Physiologically based pharmacokinetic combined BTK occupancy modeling for optimal dosing regimen prediction of acalabrutinib in patients alone, with different CYP3A4 variants, co-administered with CYP3A4 modulators and with hepatic impairment.
Purpose: To develop a mathematical model combined between physiologically based pharmacokinetic and BTK occupancy (PBPK-BO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of acalabrutinib (ACA) and active metabolite ACP-5862 in healthy humans as well as PD in patient...
| Published in: | European Journal of Clinical Pharmacology Vol. 78; no. 9; pp. 1435 - 1447 |
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| Main Authors: | , , , , , |
| Format: | equations & formulas research tables/charts Journal Article |
| Published: |
Springer Nature
Sep2022
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=158447227&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 158447227 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Sep2022 vid: 78 iid: 9 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 158447227 157344966 158447227 158447227 10.1007/s00228-022-03338-7 158447227 ppf: 1435 ppct: 12 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Physiologically based pharmacokinetic combined BTK occupancy modeling for optimal dosing regimen prediction of acalabrutinib in patients alone, with different CYP3A4 variants, co-administered with CYP3A4 modulators and with hepatic impairment. aug: au: Xu, Lifang Yu, Shuang Liu, Huining Yi, Bowen Wang, Guopeng Liu, Yang affil: Affiliated Hospital of Jiangxi University of Chinese Medicine, Jiangxi Province, 330006, Nanchang, China sug: subj: Liver Diseases Drug Therapy Tyrosine Kinase Inhibitors Pharmacodynamics Tyrosine Kinase Inhibitors Pharmacokinetics Treatment Outcomes Tyrosine Kinase Inhibitors Administration and Dosage Oxidoreductases Administration and Dosage Drug Therapy, Combination Human Erythromycin Clarithromycin Itraconazole Simulations Biochemical Phenomena ab: Purpose: To develop a mathematical model combined between physiologically based pharmacokinetic and BTK occupancy (PBPK-BO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of acalabrutinib (ACA) and active metabolite ACP-5862 in healthy humans as well as PD in patients. Next, to use the PBPK-BO to determine the optimal dosing regimens in patients alone, with different CYP3A4 variants, when co-administration with four CYP3A4 modulators and in patients with hepatic impairment, respectively. Methods: The PBPK-BO model was built using physicochemical and biochemical properties of ACA and ACP-5862 and then verified by observed PK and PD data from healthy humans and patients. Finally, the model was applied to determine optimal dosing regimens in various clinical situations. Results: The simulations demonstrated that 100 mg ACA twice daily (BID) was the optimal dosing regimen in patients alone. Additionally, dosage regimens might be reduced to 50 mg BID in patients with five CYP3A4 variants. Moreover, the dosing regimen should be modified to 100 mg (even to 50 mg) once daily (QD) when co-administration with erythromycin or clarithromycin, and be increased to 200 mg BID with rifampicin, and but be avoided co-administration with itraconazole. Furthermore, dosage regimen simulations showed that optimal dosing might be decreased to 50 mg BID in patients with mild and moderate hepatic impairment, and be avoided taking ACA in severely hepatically impaired patients. Conclusion: This PBPK-BO model can predict PK and PD in healthy humans and patients and also predict the optimal dosing regimens in various clinical situations. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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