III-19 Yuchen Guo

Modeling spatial pharmacokinetics of drugs in mucus in patients with cystic fibrosis

Yuchen Guo (1), Jinqiu Yin (1), Sirin Yonucu (1), Tingjie Guo (1), J. G. Coen van Hasselt (1)

(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

Introduction: Cystic fibrosis (CF) is a genetic disease causing extensive mucus formation in lung[1], and which is associated with chronic bacterial infections that lead to pulmonary disease exacerbations impairing the quality of life [2]. Design of antibacterial and/or anti-inflammatory treatments is primarily driven by drug plasma concentrations, while the drug effect is driven by the concentration at the site of action e.g. in lung, and specifically the mucus. The mucus forms a barrier that has been suggested to reduce the effective concentration of drugs [3-6]. However, most of these studies have been based on in vitro experiments, and the quantification of expected in vivo spatial pharmacokinetics (PK) of drug in mucus remains unclear.

Objectives: We developed a spatial PK modeling framework to (1) characterize the drug spatial distribution kinetics in patients’ mucus, and (2) identify drug- and biological system-specific factors that may influence spatial drug distribution.

Methods: A spatial PK model in mucus was established using discretized partial differential equations. We used an existing plasma PK model to generate the input data set used for the boundary condition of spatial model. Diffusion coefficients were calculated based on molecule size using a modified Stokes-Einstein (SE) equation. We investigated the radius of drug molecules ranging from 0.1nm to 50nm, covering both small molecules and antimicrobial monoclonal antibodies. Binding affinity related parameters including Ka, Kon, and Koff were also considered. A series of hypothetical drugs with varying radius, Ka and half-life were used to investigate the impact of these parameters on drug distribution in mucus. In addition, both intermittent and continuous intravenous infusions were investigated to illustrate the impact of dosing schedules on drug spatial PK in mucus. The ratio of free concentration in mucus to concentration in plasma was calculated to indicate the equilibrium of mass transfer between plasma and lung mucus.

Results: The magnitude of diffusion coefficients calculated using modified SE equation was in line with literatures. The results showed that molecules size is the main influential factor for drug diffusion into mucus. When the radius of the drug molecule is small, e.g. around 1nm, the PK profiles in mucus and plasma are nearly identical. Drugs with a larger molecule size exhibited reduced diffusivities and greater extents of retardation in spatial distribution in mucus. The binding affinity of drugs to mucin showed limited impact on the diffusion of drug in mucus. Finally, we showed that drugs with extended half-lives more rapidly led to an equilibrium of drug concentration between plasma and mucus.

Conclusions: Our study utilized spatial modeling to quantitatively describe the drug spatial distribution in mucus of CF patients. Molecule size plays a predominant role in the drug diffusion in mucus. Drug-mucin binding affinity has a negligible impact on diffusivity.

References:

  1. Morrison, C.B., M.R. Markovetz, and C. Ehre, Mucus, mucins, and cystic fibrosis. Pediatric pulmonology, 2019. 54: p. S84-S96.
  2. Ciofu, O., C.R. Hansen, and N. Høiby, Respiratory bacterial infections in cystic fibrosis. Current opinion in pulmonary medicine, 2013. 19(3): p. 251-258.
  3. Bhat, P.G., D.R. Flanagan, and M.D. Donovan, Drug diffusion through cystic fibrotic mucus: steady-state permeation, rheologic properties, and glycoprotein morphology. Journal of pharmaceutical sciences, 1996. 85(6): p. 624-630.
  4. Bos, A.C., et al., The fate of inhaled antibiotics after deposition in cystic fibrosis: how to get drug to the bug? Journal of Cystic Fibrosis, 2017. 16(1): p. 13-23.
  5. Cone, R.A., Barrier properties of mucus. Advanced drug delivery reviews, 2009. 61(2): p. 75-85.
  6. Stewart, P.S., Theoretical aspects of antibiotic diffusion into microbial biofilms. Antimicrobial agents and chemotherapy, 1996. 40(11): p. 2517-2522.

Reference: PAGE 30 (2022) Abstr 10080 [www.page-meeting.org/?abstract=10080]

Poster: Drug/Disease Modelling - Infection