Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
Abstract Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-11-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12711 |
| _version_ | 1819041309135994880 |
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| author | Xia Pu Mark Sale Feng Yang Yi Zhang John D. Davis Nidal Al‐Huniti |
| author_facet | Xia Pu Mark Sale Feng Yang Yi Zhang John D. Davis Nidal Al‐Huniti |
| author_sort | Xia Pu |
| collection | DOAJ |
| description | Abstract Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics (PD) of evinacumab using pooled phase III clinical data. Total evinacumab PK were described by a two‐compartment model with combined linear and saturable (Michaelis–Menten) elimination, and first‐order absorption. At clinically relevant concentrations, plasma drug concentrations were mainly influenced by the linear clearance pathway. Although the maximum target‐mediated rate of elimination (Vmax) parameter for the saturable pathway was found to be positively related to baseline ANGPLTL3, variability in body weight contributed more to the variability in evinacumab exposure than variability in ANGPTL3. An effect of HoFH versus healthy volunteers on Vmax was also identified. Weight‐based dosing regimens resulted in consistent evinacumab exposure across weight ranges. An indirect exposure–response model adequately described the relationship between evinacumab and LDL‐C, where drug concentration is assumed to inhibit LDL‐C production. The final population PK/PD model included two nonclinically significant covariates (race and baseline body weight) on the maximum drug‐induced inhibitory effect (Imax) and one (baseline LDL‐C) on the evinacumab concentration inducing 50% of Imax (IC50). A smaller IC50 was observed in patients with higher baseline LDL‐C, suggesting greater sensitivity to treatment. Population exposure–response analysis permitted estimation of derived PD parameters and individual LDL‐C levels over time for patients with HoFH. The model accurately predicted the proportion of patients with HoFH achieving prespecified LDL‐C goals with evinacumab during the ELIPSE HoFH study, further supporting a dosing strategy. |
| first_indexed | 2024-12-21T09:22:56Z |
| format | Article |
| id | doaj.art-7d13c590a1c64df5a16b0dbf274cfafe |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-12-21T09:22:56Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-7d13c590a1c64df5a16b0dbf274cfafe2022-12-21T19:08:58ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062021-11-0110111412142110.1002/psp4.12711Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemiaXia Pu0Mark Sale1Feng Yang2Yi Zhang3John D. Davis4Nidal Al‐Huniti5Regeneron Pharmaceuticals, Inc. Tarrytown New York USANuventra Durham North Carolina USARegeneron Pharmaceuticals, Inc. Tarrytown New York USARegeneron Pharmaceuticals, Inc. Tarrytown New York USARegeneron Pharmaceuticals, Inc. Tarrytown New York USARegeneron Pharmaceuticals, Inc. Tarrytown New York USAAbstract Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics (PD) of evinacumab using pooled phase III clinical data. Total evinacumab PK were described by a two‐compartment model with combined linear and saturable (Michaelis–Menten) elimination, and first‐order absorption. At clinically relevant concentrations, plasma drug concentrations were mainly influenced by the linear clearance pathway. Although the maximum target‐mediated rate of elimination (Vmax) parameter for the saturable pathway was found to be positively related to baseline ANGPLTL3, variability in body weight contributed more to the variability in evinacumab exposure than variability in ANGPTL3. An effect of HoFH versus healthy volunteers on Vmax was also identified. Weight‐based dosing regimens resulted in consistent evinacumab exposure across weight ranges. An indirect exposure–response model adequately described the relationship between evinacumab and LDL‐C, where drug concentration is assumed to inhibit LDL‐C production. The final population PK/PD model included two nonclinically significant covariates (race and baseline body weight) on the maximum drug‐induced inhibitory effect (Imax) and one (baseline LDL‐C) on the evinacumab concentration inducing 50% of Imax (IC50). A smaller IC50 was observed in patients with higher baseline LDL‐C, suggesting greater sensitivity to treatment. Population exposure–response analysis permitted estimation of derived PD parameters and individual LDL‐C levels over time for patients with HoFH. The model accurately predicted the proportion of patients with HoFH achieving prespecified LDL‐C goals with evinacumab during the ELIPSE HoFH study, further supporting a dosing strategy.https://doi.org/10.1002/psp4.12711 |
| spellingShingle | Xia Pu Mark Sale Feng Yang Yi Zhang John D. Davis Nidal Al‐Huniti Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia CPT: Pharmacometrics & Systems Pharmacology |
| title | Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia |
| title_full | Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia |
| title_fullStr | Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia |
| title_full_unstemmed | Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia |
| title_short | Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia |
| title_sort | population pharmacokinetics and exposure response modeling for evinacumab in homozygous familial hypercholesterolemia |
| url | https://doi.org/10.1002/psp4.12711 |
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