[Population Pharmacokinetics] Semi-Mechanism-Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib

Vismodegib, approved for the treatment of advanced basal cell carcinoma, has shown unique pharmacokinetic (PK) nonlinearity and binding to α1-acid glycoprotein (AAG) in humans. A semi-mechanism-based population pharmacokinetic (PopPK) model was developed from a meta-dataset of 225 subjects enrolled in five clinical studies to quantitatively describe the clinical PK of vismodegib and identify sources of interindividual variability. Total and unbound vismodegib were analyzed simultaneously, together with time-varying AAG data. The PK of vismodegib was adequately described by a one-compartment mo......

[Population Pharmacokinetics] Population Pharmacokinetics of Vernakalant Hydrochloride Injection (RSD1235) in Patients With Atrial Fibrillation or Atrial Flutter

Abstract
Vernakalant hydrochloride is a novel, predominantly atrial‐selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration‐time data were best fit by a 2‐compartment mammillary model, with rapid first‐order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 2......

[Population Pharmacokinetics] Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates.

ABSTRCT
PURPOSE:
Trastuzumab emtansine (TDM1) is an antibody drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of TDM1 PK parameters and the effects of clinically relevant covariates.

METHODS:
Serum samples were collected from 671 patients with human epidermal growth factor receptor 2 positive locally advanced or metastatic breast cancer (MBC) who received single-agent TDM1 in five phase I to phase III st......

[Population Pharmacokinetics] Population pharmacokinetic modeling of idelalisib, a novel PI3Kδ inhibitor, in healthy subjects and patients with hematologic malignancies.

ABSTRACT
PURPOSE:
Idelalisib is a potent PI3Kδ inhibitor that was recently approved for treating hematologic malignancies. The objective of this analysis was to develop a population pharmacokinetic model for idelalisib and its inactive metabolite GS563117 and to evaluate the impact of covariates on idelalisib/GS563117 PK.

METHODS:
Data from 10 phase I or II studies in healthy volunteers or patients with hematologic malignancies (n = 736) were analyzed using NONMEM. Stepwise forward addition followed by backward elimination was implemented in the covariate (age, gender, race, body weight,......

[Population Pharmacokinetics] Population pharmacokinetics and pharmacodynamics of dalfampridine-ER in healthy volunteers and in patients with multiple sclerosis.

ABSTRACT
OBJECTIVE:
Using data pooled from several studies of dalfampridine extended release (ER), a population pharmacokinetic model was developed for the purposes of characterizing the population pharmacokinetics and pharmacodynamics of dalfampridine ER with respect to variability in pharmacokinetics, covariates affecting the pharmacokinetics, and whether the current therapeutic dosage represents an optimal dosage. Studies were conducted in healthy volunteers and multiple sclerosis (MS) patients over the course of development and registration of dalfampridine extended release tablets (dalf......