Ramucirumab (RAM) exposure-response (ER) relationship in RANGE: A randomized phase III trial of RAM plus docetaxel (DOC) versus placebo (P) plus DOC in advanced platinum-refractory urothelial carcinoma (UC) patients (pts).

353 Background: Recent RANGE results showed significant improvement in PFS, a non-significant positive trend in OS, increased ORR and acceptable safety with RAM+DOC vs P+DOC in UC pts (Petrylak et al. Lancet 2017; Petrylak et al. ESMO 2018, abstr 865PD). RAM ER-OS relationships in RANGE are reported here. Methods: Pts received RAM (10 mg/kg) + DOC or P + DOC (Day 1 of a 21 day cycle) until discontinuation criteria were met. Population pharmacokinetic analysis predicted RAM minimum concentrations after first dose (RAM Cmin, 1). Multivariate Cox regression & matched case control (MCC) analyses using exposure treated as a continuous covariate, or grouped as quartiles, evaluated the ER-OS relationship. Results: Several poor prognostic factors, including Bellmunt risk factors, appeared to be more frequent in the lower exposure quartiles, suggesting a possible disease-PK interaction. Increasing RAM exposure as a continuous covariate in an ER population of n=246 pts significantly ( p=0.01) associated with improvements in OS. Higher exposure quartiles trended toward longer survival & smaller HRs compared to P (Table, Q1=lowest). Conclusions: OS and ORR benefits favored Q4, a group which was associated with more favorable prognostic features and higher exposure. The observed disease-PK interaction may confound the interpretation of the ER results and warrants further exploration. Clinical trial information: NCT02426125. [Table: see text]

Download Full-text

Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling

Clinical Pharmacokinetics ◽

10.1007/s40262-017-0526-4 ◽

2017 ◽

Vol 56 (11) ◽

pp. 1355-1368 ◽

Cited By ~ 25

Author(s):

Neeraj Gupta ◽

Paul M. Diderichsen ◽

Michael J. Hanley ◽

Deborah Berg ◽

Helgi van de Velde ◽

...

Keyword(s):

Proteasome Inhibitor ◽

Population Pharmacokinetic Analysis ◽

Phase Iii ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic

Download Full-text

A Population Pharmacokinetic Analysis of Nelfinavir Mesylate in Human Immunodeficiency Virus-Infected Patients Enrolled in a Phase III Clinical Trial

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.7.1832-1837.2000 ◽

2000 ◽

Vol 44 (7) ◽

pp. 1832-1837 ◽

Cited By ~ 25

Author(s):

Kimberley A. Jackson ◽

Sara E. Rosenbaum ◽

Bradley M. Kerr ◽

Yazdi K. Pithavala ◽

Geoffrey Yuen ◽

...

Keyword(s):

Clinical Trial ◽

Human Immunodeficiency Virus ◽

Population Pharmacokinetic Analysis ◽

Phase Iii ◽

Baseline Viral Load ◽

Accurate Estimation ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Phase Iii Clinical Trial ◽

Immunodeficiency Virus

ABSTRACT A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (ka ). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F),V/F, and ka were estimated, and model 2, in which V/F and ka were fixed to known values and only CL/F was estimated. Estimates of CL/F ranged from 41.9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL/F. Patients who received concomitant therapy with fluconazole had a statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.

Download Full-text