The Irrelevance of In Vitro Dissolution in Setting Product Specifications for Drugs Like Dextromethorphan That are Subject to Lysosomal Trapping
The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area...
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| Vydané v: | Journal of pharmaceutical sciences Ročník 108; číslo 1; s. 268 |
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| Hlavní autori: | , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
United States
01.01.2019
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| ISSN: | 1520-6017, 1520-6017 |
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| Abstract | The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area under the concentration-time curve for immediate release formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and physiologically based pharmacokinetic model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence. This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX immediate release product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX. |
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| AbstractList | The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area under the concentration-time curve for immediate release formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and physiologically based pharmacokinetic model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence. This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX immediate release product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX.The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area under the concentration-time curve for immediate release formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and physiologically based pharmacokinetic model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence. This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX immediate release product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX. The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area under the concentration-time curve for immediate release formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and physiologically based pharmacokinetic model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence. This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX immediate release product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX. |
| Author | Bolger, Michael B Almukainzi, May Macwan, Joyce S Sarfraz, Muhammad Löbenberg, Raimar |
| Author_xml | – sequence: 1 givenname: Michael B surname: Bolger fullname: Bolger, Michael B organization: Simulations Plus, Inc., Lancaster, California 93534; USC School of Pharmacy, Pharmacology and Pharmaceutical Sciences, Los Angeles, California 90089 – sequence: 2 givenname: Joyce S surname: Macwan fullname: Macwan, Joyce S organization: Simulations Plus, Inc., Lancaster, California 93534 – sequence: 3 givenname: Muhammad surname: Sarfraz fullname: Sarfraz, Muhammad organization: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2E1 Canada; College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates – sequence: 4 givenname: May surname: Almukainzi fullname: Almukainzi, May organization: College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia – sequence: 5 givenname: Raimar surname: Löbenberg fullname: Löbenberg, Raimar email: Raimar@ualberta.ca organization: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2E1 Canada. Electronic address: Raimar@ualberta.ca |
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| CitedBy_id | crossref_primary_10_1007_s11095_022_03319_6 crossref_primary_10_3390_pharmaceutics12111073 crossref_primary_10_1016_j_ijbiomac_2025_146381 crossref_primary_10_1016_j_jddst_2022_103152 crossref_primary_10_3390_ph14050479 crossref_primary_10_1016_j_ejpb_2020_08_005 crossref_primary_10_1002_psp4_12776 crossref_primary_10_1002_psp4_12634 crossref_primary_10_1208_s12248_019_0346_6 crossref_primary_10_3389_fphar_2022_1029073 crossref_primary_10_3390_pharmaceutics15051544 crossref_primary_10_1002_bdd_2389 crossref_primary_10_1016_j_xphs_2020_04_021 crossref_primary_10_1016_j_jconrel_2022_10_040 crossref_primary_10_1016_j_xphs_2023_07_012 |
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| Keywords | dissolution rate absorption computational ADME CYP enzymes pharmacokinetics metabolite kinetics metabolism genetic polymorphisms bioequivalence |
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| SubjectTerms | Absorption, Physiological Area Under Curve Caco-2 Cells Computer Simulation Cytochrome P-450 CYP3A - genetics Dextromethorphan - blood Dextromethorphan - chemistry Enterocytes - metabolism Humans Lysosomes - metabolism Metabolic Clearance Rate - genetics Models, Biological Permeability Polymorphism, Genetic Solubility Therapeutic Equivalency |
| Title | The Irrelevance of In Vitro Dissolution in Setting Product Specifications for Drugs Like Dextromethorphan That are Subject to Lysosomal Trapping |
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