Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations
Pharmacometric analysis is often used to quantify the differences and similarities between formulation prototypes. In the regulatory framework, it plays a significant role in the evaluation of bioequivalence. While non-compartmental analysis provides an unbiased data evaluation, mechanistic compartm...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/4/1258 |
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| author | Nadezhda Osipova Andrey Budko Olga Maksimenko Elena Shipulo Ludmila Vanchugova Wenqian Chen Svetlana Gelperina Matthias G. Wacker |
| author_facet | Nadezhda Osipova Andrey Budko Olga Maksimenko Elena Shipulo Ludmila Vanchugova Wenqian Chen Svetlana Gelperina Matthias G. Wacker |
| author_sort | Nadezhda Osipova |
| collection | DOAJ |
| description | Pharmacometric analysis is often used to quantify the differences and similarities between formulation prototypes. In the regulatory framework, it plays a significant role in the evaluation of bioequivalence. While non-compartmental analysis provides an unbiased data evaluation, mechanistic compartmental models such as the physiologically-based nanocarrier biopharmaceutics model promise improved sensitivity and resolution for the underlying causes of inequivalence. In the present investigation, both techniques were applied to two nanomaterial-based formulations for intravenous injection, namely, albumin-stabilized rifabutin nanoparticles and rifabutin-loaded PLGA nanoparticles. The antibiotic rifabutin holds great potential for the treatment of severe and acute infections of patients co-infected with human immunodeficiency virus and tuberculosis. The formulations differ significantly in their formulation and material attributes, resulting in an altered biodistribution pattern as confirmed in a biodistribution study in rats. The albumin-stabilized delivery system further undergoes a dose-dependent change in particle size which leads to a small yet significant change in the in vivo performance. A second analysis was conducted comparing the dose fraction-scaled pharmacokinetic profiles of three dose levels of albumin-stabilized rifabutin nanoparticles. The dose strength affects both the nanomaterial-related absorption and biodistribution of the carrier as well as the drug-related distribution and elimination parameters, increasing the background noise and difficulty of detecting inequivalence. Depending on the pharmacokinetic parameter (e.g., AUC, C<sub>max</sub>, Cl<sub>obs</sub>), the relative (percentage) difference from the average observed using non-compartmental modeling ranged from 85% to 5.2%. A change in the formulation type (PLGA nanoparticles vs. albumin-stabilized rifabutin nanoparticles) resulted in a similar level of inequivalence as compared to a change in the dose strength. A mechanistic compartmental analysis using the physiologically-based nanocarrier biopharmaceutics model led to an average difference of 152.46% between the two formulation prototypes. Albumin-stabilized rifabutin nanoparticles tested at different dose levels led to a 128.30% difference, potentially due to changes in particle size. A comparison of different dose strengths of PLGA nanoparticles, on average, led to a 3.87% difference. This study impressively illustrates the superior sensitivity of mechanistic compartmental analysis when dealing with nanomedicines. |
| first_indexed | 2024-03-11T04:38:38Z |
| format | Article |
| id | doaj.art-c8f1483caacb496ca24e0afc6f0f49cb |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T04:38:38Z |
| publishDate | 2023-04-01 |
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| spelling | doaj.art-c8f1483caacb496ca24e0afc6f0f49cb2023-11-17T20:54:58ZengMDPI AGPharmaceutics1999-49232023-04-01154125810.3390/pharmaceutics15041258Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin FormulationsNadezhda Osipova0Andrey Budko1Olga Maksimenko2Elena Shipulo3Ludmila Vanchugova4Wenqian Chen5Svetlana Gelperina6Matthias G. Wacker7Nanosystem Ltd., Kolomenskiy Proezd 13A, 115446 Moscow, RussiaN.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Science, Kashirskoye Shosse 24, 115478 Moscow, RussiaNanosystem Ltd., Kolomenskiy Proezd 13A, 115446 Moscow, RussiaNanosystem Ltd., Kolomenskiy Proezd 13A, 115446 Moscow, RussiaNanosystem Ltd., Kolomenskiy Proezd 13A, 115446 Moscow, RussiaDepartment of Pharmacy, Faculty of Science, 4 Science Drive 2, Singapore 117544, SingaporeNanosystem Ltd., Kolomenskiy Proezd 13A, 115446 Moscow, RussiaDepartment of Pharmacy, Faculty of Science, 4 Science Drive 2, Singapore 117544, SingaporePharmacometric analysis is often used to quantify the differences and similarities between formulation prototypes. In the regulatory framework, it plays a significant role in the evaluation of bioequivalence. While non-compartmental analysis provides an unbiased data evaluation, mechanistic compartmental models such as the physiologically-based nanocarrier biopharmaceutics model promise improved sensitivity and resolution for the underlying causes of inequivalence. In the present investigation, both techniques were applied to two nanomaterial-based formulations for intravenous injection, namely, albumin-stabilized rifabutin nanoparticles and rifabutin-loaded PLGA nanoparticles. The antibiotic rifabutin holds great potential for the treatment of severe and acute infections of patients co-infected with human immunodeficiency virus and tuberculosis. The formulations differ significantly in their formulation and material attributes, resulting in an altered biodistribution pattern as confirmed in a biodistribution study in rats. The albumin-stabilized delivery system further undergoes a dose-dependent change in particle size which leads to a small yet significant change in the in vivo performance. A second analysis was conducted comparing the dose fraction-scaled pharmacokinetic profiles of three dose levels of albumin-stabilized rifabutin nanoparticles. The dose strength affects both the nanomaterial-related absorption and biodistribution of the carrier as well as the drug-related distribution and elimination parameters, increasing the background noise and difficulty of detecting inequivalence. Depending on the pharmacokinetic parameter (e.g., AUC, C<sub>max</sub>, Cl<sub>obs</sub>), the relative (percentage) difference from the average observed using non-compartmental modeling ranged from 85% to 5.2%. A change in the formulation type (PLGA nanoparticles vs. albumin-stabilized rifabutin nanoparticles) resulted in a similar level of inequivalence as compared to a change in the dose strength. A mechanistic compartmental analysis using the physiologically-based nanocarrier biopharmaceutics model led to an average difference of 152.46% between the two formulation prototypes. Albumin-stabilized rifabutin nanoparticles tested at different dose levels led to a 128.30% difference, potentially due to changes in particle size. A comparison of different dose strengths of PLGA nanoparticles, on average, led to a 3.87% difference. This study impressively illustrates the superior sensitivity of mechanistic compartmental analysis when dealing with nanomedicines.https://www.mdpi.com/1999-4923/15/4/1258nanoparticlesrifabutinpopulation modelingmodelingbioequivalenceinjectables |
| spellingShingle | Nadezhda Osipova Andrey Budko Olga Maksimenko Elena Shipulo Ludmila Vanchugova Wenqian Chen Svetlana Gelperina Matthias G. Wacker Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations Pharmaceutics nanoparticles rifabutin population modeling modeling bioequivalence injectables |
| title | Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations |
| title_full | Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations |
| title_fullStr | Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations |
| title_full_unstemmed | Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations |
| title_short | Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations |
| title_sort | comparison of compartmental and non compartmental analysis to detect biopharmaceutical similarity of intravenous nanomaterial based rifabutin formulations |
| topic | nanoparticles rifabutin population modeling modeling bioequivalence injectables |
| url | https://www.mdpi.com/1999-4923/15/4/1258 |
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