Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: PBPK and QM modeling of RNA-LNP transportation and metabolism. PK profiles of ionizable lipids in LNP were modeled through the PBPK model by simulating their transportation and metabolism in different organs. The transportation of RNA-LNP in cells was also modeled through a cellular PBPK model by simulating their uptake, transportation along endosomes, exocytosis, and RNA release. The metabolism of ionizable lipid by esterase (hydrolysis of the ester bond) was modeled by QM modeling through a cluster approach focusing on the reaction in the active site that is composed of a catalytic triad and an oxyanion hole provided by the esterase.

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques:

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: The optimized PBPK model structure of the ionizable lipid PK in the RNA-LNP delivery system. The ionizable lipid was distributed in the circulating system and to all organs in the form of LNP up to its disassembly and then was metabolized. P , permeability; k in , cellular uptake rate of LNP; k dis , LNP disassembly rate to release free ionizable lipids; k el , metabolism rate of the ionizable lipid.

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques: Permeability

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: The PBPK model structure of LNP transportation in cells. First, the LNP with associated lipids (aL) and RNA (aR) is put in the culture medium. Then the LNP is taken up by cells and transferred via endosomes, in which LNP disassembly, RNA release, and egress of LNP take place , , . The left panel is the complex model that is most mechanical. The right panel is a reduced model in which the process of LNP disassembly is not specifically simulated. aL and aR, lipids and RNA associated in LNP; dL and dR, lipids and RNA disassociated from LNP; cR, RNA really released to the cytoplasm; rL and rR, lipids and RNA wrapped in autophagosomes after release event taking place. k EE_LE , transportation rate from early endosomes or macropinosomes to late endosomes; k LE_LY , transportation rate from late endosomes to lysosomes; k dis , LNP disassembly rate; k eg_Com , egress rate in the complex model, k eg_Red , egress rate in the reduced model; k rel , RNA release rate; f rel , the fraction of RNA released to the cytoplasm; k AP_AL , transportation rate from autophagosomes to autolysosomes.

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques:

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: Modeling result of rats' PK and biodegradability of ionizable lipids. (A) Rats received intravenous administration of mRNA-LNP containing different ionizable lipids (MC3, SM-102, Lipid 5) at the dose of 0.2 mg/kg mRNA (equivalent to about 2.23 mg/kg for MC3, and 2.46 mg/kg for SM-102 and Lipid 5). The mean concentration of ionizable lipids at different time points (the dots) was extracted from the original study , . The in vivo PBPK model was fitted to the original data, resulting in optimized PK curves (the solid lines) and parameter values. (B) QM calculation of the energy change between the initial reaction complex and the first tetrahedral intermediate during esterase catalyzation using the cluster approach.

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques: Concentration Assay, In Vivo

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: PBPK model fitting results of siRNA-LNP in mice and parameters fitted. (A) Mice were intravenously administered with siRNA-LNP at the lipid dose of 11.1 mg/kg. LNP was composed of MC3 as the ionizable lipid and at a particle size of around 80 nm . (B and C) Mice were intravenously administered with siRNA-LNP at the 0.3 mg/kg siRNA (equivalent to about 3.42 mg/kg DMAP-DLP). LNP was at the size of around 78 and 45 nm, respectively . The mean concentrations of ionizable lipids at different time points (the dots) were calculated based on the signal of 3H-CHE labeled on LNP in the original study. The in vivo PBPK model, which excludes the disassembly and metabolism processes, was fitted to the original data, resulting in optimized PK curves (the solid lines) and parameter values.

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques: Labeling, In Vivo

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: PBPK model fitting result of human PK data of siRNA-LNP at different doses. Healthy human subjects intravenously received patisiran at the dose of 0.01, 0.05, 0.15, 0.3, and 0.5 mg/kg (phase 1 clinical trials ALN-TTR02-001 and ALN-TTR02-005). The mean concentration of ionizable lipids MC3 at different time points (the dots) was extracted from the original study . The reduced in vivo PBPK model was fitted to the data of 0.5 mg/kg, resulting optimized PK curve (the blue solid line) and parameter values. Then, these parameters were fixed, and other doses were simulated (the other solid lines).

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques: Clinical Proteomics, Concentration Assay, In Vivo

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: Fitting result of cellular transportation of the LNP containing C12-200 or MC3. (A) Hela cells were incubated with LNP containing C12-200 for 3 h and then washed to remove the medium. The data of LNP uptake up to 3 h and LNP disassembly, and exocytosis in the following 25 h were extracted from the original study (the dots). (B) Hela cells were incubated with LNP containing MC3 for 6 h. The data of LNP uptake and fraction in early endosomes, late endosomes, and lysosomes were extracted from the original study (the dots). The cellular PBPK model was fitted to data of C12-200 (with complex and reduced model structure) and MC3 (with reduced model structure) simultaneously, sharing values of rates of transfer from early endosomes to late endosomes ( k EE_LE ) from late endosomes to lysosomes ( k LE_LY ) from autophagosomes to autolysosomes ( k AP_AL ) and egress out of cells ( k eg ). The resulting optimized PK curves (the solid lines) were presented. (C) Parameters fitted to C12-200-LNP and physiological processes.

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques: Incubation

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

doi: 10.1016/j.apsb.2024.06.011

Figure Lengend Snippet: Fitting and simulation of cellular transportation of the LNP containing L319 and MC3. (A) The reduced cellular PBPK model was fitted to uptake data (the points) of LNP containing L319 incubated with Hela cells , obtaining the uptake profile (solid line). (B) The fraction of vesicles undergoing the release event for L319 was observed in the original study (the yellow dashed line). The sum of cR and rR based on all RNA in cells was fitted to the fraction (the yellow solid line) obtaining the RNA release rate ( k rel ). Based on that, the probability of siRNA undergoing the release event, which is the fraction of cR and rR to all RNA in the modeling, was simulated (the red solid line) and compared to the experimental data (the red dashed line). (C) The fraction of RNA released to the cytoplasm for MC3 was observed in the original study (the orange dashed line). The cR based on all RNA in cells was fitted to the fraction (the orange solid line) obtaining k rel and the following simulated probability of siRNA undergoing the release event (the red solid line). (D) Comparison in critical parameters related to siRNA release of LNPs containing L319, MC3, and C12-200.

Article Snippet: The cellular PBPK model was also built with MATLAB SimBiology APP (The MathWorks, Inc.) 2022a version.

Techniques: Incubation, Comparison

Journal: Clinical Pharmacology and Therapeutics

Article Title: Physiologically‐Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID‐19

doi: 10.1002/cpt.2176

Figure Lengend Snippet: Predicted remdesivir Day 5 AUC tau and C max after intravenous administration of a loading dose (200 mg or 5 mg/kg) of remdesivir over 0.5 hours on Day 1 then a daily maintenance dose (100 mg or 2.5 mg/kg) of remdesivir over 0.5 hours on Days 2–5 to pediatric patients. The simulated remdesivir dosage regimen for pediatric patients, ≥ 40 kg, was a single remdesivir 200‐mg loading dose on Day 1 followed by four once‐daily 100‐mg maintenance doses. The simulated remdesivir dosage regimen for pediatric patients, < 40 kg, was a single remdesivir 5 mg/kg loading dose on Day 1 followed by four once‐daily 2.5‐mg/kg maintenance doses. The adult observed exposures are from the remdesivir phase I program in adult healthy volunteers. 31,32 Blue line: MAX observed AUC tau or C max after 14 daily doses of 150 mg remdesivir IV over 1 hour. ³¹ Gray lines: MIN, MED, and MAX observed AUC tau or C max from after a single loading dose of 200 mg remdesivir IV over 0.5 hours on Day 1 then daily doses of 200 mg remdesivir IV over 0.5 hours. ³² Red dots: AUC tau or C max values predicted across the weight range (2.5–80 kg) based on the remdesivir, GS‐704277, and GS‐441524 PBPK model. Black line: LOWESS smoother line of predicted AUC tau or C max across the weight range. AUC tau , area under the concentration‐time curve over the dosing interval; C max , maximum plasma drug concentration; h, hour; IV, intravenous; MAX, maximum; MED, median; MIN, minimum.

Article Snippet: Briefly, a PBPK model was developed that accurately captures observed adult healthy volunteer remdesivir, GS‐704277, and GS‐441524 PK.

Techniques: Concentration Assay

Journal: Clinical Pharmacology and Therapeutics

Article Title: Physiologically‐Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID‐19

doi: 10.1002/cpt.2176

Figure Lengend Snippet: Comparison Between remdesivir, GS‐704277, and GS‐441524 Day 5 AUC tau after intravenous administration of a loading dose (200 mg or 5 mg/kg) of remdesivir on Day 1 then a daily maintenance dose (100 mg or 2.5 mg/kg) on Days 2–5 to pediatric patients predicted by PBPK and allometry. The simulated remdesivir dosage regimen for pediatric patients, ≥ 40 kg, was a single remdesivir 200‐mg loading dose on Day 1 followed by four once‐daily 100‐mg maintenance doses. The simulated remdesivir dosage regimen for pediatric patients, < 40 kg, was a single remdesivir 5 mg/kg loading dose on Day 1 followed by four once‐daily 2.5‐mg/kg maintenance doses. The adult observed exposures are from the remdesivir phase I program in adult healthy volunteers. ³¹ , ³² Gray lines: MIN, MED, and MAX observed AUC tau from after a single loading dose of 200 mg remdesivir IV over 0.5 hours on Day 1 then daily doses of 200 mg remdesivir IV over 0.5 hours. ³¹ Blue lines: minimum (dashed), median (solid) and maximum (dashed) AUC tau values predicted across the weight range (3–70 kg) based on simple allometry (exponent of 0.75 on clearance normalized to 70 kg body weight). Red dots: AUC tau values predicted across the weight range (2.5–80 kg) based on the remdesivir, GS‐704277, and GS‐441524 PBPK model. Black line: LOWESS smoother line of predicted AUC tau or C max across the weight range. AUC tau , area under the concentration‐time curve over the dosing interval; C max , maximum plasma drug concentration; h, hour; IV, intravenous; MAX, maximum; MED, median; MIN, minimum; PBPK, physiologically‐based pharmacokinetic.

Article Snippet: Briefly, a PBPK model was developed that accurately captures observed adult healthy volunteer remdesivir, GS‐704277, and GS‐441524 PK.

Techniques: Concentration Assay

Journal: Clinical Pharmacology and Therapeutics

Article Title: Physiologically‐Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID‐19

doi: 10.1002/cpt.2176

Figure Lengend Snippet: Physicochemical and pharmacokinetic parameters

Article Snippet: Briefly, a PBPK model was developed that accurately captures observed adult healthy volunteer remdesivir, GS‐704277, and GS‐441524 PK.

Techniques: In Vivo

Journal: CPT: Pharmacometrics & Systems Pharmacology

Article Title: Mechanistic modeling of ophthalmic, nasal, injectable, and implant generic drug products: A workshop summary report

doi: 10.1002/psp4.12952

Figure Lengend Snippet: Grants and contracts including mechanistic modeling and simulation approaches (including PBPK and CFD) for ophthalmic, nasal, injectable, buccal/sublingual, and female reproductive drug products awarded during GDUFA I and II regulatory research and science programs.

Article Snippet: , Modifications and improvements to hybrid CFD‐PBPK models for prediction of nasal corticosteroid deposition, absorption, and bioavailability , 2019–2022 , Applied Research Associates, Inc. , 75F40119C10079.

Techniques: Biomarker Discovery, Ointment, In Vitro, In Silico