Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14528-e14528
Author(s):  
J. Lu ◽  
L. Claret ◽  
L. Sutjandra ◽  
M. Kuchimanchi ◽  
D. Stepan ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Thyroid Cancer ◽  
Monte Carlo Simulations ◽  
Tumor Size ◽  
Tumor Response ◽  
Area Under The Curve ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Population Pk ◽  
The Difference

e14528 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under the curve values for motesanib, which were used as the exposure measures in population PK/PD modeling (ie, longitudinal exposure-tumor response modeling of drug effect on tumor growth dynamics). Monte Carlo simulations were used to evaluate the potential effect of doses other than 125 mg QD (75 mg and 100 mg QD) on tumor response in TC pts. Results: Clearance in MTC pts was 40% faster than in DTC pts (74 vs 44 L/h). The fit was significantly improved (P<0.001) when exposure instead of dose was used in the model. The exposure-tumor response model that incorporated the difference in exposure described change in tumor size well in both MTC and DTC populations. Clinical trial simulations using the preliminary model based on week 24 data predicted that DTC pts would achieve 19.7%, 15.7%, and 11.3% reductions in tumor size at week 24 following doses of 125 mg QD, 100 mg QD, and 75 mg QD, respectively. The actual change in median tumor size at week 24 following 125-mg QD dosing in DTC pts included in the PK/PD analysis was 17.9%. Conclusions: The use of 125 mg QD motesanib in DTC pts was supported by PK/PD modeling and Monte Carlo simulations. Differences in PK may explain the difference in tumor response observed in MTC and DTC patient populations. [Table: see text]

scholarly journals A Population Pharmacokinetic Model for Concizumab Based on Phase 1 and Phase 2 Trial Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Trine Høyer Rose ◽  
Christian Hollensen ◽  
Henrik Agersø ◽  
Rune Viig Overgaard
Keyword(s):  
Rate Constant ◽  
Drug Disposition ◽  
Hemophilia A ◽  
Phase 1 ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Publicly Traded ◽  
Phase 3 ◽  
Target Mediated Drug Disposition ◽  
Population Pk

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Validation of a Monte Carlo Modelling Based Dosimetry of Extraoral Photobiomodulation

Diagnostics ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2207
Author(s):  
Anna N. Yaroslavsky ◽  
Amy F. Juliano ◽  
Ather Adnan ◽  
Wayne J. Selting ◽  
Tyler W. Iorizzo ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Light Emitting Diode ◽  
Morphological Data ◽  
Transmitted Power ◽  
Light Dosimetry ◽  
Mean Values ◽  
Mri Scans ◽  
The Difference

An in vivo validation study was performed to confirm the accuracy of extraoral photobiomodulation therapy (PBMT) dosimetry determined by modelling. The Monte Carlo technique was utilized to calculate the fluence rate and absorbed power of light delivered through multi-layered tissue. Optical properties used during Monte Carlo simulations were taken from the literature. Morphological data of four study volunteers were acquired using magnetic resonance imaging (MRI) scans. Light emitting diode (LED) coupled to a power meter were utilized to measure transmitted power through each volunteer’s cheek, in vivo. The transmitted power determined by Monte Carlo modelling was compared to the in vivo measurements to determine the accuracy of the simulations. Experimental and simulation results were in good agreement for all four subjects. The difference between the mean values of the measured transmission was within 12% from the respective transmission obtained using Monte Carlo simulations. The results of the study indicate that Monte Carlo modelling is a robust and reliable method for light dosimetry.

scholarly journals Population Pharmacokinetics of Continuous-Infusion Meropenem in Febrile Neutropenic Patients with Hematologic Malignancies: Dosing Strategies for Optimizing Empirical Treatment against Enterobacterales and P. aeruginosa

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 785
Author(s):  
Pier Giorgio Cojutti ◽  
Anna Candoni ◽  
Davide Lazzarotto ◽  
Carla Filì ◽  
Maria Zannier ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Continuous Infusion ◽  
Hematologic Malignancies ◽  
Population Pharmacokinetic Analysis ◽  
Empirical Treatment ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Strategies ◽  
Neutropenic Patients

A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) ≥1 and ≥4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs ≥ 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC ≥4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC ≥ 4 and against P. aeruginosa at Css/MIC ≥ 1. When dealing against P. aeruginosa at Css/MIC ≥ 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80–87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function.

scholarly journals Conventional versus drug-eluting beads chemoembolization for infiltrative hepatocellular carcinoma: a comparison of efficacy and safety

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Zi-shu Zhang ◽  
Hui-zhou Li ◽  
Cong Ma ◽  
Yu-dong Xiao
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Size ◽  
Tumor Response ◽  
Liver Toxicity ◽  
Objective Response ◽  
Efficacy And Safety ◽  
Tace Group ◽  
Drug Eluting Beads ◽  
Drug Eluting ◽  
The Difference

Abstract Background To compare the efficacy and safety between conventional transarterial chemoembolization (cTACE) and drug-eluting beads TACE (DEB-TACE) in patients with infiltrative hepatocellular carcinoma (iHCC). Methods A total of 89 iHCC patients who were treated with either cTACE (n = 33) or DEB-TACE (n = 56) between April 2013 and September 2017 were included in this retrospective study. Patients with the situations that might have a poor outcome were defined as advanced disease including Child-Pugh class B, bilobar lesions, tumor size greater than 10 cm, ECOG 1–2, tumor burden of 50–70%, and the presence of ascites, arterioportal shunt (APS), and portal venous tumor thrombus (PVTT). The tumor response was measured 1-month and 3-month after the procedure. Progression-free survival (PFS) was calculated. Toxicity was graded by Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). The differences in tumor response, PFS, and toxicity were compared between the DEB-TACE group and cTACE group. Results At 1-month and 3-month after the procedure, the objective response rate (ORR) in the overall study population was similar in DEB-TACE group and cTACE group. The disease control rate (DCR), at 1-month after the procedure, was significantly higher in the patients treated with DEB-TACE relative to those treated with cTACE (P = 0.034), while after 3 months, the difference did not differ between two groups. DEB-TACE showed a higher DCR than cTACE in patients with tumor size greater than 10 cm (P = 0.036) or associated with APS (P = 0.030) at 1-month after the procedure, while after 3 months, the difference was only noted in patients with APS (P = 0.036). The median PFS in DEB-TACE group was 96 days, while in cTACE group was 94 days, and there was no difference in PFS between two groups (P = 0.831). In the side effect analysis, abdominal pain (P = 0.034) and fever (P = 0.009) were more frequently present in the cTACE group than DEB-TACE group, but there was no difference in high grade liver toxicity between the two groups. Conclusions Compared to cTACE, DEB-TACE offers slightly better DCR and tolerability for iHCC patients, particularly in patients associated with APS and large tumor size. However, DEB-TACE does not provide higher PFS than cTACE.

scholarly journals Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Cédric Carrié ◽  
Faustine Delzor ◽  
Stéphanie Roure ◽  
Vincent Dubuisson ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Body Weight ◽  
Monte Carlo Simulations ◽  
Critically Ill ◽  
Negative Pressure ◽  
Critically Ill Patients ◽  
Open Abdomen ◽  
Population Pharmacokinetic ◽  
Pressure Therapy ◽  
Dosing Regimens

ABSTRACT The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0–24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

scholarly journals Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

2011 ◽  
Vol 55 (4) ◽  
pp. 1677-1683 ◽  
Author(s):  
Nimish Patel ◽  
Katie Cardone ◽  
Darren W. Grabe ◽  
Shari Meola ◽  
Christopher Hoy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monte Carlo ◽  
Body Weight ◽  
Infective Endocarditis ◽  
Population Model ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Exposure Profile ◽  
Trough Concentrations

ABSTRACTThis study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in theStaphylococcus aureusbacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of ≥24.3 mg/liter. Separate HD dosing schemes were developed for each FDA-approved regimen and for two weekly interdialytic periods (48 and 72 h). Administration of the same parent daptomycin dose intra-HD and post-HD resulted in AUC, maximum concentration of drug in serum (Cmax), andCminvalues most comparable to those for SAB-IE simulations for the 48-hour interdialytic period. In contrast, all candidate HD dosing schemes provided AUC48-72values that were at least 50% lower than the SAB-IE AUC48-72values. Increasing the parent dose by 50% provided more comparable AUC48-72values while maintaining acceptableCminvalues. Administration of the daptomycin parent dose intra-HD or post-HD was optimal for the 48-h interdialytic period. For the 72-h interdialytic period, clinicians should consider increasing the dose by 50% to achieve more comparable AUC48-72values.

scholarly journals Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice

2015 ◽  
Vol 59 (10) ◽  
pp. 6344-6351 ◽  
Author(s):  
A. Smits ◽  
R. F. W. De Cock ◽  
K. Allegaert ◽  
S. Vanhaesebrouck ◽  
M. Danhof ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Steady State ◽  
Monte Carlo Simulations ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Prospective Evaluation ◽  
Dosing Regimen ◽  
Model Based ◽  
Almost All ◽  
Trough Levels

ABSTRACTBased on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.

Initial results from a phase II trial of motesanib diphosphate (AMG 706) in patients with differentiated thyroid cancer (DTC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6017-6017 ◽  
Author(s):  
S. I. Sherman ◽  
M. J. Schlumberger ◽  
J. Droz ◽  
M. Hoffmann ◽  
L. Wirth ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Antitumor Activity ◽  
Tumor Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Resistant Disease ◽  
Objective Tumor Response ◽  
Grade 5 ◽  
Grade 3

6017 Background: This phase 2 study evaluated the safety and efficacy of AMG 706, an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF, and Kit receptors and RET, in pts with advanced DTC or medullary thyroid cancer (MTC). Presented here are results from the DTC stratum. Methods: This was a multicenter, phase 2, open-label, single-arm study of pts with advanced thyroid cancer stratified by DTC or MTC (planned n=80 each). The primary endpoint was objective tumor response per modified RECIST by independent central review. Secondary DTC endpoints were duration of response and progression-free survival (PFS). Pts = 18 yrs with progressive, 131I-resistant disease, ECOG 0–2, and no prior treatment with VEGFr MKIs received AMG 706 125mg QD until disease progression or unacceptable toxicity. Assessments included tumor response (q8w), pharmacokinetics (PK), and safety. Results: 93 pts with DTC were enrolled and received at least 1 dose of AMG 706. DTC subtypes were: papillary, 58%; Hürthle cell, 18%; follicular, 16%; other, 8%. Median (range) age was 62 (36–81) yrs. 20% of pts had prior chemotherapy; 96% had prior 131I therapy. With median follow-up of 32 wks, objective tumor response (CR or PR) rate (95% CI) was 12% (6.1, 20.2); SD, n=64 (69%; durable SD =24 wks, 24%); PD, n=7 (8%). Median (95% CI) time to response was 103 (53, 161) days; median PFS was 276 (221, not estimable) days. 85% of pts were alive >8 months after starting therapy. All pts (100%) had some treatment- emergent adverse events (AE): grade 3, 55%; grade 4, 10%; grade 5, 5% (all grade 5 were deemed unrelated to AMG 706). Common AEs included diarrhea (70%; 11% grade 3), fatigue (58%; 5% grade 3), hypertension (49%; 22% grade 3), headache (43%; 4% grade 3), nausea (40%; 2% grade 3), and hypothyroidism and/or increased TSH (17%; no grade 3); none of these were grade 4 or 5. 6% of pts had cholecystitis. PK results showed that AMG 706 PK at 125mg QD was comparable to data obtained in other monotherapy studies at the same dose level. Conclusions: In this study of pts with advanced 131I-resistant DTC, AMG 706 showed encouraging antitumor activity and had tolerable and manageable toxicities. Further investigation is warranted. No significant financial relationships to disclose.

A modeling framework to simulate motesanib efficacy in thyroid cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14553-e14553
Author(s):  
L. Claret ◽  
J. Lu ◽  
Y. Sun ◽  
D. Stepan ◽  
R. Bruno
Keyword(s):  
Thyroid Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Dose Response ◽  
Tumor Size ◽  
Clinical Development ◽  
Tumor Growth Inhibition ◽  
Population Pharmacokinetic ◽  
Modeling Framework ◽  
Dose Reductions

e14553 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR, and Kit with antiangiogenic and direct antitumor activity. A modeling framework that simulates clinical endpoints, including objective response rate (ORR; per RECIST) and progression-free survival (PFS), was developed to support clinical development of motesanib. This study evaluated the framework using results from a trial of motesanib in thyroid cancer (TC). Methods: Models for tumor growth inhibition (J Clin Oncol 24[18S]:abstract 6025, 2006) with drug effect driven by area under the curve (AUC) (as predicted by a population pharmacokinetic model), overall survival, and probability and duration of dose reductions were developed based on data from 93 differentiated TC (DTC) and 91 medullary TC patients who received motesanib monotherapy (125 mg once daily [QD]) in a phase 2 study (Horm Res 68[suppl 3]:28–9, 2007; NEJM 359:31–42, 2008). The full simulation framework was assessed in predicting dose intensity (starting dose of 125 mg QD), tumor size over time, ORR, and PFS. Dose-response simulations were performed in DTC patients. Results: Survival times followed a Weibull distribution with ECOG performance status, baseline tumor size, and change in tumor size from baseline at week 7 as predictors. The probability of dose reductions was dependent on time and AUC. Time to event Weibull models predicted the duration of dose reductions and dose interruptions. The models correctly predicted median daily exposure intensities up to week 24. The predicted ORR in DTC patients was 15.0% (95% prediction interval [PI], 7.5%-23.7%) compared with the observed ORR of 14.0%. Predicted median PFS was 40 weeks (95% PI, 32–49 wk) compared with the observed median PFS of 40 weeks. Dose- response simulations confirmed the appropriateness of 125-mg QD dosing in DTC: the modeling framework predicted no clinically relevant improvement in PFS would be obtained by dose intensification. Conclusions: This modeling framework (dose reduction/tumor growth inhibition/survival) will be an important tool to simulate clinical response and support clinical development decisions. Further evaluation of the model using additional datasets will be required. [Table: see text]

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