[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......

[Model Based Meta Analysis] Model-based meta-analysis for quantifying Paclitaxel dose response in cancer patients

Model based meta analysis of dose response is a sophisticated method to guide dose and regimen selection. In this report, the effects of paclitaxel dose and regimen (weekly or every 3 weeks) on the efficacy and safety in cancer patients were quantified by model based meta analysis of 29 monotherapy trials. Logistic regression models were developed to assess the relationship between dose and objective response rate or neutropenia rate. Survival models were developed to assess the relationship between dose and overall survival or progression free survival. Paclitaxel efficacy (e.g., objective re......

[Model Based Meta Analysis] Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis

OBJECTIVE:
To compare placebo responses in neuropathic pain syndromes.
CONCLUSIONS:
Placebo response is influenced by the pain syndrome evaluated. These differences should be considered when evaluating novel compounds for the treatment of neuropathic pain conditions.

[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......