Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture

Perazzolo, Simone; Shireman, Laura M.; Shen, Danny D.; Ho, Rodney J. Y.

doi:10.1016/j.xphs.2021.10.007

Cited by 7 publications

(9 citation statements)

References 47 publications

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“…Earlier studies with TFV-in-DcNP containing lopinavir/ritonavir introduced into systemic circulation by IV dosing indicates that >90% of TFV remained associated with DcNP in blood circulation [24]. Therefore, the observed peaks followed by sustained levels in the time-course are likely due to a combination of lymphatic 'first pass' absorption, cellular uptake and retention, and in-vivo formulation stability [24,26,27].…”

Section: Discussionmentioning

confidence: 99%

A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable

Perazzolo,

Stephen,

Eguchi

et al. 2023

Aids

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Objective: To develop an injectable dosage form of the daily oral HIV drugs, tenofovir (T), lamivudine (L), and dolutegravir (D), creating a single, complete, all-in-one TLD 3-drug-combination that demonstrates long-acting pharmacokinetics. Design: Using drug-combination-nanoparticle (DcNP) technology to stabilize multiple HIV drugs, the 3 HIV drugs TLD, with disparate physical-chemical properties, are stabilized and assembled with lipid-excipients to form TLD-in-DcNP. TLD-in-DcNP is verified to be stable and suitable for subcutaneous administration. To characterize the plasma time-courses and PBMC concentrations for all 3 drugs, single subcutaneous injections of TLD-in-DcNP were given to nonhuman primates (NHP, M. nemestrina). Results: Following single-dose TLD-in-DcNP, all drugs exhibited long-acting profiles in NHP plasma with levels that persisted for 4 weeks above predicted viral-effective concentrations for TLD in combination. Times-to-peak were within 24 hr in all NHP for all drugs. Compared to a free-soluble TLD, TLD-in-DcNP provided exposure enhancement and extended duration 7.0-, 2.1-, and 20-fold as AUC boost and 10-, 8.3-, and 5.9-fold as half-life extension. Additionally, DcNP may provide more drug exposure in cells than plasma with PBMC-to-plasma drug ratios exceeding one, suggesting cell-targeted drug-combination delivery. Conclusions: This study confirms that TLD with disparate properties can be made stable by DcNP to enable TLD concentrations of 4 weeks in NHP. Study results highlighted the potential of TLD-in-DcNP as a convenient all-in-one, complete HIV long-acting product for clinical development.

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Section: Discussionmentioning

confidence: 99%

A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable

Perazzolo,

Stephen,

Eguchi

et al. 2023

Aids

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“…Since an increase in the phosphorylation rates should lead to an increase in IADM levels, we employed a simplified version of a TFV-validated PBPK model built by Perazzolo et al. ( 30 ) as an investigational tool to test the PK hypothesis. Modeling an increase in the phosphorylation rates ( k f1 and/or k f2 ) coupled with changes in lymphocytes trafficking rates as result of ART-induced reduction in immune activation ( 55 ) led to an increase in IADM levels in both LNMC and PBMC, with a steeper growth in the former compartment, as observed in our dataset.…”

Section: Discussionmentioning

confidence: 99%

“…This model was simplified from a novel and extended PBPK model recently proposed by Perazzolo et al. ( 30 ) and properly validated for TFV in nonhuman primates, which included a more complex representation of the lymphatic system and its communication with other anatomic compartments. The reduced PBPK model here consisted of seven compartments: subcutaneous space, blood (plasma and PBMC), lymph nodes (sinus and LNMC), kidney, and rest-of-body.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, the absorption of TFV into the blood from the subcutaneous injection site was considered fast and complete in NHP (Viread Label, Gilead Sciences, Inc.). Since <1% of the subcutaneous dose goes directly to the lymphatics ( 30 ), the direct lymphatic uptake was ignored.…”

Section: Methodsmentioning

confidence: 99%

“…The compartment volumes, flow rates, and pharmacokinetic parameters and their values for a typical nonhuman primate were imported from Perazzolo et al. ( 30 ) and reported in Supplementary Table 5 . The model construction and simulations were carried out in MATLAB 2020a (The MathWorks, Inc. MA).…”

Section: Methodsmentioning

confidence: 99%

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Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques

Srinivasula,

Degrange,

Perazzolo

et al. 2023

Front. Immunol.

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Introduction and methodsTo understand the relationship between immunovirological factors and antiretroviral (ARV) drug levels in lymph nodes (LN) in HIV therapy, we analyzed drug levels in twenty-one SIV-infected rhesus macaques subcutaneously treated with daily tenofovir (TFV) and emtricitabine (FTC) for three months.ResultsThe intracellular active drug-metabolite (IADM) levels (TFV-dp and FTC-tp) in lymph node mononuclear cells (LNMC) were significantly lower than in peripheral blood mononuclear cells (PBMC) (P≤0.005). Between Month 1 and Month 3, IADM levels increased in both LNMC (P≤0.001) and PBMC (P≤0.01), with a steeper increase in LNMC (P≤0.01). The viral dissemination in plasma, LN, and rectal tissue at ART initiation correlated negatively with IADM levels at Month 1. Physiologically-based pharmacokinetic model simulations suggest that, following subcutaneous ARV administration, ART-induced reduction of immune activation improves the formation of active drug-metabolites through modulation of kinase activity and/or through improved parent drug accessibility to LN cellular compartments.ConclusionThese observations have broad implications for drugs that need to phosphorylate to exert their pharmacological activity, especially in the settings of the pre-/post-exposure prophylaxis and efficacy of antiviral therapies targeting pathogenic viruses such as HIV or SARS-CoV-2 replicating in highly inflammatory anatomic compartments.

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SAAM II: A general mathematical modeling rapid prototyping environment

Perazzolo

2024

CPT Pharmacom & Syst Pharma

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Simulation Analysis and Modeling II (SAAM II) is a graphical modeling software used in life sciences for compartmental model analysis, particularly, but not exclusively, appreciated in pharmacokinetics (PK) and pharmacodynamics (PD), metabolism, and tracer modeling. Its intuitive “circles and arrows” visuals allow users to easily build, solve, and fit compartmental models without the need for coding. It is suitable for rapid prototyping of models for complex kinetic analysis or PK/PD problems, and in educating students and non‐modelers. Although it is straightforward in design, SAAM II incorporates sophisticated algorithms programmed in C to address ordinary differential equations, deal with complex systems via forcing functions, conduct multivariable regression featuring the Bayesian maximum a posteriori, perform identifiability and sensitivity analyses, and offer reporting functionalities, all within a single package. After 26 years from the last SAAM II tutorial paper, we demonstrate here SAAM II's updated applicability to current life sciences challenges. We review its features and present four contemporary case studies, including examples in target‐mediated PK/PD, CAR‐T‐cell therapy, viral dynamics, and transmission models in epidemiology. Through such examples, we demonstrate that SAAM II provides a suitable interface for rapid model selection and prototyping. By enabling the fast creation of detailed mathematical models, SAAM II addresses a unique requirement within the mathematical modeling community.

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Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture

Cited by 7 publications

References 47 publications

A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable

A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable

Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques

SAAM II: A general mathematical modeling rapid prototyping environment

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