Computing optimal drug dosing regarding efficacy and safety: the enhanced OptiDose method in NONMEM.

Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal drug doses for any pharmacometrics model for a given dosing scenario. In the present work, we enhance the OptiDose concept to compute optimal drug dosing with respect to both efficacy and safety targets. Usually, these are not of equal importance, but one is a top priority, that needs to be satisfied, whereas the other is a secondary target and should be achieved as good as possible without failing the top priority target.

Pharmacodynamic Age Structured Population Model For Cell Trafficking.

Objectives: Cell trafficking encompasses movement of the immune system cells (e.g., granulocytes, lymphocytes) between the blood and the extravascular tissues (e.

Computing optimal drug dosing with OptiDose: implementation in NONMEM.

Determining a drug dosing recommendation with a PKPD model can be a laborious and complex task. Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal doses for any pharmacometrics/PKPD model for a given dosing scenario. In the present work, we reformulate the underlying optimal control problem and elaborate how to solve it with standard commands in the software NONMEM.

Delay differential equations based models in NONMEM.

Delay differential equations (DDEs) are commonly used in pharmacometric models to describe delays present in pharmacokinetic and pharmacodynamic data analysis. Several DDE solvers have been implemented in NONMEM 7.5 for the first time.

EVO100 prevents chlamydia and gonorrhea in women at high risk of infection.

Background: According to the Centers for Disease Control and Prevention, rates of infection for Chlamydia trachomatis and Neisseria gonorrhoeae are increasing in the United States. EVO100 is an investigational antimicrobial, pH-modulating, vaginal gel with active ingredients L-lactic acid, citric acid, and potassium bitartrate that is being evaluated for the prevention of sexually transmitted infections.

Objective: The objective of this phase 2B/3 study was to assess the efficacy and safety of EVO100 for the prevention of chlamydia and gonorrhea.

Saddle-Reset for Robust Parameter Estimation and Identifiability Analysis of Nonlinear Mixed Effects Models.

Parameter estimation of a nonlinear model based on maximizing the likelihood using gradient-based numerical optimization methods can often fail due to premature termination of the optimization algorithm. One reason for such failure is that these numerical optimization methods cannot distinguish between the minimum, maximum, and a saddle point; hence, the parameters found by these optimization algorithms can possibly be in any of these three stationary points on the likelihood surface. We have found that for maximization of the likelihood for nonlinear mixed effects models used in pharmaceutical development, the optimization algorithm Broyden-Fletcher-Goldfarb-Shanno (BFGS) often terminates in saddle points, and we propose an algorithm, saddle-reset, to avoid the termination at saddle points, based on the second partial derivative test.

NONMEM Tutorial Part I: Description of Commands and Options, With Simple Examples of Population Analysis.

In this tutorial, the various components of NONMEM will be described, and the basic steps of setting up NONMEM control stream files and data files will be demonstrated. Some basic concepts of nonlinear mixed effects modeling will be discussed, along with simple examples demonstrating how to use NONMEM to perform population analysis of clinical data.

NONMEM Tutorial Part II: Estimation Methods and Advanced Examples.

In this second tutorial on NONMEM, the examples of typical pharmacokinetic/pharmacodynamic modeling problems that occur in the pharmaceutical field will be presented, which the reader can use as a template for his or her own modeling endeavors. Each of the problems presented is challenging in some way, and the logic behind setting up each problem is discussed. Logical concepts of the problem itself as well as the technical aspect of how to set it up in NONMEM are described and demonstrated.

Tyrosine kinase inhibitor interruptions, discontinuations and switching in patients with chronic-phase chronic myeloid leukemia in routine clinical practice: SIMPLICITY.

SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor (TKI) use and management patterns in patients with chronic phase-chronic myeloid leukemia in the US and Europe in routine clinical practice. Herein we describe interruptions, discontinuations and switching of TKI therapy during the initial 2 years of treatment among 1121 patients prospectively enrolled between October 1, 2010 and March 7, 2017. Patient characteristics were broadly similar between the imatinib (n = 370), dasatinib (n = 376), and nilotinib (n = 375) cohorts.

Non-invasive early detection of malignant pulmonary nodules by FISH-based sputum test.

Background: Early detection decreases lung cancer mortality. The Target-FISH Lung Cancer Detection (LCD) Test is a non-invasive test designed to detect chromosomal changes (deletion or amplification) via Fluorescence in situ Hybridization (FISH) in sputum specimens from persons suspected of having lung cancer. We evaluated the performance of the LCD test in patients with highly suspicious pulmonary nodules who were scheduled for a biopsy procedure.