Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

Abstract

We extended a generic whole‐body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems (i.e., the testes and the thyroid gland). An extensive literature search was performed, first, to determine the most generic organ model structures for testes and thyroid across species, and, second, to identify the corresponding anatomic and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK‐Sim and MoBi. The capability of the PBPK approach to simulate the testes and thyroid tissue concentration data was demonstrated using a series of test compounds. The presented organ model structures and parameterization yielded a close agreement between observed and simulated tissue concentrations over time. The organ models are ready to be used to predict the pharmacokinetics of passively entering drugs in the testes and thyroid tissue in a generic PBPK modeling framework.

A workflow to build PBTK models for novel species

“…If no tox organs need to be introduced, the initial PBTK model of a novel target species with the standard organs can be refined by generally setting species-specific parameters if available from a literature review, interspecies scaling or, ideally, one’s own experimental data. If a tox organ is to be additionally considered, species-specific parameters need to be set analogously (Pilari et al 2017 ) (Table 3 , third column); however, the parametrisation of the tox organ in novel species should be given particular attention to increase the accuracy of the computational predictions. Once the initial PBTK model of the target species is established, it should be iteratively qualified with PK data.…”

“…Concentration–time profiles in different tissues were used, in particular venous blood plasma and the intracellular space in the gonads and the brain. The latter two represent relevant examples for the prediction of organ-specific side effects (Pilari et al 2017 ), henceforth referred to as tox organs. The parameters were ranked according to the maximum sensitivity that a parameter exhibited across all models, substances and application methods: …”

A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors

“…Distribution within these organ compartments was assumed to be homogenous. Also, the thyroid gland was added to the standardized organism using previously published data [ 30 ]. The organs were linked by arterial and venous blood compartments, and each organ was further characterized by a specific blood flow, volume, tissue-partition coefficient and permeability [ 21 , 22 ].…”

Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients

“…Previous modeling efforts on fentanyl neither included the metabolite norfentanyl nor predicted DDI scenarios [ 13 , 14 , 15 ]. Consequently, the fraction of fentanyl metabolized to norfentanyl could not be assessed.…”

“…An increasing number of drug applications submitted to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have investigated the impact of hepatic disease, pharmacogenomics, and DDIs on drug PK with the help of PBPK modeling [ 10 , 12 ]. Previous PBPK efforts on fentanyl have focused on methodological aspects of simplifying PBPK models [ 13 ], on a PBPK approach to support the development of Provisional Advisory Levels (PALs) for hazardous agents [ 14 ], and on simulating thyroid and testes tissue concentrations [ 15 ], respectively.…”