– Mesothelioma
`• Soft tissue sarcoma
`– Malignant mixed mullerian, liposarcoma
`leiomyosarcoma, GIST
`• Other sarcoma
`– Ewing’s tumor, Osteosarcoma
`• Breast
`• Head and neck
`• Other **
`
`6
`
`--
`
`--
`--
`12
`
`5
`
`3
`
`2
`2
`8
`
`*NSCLC = non small cell lung cancer
`**Other tumor types included:
`Trial 101 – Adenocarcinoma (2), cholangiocarcinoma, esophageal adenocarcinoma, medually thryoid, melanoma,
`ovarian, periampullary, prostate, small bowel carcinoma, squamous cell carcinoma, transitional cell bladder cancer.
`Trial 102 - Hepatocellular, hurtle cell thyroid, large cell lymphoma, melanoma, pancreatic, prostate, uterine cancer,
`neuroendocrine
`
`Trial 101 – 31M/15F, median age 61.5 yrs
`• Maximum Tolerated Dose (MTD) = 75 mg
`• Dose Limiting Toxicity: Two (2) occurrences of
`Grade 2/3 mucositis at 100 mg
`
`Trial 102 – 17M/16F, median age 51.0 yrs
`• Maximum Tolerated Dose (MTD) = 18.75 mg
`• Dose Limiting Toxicity: Two (2) occurrences
`of Grade 3 mucositis at 28 mg
`
`120
`100
`80
`140
`120
`100
`80
`Time Since Last Dose (hr)
`Time Since Last Dose (hr)
`• At therapeutic doses of 50 mg QW and 12.5 mg QD x 5 (TD = 62.5 mg), AP23573 blood concentrations exceed the IC50
`of various tumor types for > 180 hr
`Mean Predicted Blood PK Parameters of AP23573
`Trial
`Dose (mg)
`Cmax
`AUC 0-¥ or 0-24
`CL (L/hr)
`T1/2 (hr)
`(N)
`(ng/mL)
`(µg*hr/mL)
`6.25 (1)
`329
`3.1
`12.5 (3)
`394 ± 56
`4.6 ± 1.5
`25 (4)
`570 ± 56
`7.6 ± 1.7
`50 (15)
`982 ± 194
`10.0 ± 2.6
`75 (15)
`1195 ± 279
`11.8 ± 3.6
`100 (4)
`1255 ± 97
`11.9 ± 2.4
`3 (1)
`263a
`2.0
`6.25 (2)
`321 ± 57a
`2.8
`12.5 (2)
`618 ± 212a
`4.7
`15 (6)
`576 ± 89a
`4.4 ± 0.8
`18.75 (12)
`611 ± 178a
`4.4 ± 1.0
`28 (6)
`774 ± 232a
`6.0 ± 2.4
`
`57.3
`52.6 ± 13.9
`44.8 ± 6.7
`57.6 ± 27.6
`58.2 ± 16.6
`50.9 ± 4.0
`55.7
`65.1
`73.5
`59.5 ± 11.6
`61.7 ± 12.4
`70.7 ± 26.8
`
`2.0
`3.0 ± 1.1
`3.4 ± 0.7
`5.4 ± 1.5
`7.0 ± 2.2
`8.7 ± 1.9
`1.5
`2.4
`2.7
`3.5 ± 0.5
`4.4 ± 0.9
`5.4 ± 2.3
`
`148
`167 ± 30
`188 ± 20
`322 ± 72
`429 ± 89
`523 ± 83
`59.2
`137
`171
`150 ± 33
`206 ± 45
`248 ± 87
`
`Single Dose
`(Trial101:
`Single N = 42*
`
`Multiple Dose
`(Trial102:
`Day 5)
`N = 29*
`
`Mean predicted blood PK parameters for AP23573. * represents the PK evaluable population.
`a Observed Cmax is on Day 1, b Vss - steady-state volume of distribution
`
`300
`
`270
`
`240
`
`210
`
`180
`
`150
`
`120
`
`90
`
`60
`
`30
`
`0
`
`Vss(L)
`
`1.0
`
`1.2
`
`1.4
`
`1.6
`
`2.2
`
`2.4
`
`2.6
`
`2.8
`
`3.0
`
`2.4
`
`2.8
`
`3.2
`
`4.8
`
`5.2
`
`5.6
`
`6.0
`
`360
`
`320
`
`280
`
`240
`
`200
`
`160
`
`120
`
`80
`
`40
`
`0
`
`Vss(L)
`
`AP23573 Once Daily
`
`Patient 102-418
`18.75 mg
`
`Observed
`Predicted
`
`1000.0
`
`100.0
`
`10.0
`
`1.0
`
`AP23573 Blood Concentration (ng/mL)
`
`AP23573 Once Weekly
`
`Patient 101-408
`50 mg
`
`Observed
`Predicted
`
`10000
`
`1000
`
`100
`
`10
`
`1
`
`0
`
`20
`
`40
`
`AP23573 Blood Concentration (ng/mL)
`
`Representative
`model-fitted and
`observed
`AP23573
`concentration-
`time profiles for
`patients in the
`once weekly or
`daily dosing trials
`
`V2
`Highly Perfused
`Tissues
`2
`
`DIV
`
`CLD (1, 2)
`
`C L D
`
` 3 )
`
`( 1 ,
`
`Vp
`
`Plasma
`
`Blood
`
`1
`
`VRBC
`
`CLPL-RBC
`RBC
`
`CLt
`
`V3
`Less Perfused
`Tissues
`
`3
`
`•
`
`†presenting author
`
`Dose (mg)
`
`1.8
`2.0
`BSA (m2)
`12.50
`
`6.25
`
`18.75
`
`3.6
`4.0
`4.4
`RBC (cells x106/mm3)
`6.25
`12.50
`
`18.75
`
`Dose (mg)
`
`• Vertical lines represent the data range on which the model was developed. In Trial 102, BSA ranged from 1.5-2.4 m2 and RBC ranged
`from 3.1-5.4 cells x106/mm3
`
`Trial 101 (Weekly)
`Trial 102 (Daily)
`• AUC increases disproportionately with dose
`• AUC increases disproportionately with dose
`• CL increases with dose and in females
`• CL increases with dose, but is inversely related to RBC
`• Vss increases with dose, but is inversely related to RBC
`• Vss increases with dose and BSA, but is inversely related to RBC
`Incidence of Mucositis following Weekly or QDx5 Dosing
`
`27
`
`24
`
`n=5
`
`n=10
`
`14
`
`n=9
`
`130
`120
`110
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`0
`
`10
`
`20
`
`30
`
`T1/2(hr)
`
`• Whole blood AP23573 samples were analyzed using
`LC/MS/MS
`• Using a two-stage population PK approach, each
`individual’s AP23573 blood concentrations were best fit to
`a 3-compartment model using WinNonlin. Model
`characteristics include separate compartments for highly-
`and less-perfused tissues
`• Compartmental modeling best captured the tri-exponential
`decline of AP23573 blood concentrations over time, thus
`providing reasonable PK parameter estimates of T1/2, Vss,
`CL, and AUC
`Linear and nonlinear regression methods were utilized to
`evaluate patient covariate effects on dose-dependent
`AP23573 PK parameters; AUC, CL, and Vss
`– Patient factors include sex, age, baseline RBC, body
`weight, and BSA
`– Significance was determined at a = 0.05
`
`DIV = IV infusion of AP23573
`CLt = apparent total body clearance
`CLD (1, 2) = distributional clearance between plasma and highly perfused tissues
`CLD (1, 3) = distributional clearance between plasma and less perfused tissues
`Vp, VRBC , V2, and V3 are the plasma, red blood cell, and tissue volumes of distribution,
`respectively
`
`Once Weekly Dosing
`
`Once Daily Dosing for 5 Days (Day 5)
`
`3 6
`
`.25
`
`12.5
`
`15
`
`18.75
`
`28
`
`IC50 < 6 ng/mL
`
`1000
`
`100
`
`10
`
`6.25
`
`12.5
`
`25
`
`50
`
`75
`
`100
`
`10000
`
`1000
`
`100
`
`10
`
`Half-life vs. Dose Following Once Weekly or Daily Dosing
`
`100 120 140 160 180
`80
`60
`Time Since First Dose (hr)
`
`200
`
`0.1
`0
`
`100
`
`500
`400
`300
`200
`Time Since First Dose (hr)
`
`600
`
`36
`
`.25
`12.5
`15
`18.75
`28
`
`20
`
`25
`
`30
`
`15
`Daily Dose (mg)
`
`5
`
`10
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`T1/2 (hr)
`
`6.25
`12.5
`25
`50
`75
`100
`
`70
`
`80
`
`90
`
`100
`
`60
`50
`40
`Weekly Dose (mg)
`
`AUC vs. Dose Following Once Weekly or Daily Dosing
`
`Ex. 1108-0001
`
`