Multiple-Dose Pharmacodynamics and Pharmacokinetics of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Subjects

Krishna, Rajesh; Bergman, AJ; Jin, Bo; Fallon, Marissa S.; Côté, Josée; Hoydonck, Pascale Van; Laethem, Tine; Gendrano, Isaias Noel; Dyck, Kristien Van; Hilliard, Deborah; Laterza, Omar; Snyder, Karen; Chavez‐Eng, Cynthia; Lutz, Ryan; Chen, J; Bloomfield, DM; Smet, M. De; Bortel, L. Van; Gutiérrez, María J.; Al‐Huniti, Nidal; Dykstra, Kevin; Gottesdiener, K.; Ja, Wagner

doi:10.1038/clpt.2008.109

Cited by 94 publications

(116 citation statements)

References 17 publications

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“…These results were consistent with the day 1 observed t ½ in the present study but much shorter than the t ½ after the 6-week multiple dose regimen (Table 2). This phenomenon was also observed in humans, where single-dose studies underpredicted the t ½ after longer-term treatment (Krishna et al, 2008;Gutstein et al, 2012). A potential explanation is that the mechanistic causes of long t ½ are linked to the drug's tissue accumulation and retention characteristics.…”

Section: Discussionmentioning

confidence: 71%

“…In addition to lowering LDL and raising HDL, the phase 3 Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib trial demonstrated that CETP inhibition by anacetrapib was well tolerated and that anacetrapib was devoid of torcetrapib-like liabilities such as blood pressure increases (Krishna et al, 2008;Bloomfield et al, 2009;Gotto et al, 2014 a,b); however, anacetrapib exhibits complex accumulation and washout kinetics in circulation in humans. As the clinical development of anacetrapib progressed and patients were treated for longer duration, the t ½ appeared to be longer than had been predicted from initial studies with shorter treatment duration.…”

Section: Introductionmentioning

confidence: 99%

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Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Hartmann

Kumar

Johns

et al. 2015

Drug Metabolism and Disposition

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The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibits a long terminal half-life (t ½ ) in humans; however, the dispositional mechanisms that lead to this long t ½ are still being elucidated. As it is hypothesized that disposition into adipose tissue and binding to CETP might play a role, we sought to delineate the relative importance of these factors using a preclinical animal model. A multiple-dose pharmacokinetic study was conducted in C57BL6 wild-type (WT) lean, WT diet-induced obese (DIO), natural flanking region (NFR) CETP-transgenic lean, and NFR-DIO mice. Mice were dosed orally with 10 mg/kg anacetrapib daily for 42 days. Drug concentrations in blood, brown and white adipose tissue, liver, and brain were measured up to 35 weeks postdose. During dosing, a 3-to 9-fold accumulation in 72-hour postdose blood concentrations of anacetrapib was observed. Drug concentrations in white adipose tissue accumulated ∼20-to 40-fold, whereas 10-to 17-fold accumulation occurred in brown adipose and approximately 4-fold in liver. Brain levels were very low (<0.1 mM), and a trend of accumulation was not seen. The presence of CETP as well as adiposity seems to play a role in determining the blood concentrations of anacetrapib. The highest blood concentrations were observed in NFR DIO mice, whereas the lowest concentrations were seen in WT lean mice. In adipose and liver tissue, higher concentrations were seen in DIO mice, irrespective of the presence of CETP. This finding suggests that white adipose tissue serves as a potential depot and that disposition into adipose tissue governs the long-term kinetics of anacetrapib in vivo.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Hartmann

Kumar

Johns

et al. 2015

Drug Metabolism and Disposition

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“…Initially, HDL-C levels increased with declining CETP activity, as expected; however, at later time points HDL-C appears to increase with increasing CETP activity. These characteristics are due to the fact that CETP activity declines sharply on the first day of dosing, but the effect is not as pronounced after subsequent doses, even though the lipid effects do not change appreciably over time with continuous daily dosing (2). Trough CETP inhibition and 24 h average CETP inhibition were also not consistently predictive of HDL-C levels.…”

Section: Pk/pd Model Developmentmentioning

confidence: 82%

“…Anacetrapib has been generally well tolerated in phase I and II studies, and has demonstrated lipid-altering effects greater than any member of its class (1)(2)(3)(4). Key development questions for this drug included selection of an optimal dose for phase III development, understanding the effects of formulation or fed state on drug exposure and lipid effects, elucidation of a predictive exposure-response relationship between anacetrapib and high-density lipoprotein (HDL-C) or lowdensity lipoprotein cholesterol (LDL-C), and the likely extent to which these effects change when patients are treated with anacetrapib in combination with an HMGCoA reductase inhibitor (statin).…”

Section: Introductionmentioning

confidence: 99%

“…In controlled phase I studies of a hot-melt extruded tablet (HME), administration of a standard high-fat breakfast with single or multiple doses of 150 mg anacetrapib resulted in ∼7.5-fold increase in area under curve (AUC) and ∼17-fold increase in C max relative to the fasted state. A low-fat meal increased AUC ∼2.2-fold (∼3.7-fold increase in C max ) (2,4). An Imwitor/Tween liquidfilled capsule (LFC) formulation was used in early phase I development while the HME tablet was introduced in phase III following limited phase I evaluation.…”

Section: Introductionmentioning

confidence: 99%

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Model-Based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

Krishna

Bergman

Green

et al. 2011

AAPS J

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Abstract. A model-based strategy was used to inform the early clinical development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor under development for the treatment of hyperlipidemia. The objectives of this model-based approach were to enable bridging variable pharmacokinetic effects, differences among formulations used in development, and to identify an appropriate dose for the phase III confirmatory program. Nonlinear mixed effects PK/PD models were initially developed based on data obtained from multiple phase I studies and later were updated with data from a phase IIb study. The population pharmacokinetic model described differences between the liquid-filled capsule used in phase I and phase IIb and the hot-melt extruded (HME) tablet formulation introduced in phase III, allowing for bridging of the two formulations, and quantified the complex relationship of apparent anacetrapib bioavailability with subject meal intake. Proportional E max models quantified the relationships between anacetrapib trough concentration and lipoprotein effects (LDL-C and HDL-C), with covariate effects of study population (normal volunteers vs. patients), and co-administration with HMG-CoA reductase inhibitor ("statin"). The interaction between anacetrapib and atorvastatin suggested pharmacological independence, i.e., that when given together, each agent exerts the same proportional lipid effect observed from monotherapy. Clinical trial simulation was used to examine the robustness of the effects to random dietary indiscretion, and found that the results were robust as long as patients generally adhered to a low-fat diet. These results allowed the selection of the 100 mg dose with the HME formulation for phase III development even though this dose and formulation were not specifically studied in a phase IIb trial.

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Atherosclerosis II : HDL Elevation

Ali

Hunt

Sinclair

2010

Burger's Medicinal Chemistry and Drug Discovery

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Atherosclerosis is an arterial disease associated with elevated plasma lipid levels and is a major cause of morbidity and mortality worldwide. Clinical trials have demonstrated that reduction of low‐density lipoprotein cholesterol (LDL‐C), as can be accomplished with HMG‐CoA reductase inhibitors (statins), leads to a reduction in coronary events and mortality by about 25%. Conversely, epidemiological evidence indicates that high‐density lipoprotein cholesterol (HDL‐C) levels have an inverse correlation with risk of coronary artery disease. The beneficial effects of HDL have been attributed to its involvement in the movement of cholesterol from the periphery to the liver as well as to its apparent antioxidant and anti‐inflammatory activities. Consequently, there is much interest in identifying therapeutic approaches to raising HDL that will be useful as a treatment for atherosclerosis and dyslipidemias. The properties and physiologic role of HDL, as well as approaches to increasing plasma HDL concentrations, will be summarized.

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Multiple-Dose Pharmacodynamics and Pharmacokinetics of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Subjects

Cited by 94 publications

References 17 publications

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Model-Based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

Atherosclerosis II : HDL Elevation

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