Population pharmacokinetic/pharmacodynamic modeling of histamine response measured by histamine iontophoresis laser Doppler

Abstract

The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults. However, due to the high sampling frequency (up to 40Hz), the output files are usually too cumbersome to be directly used for further analysis. In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional Emax model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094 /min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1 flux unit; maximum effect (Emax), 13.4; concentration at half maximum effect (EC50) 31.1 mg/L. Covariate analysis indicated that age and race had significant influence on Tlag and EC50, respectively.

Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma

“…A population PK/PD linked effect model was developed to describe the histamine response over time monitored by HILD. Secondary modeling analysis provided parameter estimates for area under the effect curve (AUEC), and relative maximal response over baseline (Emax) and time of maximal response (Tmax) (Liu et al, 2016). …”

Dose-Response-Time Data Analysis: An Underexploited Trinity

“…DRT analyses may play an important role in iontophoretic systems due to their time-and concentration-wise detachment from systemic exposure, although information that fully characterizes the rate and extent of drug input is still a key factor that needs to be sorted out prior to proposing a biophase structure. However, promising results were recently collected during histamine iontophoresis with laser Doppler monitoring (Liu et al, 2016). This approach allowed a fixed dose of histamine Dose-Response-Time Data Analysis to be delivered and an objective, continuous, and dynamic measurement of histamine epicutaneous response to be recorded in children and adults.…”

The impact of skin color and tone on histamine iontophoresis and Doppler flowmetry measurements as a pharmacodynamic biomarker

“…The HILD technique provides an objective and quantitative assessment of individual histamine pharmacodynamic response. 3 The Doppler flowmetry uses a laser light beam to transmit through epicutaneous tissue, allowing for backscattered light to be converted into a quantified signal that is transmitted and recorded via a computer software. This signal is used to calculate a value of blood flow at the site described as "flux."…”