Pharmacokinetic and screening studies of the interaction between mononuclear phagocyte system and nanoparticle formulations and colloid forming drugs

Lucas, Andrew T.; Herity, Leah B.; Kornblum, Zack A.; Madden, Andrew J.; Gabizón, Alberto; Kabanov, Alexander V.; Ajamie, Rose T.; Bender, David M.; Kulanthaivel, Palaniappan; Sánchez-Félix, Manuel; Havel, Henry A.; Zamboni, William C.

doi:10.1016/j.ijpharm.2017.04.079

Cited by 17 publications

(11 citation statements)

References 42 publications

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“…Studies with small molecule drugs have successfully discriminated the impact of individual physicochemical descriptors on the accuracy of allometric scaling CL in humans 27, 28. Similar analysis on the basis of individual nanomaterial physicochemical parameters are very limited 29 and may be unfeasible as revealed in the interspecies allometric scaling of PEGylated liposomes: it was discovered that three PEGylated liposomal anticancer drugs with similar physicochemical characteristics exhibited dissimilar allometric coefficients and exponents due to unexpectedly divergent pharmacokinetic profiles, even within the same species and at comparable drug doses 10. Thus, the available evidence, albeit limited, suggest that even comparable nanomaterials with broadly similar physicochemical characteristics can exhibit dramatic differences in their disposition and pharmacokinetic profiles, which makes generalizations of allometric relationships on the basis of physicochemical descriptors impractical for nanomaterials.…”

Section: Extrapolating Nanomaterials Pharmacokinetics From Preclinicalmentioning

confidence: 99%

Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans

Valic¹,

Zheng²

2019

Theranostics

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A critical step in the translational science of nanomaterials from preclinical animal studies to humans is the comprehensive investigation of their disposition (or ADME) and pharmacokinetic behaviours. Disposition and pharmacokinetic data are ideally collected in different animal species (rodent and nonrodent), at different dose levels, and following multiple administrations. These data are used to assess the systemic exposure and effect to nanomaterials, primary determinants of their potential toxicity and therapeutic efficacy. At toxic doses in animal models, pharmacokinetic (termed toxicokinetic) data are related to toxicologic findings that inform the design of nonclinical toxicity studies and contribute to the determination of the maximum recommended starting dose in clinical phase 1 trials. Nanomaterials present a unique challenge for disposition and pharmacokinetic investigations owing to their prolonged circulation times, nonlinear pharmacokinetic profiles, and their extensive distribution into tissues. Predictive relationships between nanomaterial physicochemical properties and behaviours in vivo are lacking and are confounded by anatomical, physiological, and immunological differences amongst preclinical animal models and humans. These challenges are poorly understood and frequently overlooked by investigators, leading to inaccurate assumptions of disposition, pharmacokinetic, and toxicokinetics profiles across species that can have profoundly detrimental impacts for nonclinical toxicity studies and clinical phase 1 trials. Herein are highlighted two research tools for analysing and interpreting disposition and pharmacokinetic data from multiple species and for extrapolating this data accurately in humans. Empirical methodologies and mechanistic mathematical modelling approaches are discussed with emphasis placed on important considerations and caveats for representing nanomaterials, such as the importance of integrating physiological variables associated with the mononuclear phagocyte system (MPS) into extrapolation methods for nanomaterials. The application of these tools will be examined in recent examples of investigational and clinically approved nanomaterials. Finally, strategies for applying these extrapolation tools in a complementary manner to perform dose predictions and in silico toxicity assessments in humans will be explained. A greater familiarity with the available tools and prior experiences of extrapolating nanomaterial disposition and pharmacokinetics from preclinical animal models to humans will hopefully result in a more straightforward roadmap for the clinical translation of promising nanomaterials.

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Section: Extrapolating Nanomaterials Pharmacokinetics From Preclinicalmentioning

confidence: 99%

Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans

Valic¹,

Zheng²

2019

Theranostics

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“…MPS screening for mouse and rat blood emulated human MPS behaviors, demonstrating a trend in the reduction of phagocytosis of SM-doxorubicin > SP1049C > DaunoXome > Doxil [156]. This trend was most likely due to cytotoxic effects on monocytes and dendritic cells from the SM formulations and increasing protective properties of the various formulations from traditional systemic clearance mechanisms and recognition by the MPS [156]. Understanding this phagocytic activity can be crucial in developing new model species to predict the PK of NP agents.…”

Section: Preclinical Model Selection: Variability In Patients and Animalsmentioning

confidence: 94%

“…In a study by Lucas et al, a unique ex vivo profiling platform of the MPS was used to compare the pharmacokinetic differences between multiple NP formulations of anthracyclines, including: PEGylated liposomes (i.e., Doxil), non-PEGylated liposomes (i.e., DaunoXome), micellar doxorubicin (i.e., SP1049C) and traditional small molecule doxorubicin (i.e., Adriamycin). These agents were then screened within common nonclinical models, such as SCID mice, Sprague-Dawley rats, and beagle dogs [156]. This MPS screening measured the function of MPS cells (via the amount of phagocytosis that was seen) for each given formulation [156].…”

Section: Preclinical Model Selection: Variability In Patients and Animalsmentioning

confidence: 99%

“…These agents were then screened within common nonclinical models, such as SCID mice, Sprague-Dawley rats, and beagle dogs [156]. This MPS screening measured the function of MPS cells (via the amount of phagocytosis that was seen) for each given formulation [156]. MPS screening for mouse and rat blood emulated human MPS behaviors, demonstrating a trend in the reduction of phagocytosis of SM-doxorubicin > SP1049C > DaunoXome > Doxil [156].…”

Section: Preclinical Model Selection: Variability In Patients and Animalsmentioning

confidence: 99%

“…This MPS screening measured the function of MPS cells (via the amount of phagocytosis that was seen) for each given formulation [156]. MPS screening for mouse and rat blood emulated human MPS behaviors, demonstrating a trend in the reduction of phagocytosis of SM-doxorubicin > SP1049C > DaunoXome > Doxil [156]. This trend was most likely due to cytotoxic effects on monocytes and dendritic cells from the SM formulations and increasing protective properties of the various formulations from traditional systemic clearance mechanisms and recognition by the MPS [156].…”

Section: Preclinical Model Selection: Variability In Patients and Animalsmentioning

confidence: 99%

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Major developments in nanomedicines, such as nanoparticles (NPs), nanosomes, and conjugates, have revolutionized drug delivery capabilities over the past four decades. Although nanocarrier agents provide numerous advantages (e.g., greater solubility and duration of systemic exposure) compared to their small-molecule counterparts, there is considerable inter-patient variability seen in the systemic disposition, tumor delivery and overall pharmacological effects (i.e., anti-tumor efficacy and unwanted toxicity) of NP agents. This review aims to provide a summary of fundamental factors that affect the disposition of NPs in the treatment of cancer and why they should be evaluated during preclinical and clinical development. Furthermore, this chapter will highlight some of the translational challenges associated with elements of NPs and how these issues can only be addressed by detailed and novel pharmacology studies.

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Pharmacokinetic and screening studies of the interaction between mononuclear phagocyte system and nanoparticle formulations and colloid forming drugs

Cited by 17 publications

References 42 publications

Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans

Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans

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