Pharmacokinetic and Pharmacodynamic Modeling of Tezepelumab to Guide Phase III Dose Selection for Patients with Severe Asthma

2020 ◽  
Author(s):  
Neang Ly ◽  
Yanan Zheng ◽  
Janet M. Griffiths ◽  
Rene Merwe ◽  
Balaji Agoram ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Phase Iii ◽  
Pharmacodynamic Modeling ◽  
Dose Selection ◽  
Selection For

Model-based Dose Selection for Phase III Rivaroxaban Study in Japanese Patients with Non-valvular Atrial Fibrillation

2013 ◽  
Vol 28 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Takahiko Tanigawa ◽  
Masato Kaneko ◽  
Kensei Hashizume ◽  
Mariko Kajikawa ◽  
Hitoshi Ueda ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Japanese Patients ◽  
Phase Iii ◽  
Dose Selection ◽  
Model Based ◽  
Selection For

Exposure-response (E-R) analysis to facilitate phase III (P3) dose selection for AMG 479 (A479) in combination with gemcitabine (G) to treat metastatic pancreatic cancer (mPC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 263-263 ◽  
Author(s):  
J. Lu ◽  
H. Deng ◽  
R. Tang ◽  
C. Hsu ◽  
H. L. Kindler ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Safety Data ◽  
Area Under The Curve ◽  
Positive Association ◽  
Phase Iii ◽  
Survival Models ◽  
Confounding Factors ◽  
Dose Selection ◽  
Population Pk ◽  
Selection For

263 Background: A479 is an investigational, fully human monoclonal antibody against IGF1R. In a phase II study, 125 pts with mPC were randomized 1:1:1 to A479, placebo (P), or conatumumab in combination with G. Addition of A479 (12 mg/kg IV, Q2W) to G (1000 mg/m2) showed evidence of improved OS and PFS (Kindler, JCO 2010:28 abstr 4035). An E-R analysis was done to inform P3 dose selection for A479. Methods: A population PK model of A479 was constructed using data from multiple studies. An E-R analysis was performed with pts from the A479+G and P+G arms (∼40 pts/arm). The effect of estimated steady-state area under the curve (AUCss) on OS and PFS was evaluated with a Cox proportional hazard model. Effects of potential confounding factors on OS- AUCss and PFS-AUCss associations were assessed by multivariate analysis. Exposure-safety data were analyzed with descriptive statistics and linear regression. P3 doses for A479 were explored with Monte Carlo simulations using population PK and parametric survival models. Results: There was a positive association between OS or PFS and higher AUCss in the A479+G arm (P<0.001, <0.001) that remained even when data from the A479+G and P+G arms were combined (P=0.033, 0.022). Pts with AUCss ≥ median (19.2 mg·h/μL) had longer median OS and PFS (16.0, 7.6 months) than pts with AUCss < median (4.7, 1.9 months). OS-AUCss and PFS-AUCss associations were significant after adjusting for potential confounding factors. Sensitivity E-R analyses were done to confirm the modeling results. The incidence of most adverse events was similar between the AUCss < and ≥ median groups, although the incidence of grade ≥3 hyperglycemia, neutropenia, and thrombocytopenia trended higher in pts with AUCss ≥ median. Population PK indicated 1.7-fold higher clearance of A479 in mPC than non-mPC pts. No G-A479 PK interactions were identified. PK simulations showed similar AUCss of A479 in mPC pts at 20 mg/kg and in non-mPC pts at 12 mg/kg. Simulations projected improved OS and PFS with 20 mg/kg vs 12 mg/kg A479. Conclusions: Increased exposure to A479 is associated with improved clinical outcomes in mPC. This supports the evaluation of 20 mg/kg A479 in P3. [Table: see text]

Population Pharmacokinetic and Pharmacodynamic Modeling of AZD4901 and Simulation to Support Dose Selection for the Phase 2a Study

2016 ◽  
Vol 56 (8) ◽  
pp. 999-1008 ◽  
Author(s):  
Hongmei Xu ◽  
Jianguo Li ◽  
Lorraine Webber ◽  
Rahul Kakkar ◽  
Yingxue Chen ◽  
...  
Keyword(s):  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Dose Selection ◽  
Selection For

scholarly journals Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections

2022 ◽  
Author(s):  
Nicole E. Scangarella-Oman ◽  
Mohammad Hossain ◽  
Jennifer L. Hoover ◽  
Caroline R. Perry ◽  
Courtney Tiffany ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Infections ◽  
Clinical Evaluation ◽  
Phase Iii ◽  
Current Standard ◽  
Dose Selection ◽  
Topoisomerase Iv ◽  
Double Blind ◽  
Selection For ◽  
Tract Infections

Antibiotics are the current standard of care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC). Gepotidacin is currently in clinical development for the treatment of uUTIs and other infections. In this article, we review data for gepotidacin from nonclinical studies including: in-vitro activity, in-vivo animal efficacy, and pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models that informed dose selection for phase III clinical evaluation of gepotidacin. Based on this translational package of data, a gepotidacin 1,500 mg oral dose twice-daily for 5 days was selected for two ongoing, randomized, multicenter, parallel-group, double-blind, double-dummy, active-comparator phase III clinical studies evaluating the safety and efficacy of gepotidacin in adolescent and adult female participants with uUTIs (NCT04020341 and NCT04187144).

Confirmation of Model-based Dose Selection for a Japanese Phase III Study of Rivaroxaban in Non-valvular Atrial Fibrillation Patients

2013 ◽  
Vol 28 (4) ◽  
pp. 321-331 ◽  
Author(s):  
Masato Kaneko ◽  
Takahiko Tanigawa ◽  
Kensei Hashizume ◽  
Mariko Kajikawa ◽  
Masahiro Tajiri ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Phase Iii ◽  
Dose Selection ◽  
Model Based ◽  
Phase Iii Study ◽  
Selection For

scholarly journals Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

2016 ◽  
Vol 60 (5) ◽  
pp. 2782-2789 ◽  
Author(s):  
Ishani Landry ◽  
Li Zhu ◽  
Malaz Abu Tarif ◽  
Matthew Hruska ◽  
Brian M. Sadler ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Clinical Investigation ◽  
Central Compartment ◽  
Pharmacodynamic Modeling ◽  
Dose Selection ◽  
Phase 3 ◽  
Viral Attachment ◽  
First Order ◽  
Selection For ◽  
Hiv 1

ABSTRACTBMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4+T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n= 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8+T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the loge-transformed concentration at the end of a dosing interval (Ctau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC50) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log10copies/ml as a function of the loge-transformed PBAIC50-adjustedCtauafter 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.)

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