Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation
This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized...
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| Published in | CPT: pharmacometrics and systems pharmacology Vol. 7; no. 11; pp. 728 - 738 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
John Wiley & Sons, Inc
01.11.2018
John Wiley and Sons Inc |
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| Abstract | This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant. |
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| AbstractList | This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non-Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P-gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose-reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5-mg and 5-mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant. This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non-Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P-gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose-reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5-mg and 5-mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non-Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P-gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose-reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5-mg and 5-mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant. This analysis describes the population pharmacokinetics ( PPK ) of apixaban in nonvalvular atrial fibrillation ( NVAF ) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 ( CYP )3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP 3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant. This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant. |
| Author | Wang, Xiaoli Thanneer, Neelima LaCreta, Frank Roy, Amit Cirincione, Brenda Leil, Tarek Ueno, Takayo Boyd, Rebecca Kowalski, Kenneth Byon, Wonkyung Oishi, Masayo Frost, Charles Nielsen, Jace |
| AuthorAffiliation | 3 Kowalski PMetrics Consulting Northville Michigan USA 4 Clinical Pharmacology Pfizer Groton Connecticut USA 2 Ann Arbor Pharmacometrics Group Ann Arbor Michigan USA 5 Clinical Pharmacology and Pharmacometrics Bristol‐Myers Squibb K.K. Tokyo Japan 6 Clinical Pharmacology Pfizer Japan Inc. Tokyo Japan 1 Clinical Pharmacology and Pharmacometrics Bristol‐Myers Squibb Princeton New Jersey USA |
| AuthorAffiliation_xml | – name: 6 Clinical Pharmacology Pfizer Japan Inc. Tokyo Japan – name: 2 Ann Arbor Pharmacometrics Group Ann Arbor Michigan USA – name: 3 Kowalski PMetrics Consulting Northville Michigan USA – name: 4 Clinical Pharmacology Pfizer Groton Connecticut USA – name: 5 Clinical Pharmacology and Pharmacometrics Bristol‐Myers Squibb K.K. Tokyo Japan – name: 1 Clinical Pharmacology and Pharmacometrics Bristol‐Myers Squibb Princeton New Jersey USA |
| Author_xml | – sequence: 1 givenname: Brenda surname: Cirincione fullname: Cirincione, Brenda organization: Bristol‐Myers Squibb – sequence: 2 givenname: Kenneth surname: Kowalski fullname: Kowalski, Kenneth organization: Kowalski PMetrics Consulting – sequence: 3 givenname: Jace surname: Nielsen fullname: Nielsen, Jace organization: Ann Arbor Pharmacometrics Group – sequence: 4 givenname: Amit surname: Roy fullname: Roy, Amit organization: Bristol‐Myers Squibb – sequence: 5 givenname: Neelima surname: Thanneer fullname: Thanneer, Neelima organization: Bristol‐Myers Squibb – sequence: 6 givenname: Wonkyung surname: Byon fullname: Byon, Wonkyung organization: Pfizer – sequence: 7 givenname: Rebecca surname: Boyd fullname: Boyd, Rebecca organization: Pfizer – sequence: 8 givenname: Xiaoli surname: Wang fullname: Wang, Xiaoli organization: Bristol‐Myers Squibb – sequence: 9 givenname: Tarek surname: Leil fullname: Leil, Tarek organization: Bristol‐Myers Squibb – sequence: 10 givenname: Frank surname: LaCreta fullname: LaCreta, Frank organization: Bristol‐Myers Squibb – sequence: 11 givenname: Takayo surname: Ueno fullname: Ueno, Takayo organization: Bristol‐Myers Squibb K.K – sequence: 12 givenname: Masayo surname: Oishi fullname: Oishi, Masayo organization: Pfizer Japan Inc – sequence: 13 givenname: Charles surname: Frost fullname: Frost, Charles email: Charles.frost@bms.com organization: Bristol‐Myers Squibb |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30259707$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Age Anticoagulants Cardiac arrhythmia Clinical trials Embolisms Employees Pharmacokinetics Studies Thrombosis |
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| Title | Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation |
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