Model‐Informed Dosing of Venetoclax in Healthy Subjects: An Exposure−Response Analysis
Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B‐lymphocyte counts as an on‐target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B‐lymphocyte levels to inform dosing of vene...
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| Published in | Clinical and translational science Vol. 12; no. 6; pp. 625 - 632 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
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United States
John Wiley & Sons, Inc
01.11.2019
John Wiley and Sons Inc Wiley |
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| Abstract | Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B‐lymphocyte counts as an on‐target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B‐lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high‐fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B‐lymphocyte data to determine the exposure‐response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B‐lymphocyte levels by 24% (15–35%) and 38% (25–54%), respectively. B‐lymphocytes recovered to normal levels within an average of 48 (21–64) days and 59 (30–66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK‐PD model characterized the relationship between venetoclax exposure and reduction in B‐lymphocytes and will help design future venetoclax studies in healthy subjects. |
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| AbstractList | Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B-lymphocyte counts as an on-target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B-lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high-fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B-lymphocyte data to determine the exposure-response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B-lymphocyte levels by 24% (15-35%) and 38% (25-54%), respectively. B-lymphocytes recovered to normal levels within an average of 48 (21-64) days and 59 (30-66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK-PD model characterized the relationship between venetoclax exposure and reduction in B-lymphocytes and will help design future venetoclax studies in healthy subjects.Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B-lymphocyte counts as an on-target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B-lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high-fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B-lymphocyte data to determine the exposure-response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B-lymphocyte levels by 24% (15-35%) and 38% (25-54%), respectively. B-lymphocytes recovered to normal levels within an average of 48 (21-64) days and 59 (30-66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK-PD model characterized the relationship between venetoclax exposure and reduction in B-lymphocytes and will help design future venetoclax studies in healthy subjects. Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B‐lymphocyte counts as an on‐target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B‐lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high‐fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B‐lymphocyte data to determine the exposure‐response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B‐lymphocyte levels by 24% (15–35%) and 38% (25–54%), respectively. B‐lymphocytes recovered to normal levels within an average of 48 (21–64) days and 59 (30–66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK‐PD model characterized the relationship between venetoclax exposure and reduction in B‐lymphocytes and will help design future venetoclax studies in healthy subjects. Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B‐lymphocyte counts as an on‐target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B‐lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high‐fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B‐lymphocyte data to determine the exposure‐response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B‐lymphocyte levels by 24% (15–35%) and 38% (25–54%), respectively. B‐lymphocytes recovered to normal levels within an average of 48 (21–64) days and 59 (30–66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK‐PD model characterized the relationship between venetoclax exposure and reduction in B‐lymphocytes and will help design future venetoclax studies in healthy subjects. Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B‐lymphocyte counts as an on‐target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B‐lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high‐fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B‐lymphocyte data to determine the exposure‐response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B‐lymphocyte levels by 24% (15–35%) and 38% (25–54%), respectively. B‐lymphocytes recovered to normal levels within an average of 48 (21–64) days and 59 (30–66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK ‐ PD model characterized the relationship between venetoclax exposure and reduction in B‐lymphocytes and will help design future venetoclax studies in healthy subjects. |
| Author | Gopalakrishnan, Sathej Salem, Ahmed Hamed Mensing, Sven Dave, Nimita |
| AuthorAffiliation | 2 Department of Clinical Pharmacy Faculty of Pharmacy Ain Shams University Cairo Egypt 3 Present address: Blueprint Medicines Cambridge Massachusetts USA 1 AbbVie North Chicago Illinois USA |
| AuthorAffiliation_xml | – name: 3 Present address: Blueprint Medicines Cambridge Massachusetts USA – name: 1 AbbVie North Chicago Illinois USA – name: 2 Department of Clinical Pharmacy Faculty of Pharmacy Ain Shams University Cairo Egypt |
| Author_xml | – sequence: 1 givenname: Nimita surname: Dave fullname: Dave, Nimita organization: AbbVie – sequence: 2 givenname: Sathej surname: Gopalakrishnan fullname: Gopalakrishnan, Sathej organization: AbbVie – sequence: 3 givenname: Sven surname: Mensing fullname: Mensing, Sven organization: AbbVie – sequence: 4 givenname: Ahmed Hamed orcidid: 0000-0002-9261-1583 surname: Salem fullname: Salem, Ahmed Hamed email: ahmed.salem@abbvie.com organization: Ain Shams University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31268229$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1002_jcph_1886 crossref_primary_10_1016_j_clml_2021_07_029 crossref_primary_10_1002_hem3_146 crossref_primary_10_1111_cts_12739 crossref_primary_10_1111_cts_13807 crossref_primary_10_1111_cts_13144 crossref_primary_10_1038_s41408_023_00870_2 crossref_primary_10_1097_HS9_0000000000000432 crossref_primary_10_1021_acs_jmedchem_3c02332 crossref_primary_10_2139_ssrn_3960655 |
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| Copyright | 2019 AbbVie Inc. published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. 2019 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. 2019. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| Snippet | Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B‐lymphocyte counts as an on‐target... Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B-lymphocyte counts as an on-target... |
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| SubjectTerms | Apoptosis Bioavailability Clinical trials Dosage Drug dosages Fasting Food Information sharing Leukemia Lymphocytes Lymphocytes B Lymphoma Pharmacodynamics Pharmacokinetics Researchers Rheumatoid arthritis Studies |
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| Title | Model‐Informed Dosing of Venetoclax in Healthy Subjects: An Exposure−Response Analysis |
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