TY - JOUR
T1 - Quantitative analysis of the phase transition mechanism underpinning the systemic self-assembly of a mechanopharmaceutical device
AU - Dunne, Steven
AU - Willmer, Andrew R.
AU - Swanson, Rosemary
AU - Almeida, Deepak
AU - Ammerman, Nicole C.
AU - Stringer, Kathleen A.
AU - Capparelli, Edmund V.
AU - Rosania, Gus R.
N1 - Funding Information:
Funding: This research was funded by a grant from the National Institute of General Medical Sciences (NIGMS) awarded to GRR (R01GM127787). Dr. Stringer’s effort was supported by a grant from NIGMS (R35GM136312). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the NIH.
Funding Information:
This research was funded by a grant from the National Institute of General Medical Sciences (NIGMS) awarded to GRR (R01GM127787). Dr. Stringer?s effort was supported by a grant from NIGMS (R35GM136312). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the NIH.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/22
Y1 - 2021/12/22
N2 - Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution. This expansion reflects the soluble-to-insoluble phase transition that the drug undergoes as it precipitates out and accumulates within macrophages disseminated throughout the organism. Using mice as a model organism, we studied the mechanistic underpinnings of this increasing half-life and how the systemic pharmacokinetics of CFZ are altered with continued dosing. To this end, M. tuberculosis infection status and multiple dosing schemes were studied alongside a parameter sensitivity analysis (PSA) to further understanding of systemic drug distribution. Parameter values governing the sigmoidal expansion function that captures the phase transition were methodically varied, and in turn, the systemic concentrations of the drug were calculated and compared to the experimentally measured concentrations of drug in serum and spleen. The resulting amounts of drug sequestered were dependent on the total mass of CFZ administered and the duration of drug loading. This phenomenon can be captured by altering three different parameters of an expansion function corresponding to key biological determinants responsible for the precipitation and the accumulation of the insoluble drug mass in macrophages. Through this analysis of the context dependent pharmacokinetics of CFZ, a predictive framework for projecting the systemic distribution and self-assembly of precipitated drug complexes as intracellular mechanopharmaceutical devices of this and other drugs exhibiting similarly complex pharmacokinetics can be constructed.
AB - Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution. This expansion reflects the soluble-to-insoluble phase transition that the drug undergoes as it precipitates out and accumulates within macrophages disseminated throughout the organism. Using mice as a model organism, we studied the mechanistic underpinnings of this increasing half-life and how the systemic pharmacokinetics of CFZ are altered with continued dosing. To this end, M. tuberculosis infection status and multiple dosing schemes were studied alongside a parameter sensitivity analysis (PSA) to further understanding of systemic drug distribution. Parameter values governing the sigmoidal expansion function that captures the phase transition were methodically varied, and in turn, the systemic concentrations of the drug were calculated and compared to the experimentally measured concentrations of drug in serum and spleen. The resulting amounts of drug sequestered were dependent on the total mass of CFZ administered and the duration of drug loading. This phenomenon can be captured by altering three different parameters of an expansion function corresponding to key biological determinants responsible for the precipitation and the accumulation of the insoluble drug mass in macrophages. Through this analysis of the context dependent pharmacokinetics of CFZ, a predictive framework for projecting the systemic distribution and self-assembly of precipitated drug complexes as intracellular mechanopharmaceutical devices of this and other drugs exhibiting similarly complex pharmacokinetics can be constructed.
UR - http://www.scopus.com/inward/record.url?scp=85121676537&partnerID=8YFLogxK
U2 - 10.3390/pharmaceutics14010015
DO - 10.3390/pharmaceutics14010015
M3 - Article
AN - SCOPUS:85121676537
VL - 14
JO - Pharmaceutics
JF - Pharmaceutics
SN - 1999-4923
IS - 1
M1 - 15
ER -
