Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials
Abstract Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half‐life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP...
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Wiley
2024-12-01
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| Series: | Pharmacology Research & Perspectives |
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| Online Access: | https://doi.org/10.1002/prp2.70010 |
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| author | Stephen J. Nicholls Adam J. Nelson John J. P. Kastelein Marc Ditmarsch Andrew Hsieh Judith Johnson Danielle Curcio Douglas Kling Carol F. Kirkpatrick Michael H. Davidson |
| author_facet | Stephen J. Nicholls Adam J. Nelson John J. P. Kastelein Marc Ditmarsch Andrew Hsieh Judith Johnson Danielle Curcio Douglas Kling Carol F. Kirkpatrick Michael H. Davidson |
| author_sort | Stephen J. Nicholls |
| collection | DOAJ |
| description | Abstract Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half‐life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre‐clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13‐week recovery period. In healthy humans receiving 1–25 mg of obicetrapib, the mean terminal half‐life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6‐fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post‐treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half‐life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management. |
| format | Article |
| id | doaj-art-6dc8b9af8eaf46bdbcd2ab961d9a1ab2 |
| institution | Kabale University |
| issn | 2052-1707 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj-art-6dc8b9af8eaf46bdbcd2ab961d9a1ab22024-12-13T03:28:40ZengWileyPharmacology Research & Perspectives2052-17072024-12-01126n/an/a10.1002/prp2.70010Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trialsStephen J. Nicholls0Adam J. Nelson1John J. P. Kastelein2Marc Ditmarsch3Andrew Hsieh4Judith Johnson5Danielle Curcio6Douglas Kling7Carol F. Kirkpatrick8Michael H. Davidson9Victorian Heart Institute Monash University Melbourne Victoria AustraliaVictorian Heart Institute Monash University Melbourne Victoria AustraliaNewAmsterdam Pharma B.V Naarden The NetherlandsNewAmsterdam Pharma B.V Naarden The NetherlandsNewAmsterdam Pharma B.V Naarden The NetherlandsNewAmsterdam Pharma B.V Naarden The NetherlandsNewAmsterdam Pharma B.V Naarden The NetherlandsNewAmsterdam Pharma B.V Naarden The NetherlandsMidwest Biomedical Research Addison Illinois USANewAmsterdam Pharma B.V Naarden The NetherlandsAbstract Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half‐life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre‐clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13‐week recovery period. In healthy humans receiving 1–25 mg of obicetrapib, the mean terminal half‐life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6‐fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post‐treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half‐life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.https://doi.org/10.1002/prp2.70010accumulationanacetrapibcholesteryl ester transfer proteineliminationobicetrapibpharmacokinetics |
| spellingShingle | Stephen J. Nicholls Adam J. Nelson John J. P. Kastelein Marc Ditmarsch Andrew Hsieh Judith Johnson Danielle Curcio Douglas Kling Carol F. Kirkpatrick Michael H. Davidson Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials Pharmacology Research & Perspectives accumulation anacetrapib cholesteryl ester transfer protein elimination obicetrapib pharmacokinetics |
| title | Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials |
| title_full | Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials |
| title_fullStr | Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials |
| title_full_unstemmed | Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials |
| title_short | Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials |
| title_sort | obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors an integrated summary of results from non human primate studies and clinical trials |
| topic | accumulation anacetrapib cholesteryl ester transfer protein elimination obicetrapib pharmacokinetics |
| url | https://doi.org/10.1002/prp2.70010 |
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