Author + information
- Yan Liang1,
- Yimin Cui1,
- Ellen A. Cannady2,
- David S. Small2,
- Ping Xin3,
- Ming-Dauh Wang2,
- Jian Jun Jin3,
- Xia Zhao1 and
- Jeffrey G. Suico2
To evaluate the reciprocal pharmacokinetic (PK) effects of selected statins and evacetrapib at steady state.
Selected statins + evacetrapib were evaluated in a Phase 1, open-label, 2-part, single- and multiple-dose study in healthy native Chinese subjects. Part 1 evaluated evacetrapib PK after a single 130-mg evacetrapib dose and after once-daily (QD) dosing for 14 days. In Part 2, subjects received simvastatin (simva) 40 mg or atorvastatin (atorva) 20 mg QD for 4 days (Days 1 to 4); 130 mg evacetrapib QD for 10 days (Days 5 to 14); then statin + evacetrapib for 8 days (Days 15 to 22). Blood samples were collected predose through 24 hours postdose on Days 4, 14, and 22 to assess evacetrapib and statin concentrations. PK parameters were estimated using non-compartmental methods. Blood samples were also analyzed for high-density lipoprotein cholesterol (HDL C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglyceride (TG). Safety assessments included recording of adverse events, vital signs, physical examinations, clinical laboratory evaluations, and 12-lead electrocardiograms (ECGs).
Sixty-two subjects aged 19 to 48 years entered the study, and 60 completed (16 in Part 1; 44 in Part 2). Two subjects discontinued in Part 2: 1 withdrew consent and 1 discontinued due to an AE of abdominal pain with unknown relationship to study treatment after 4 days of evacetrapib + simva.
In Part 1, mean estimates of evacetrapib area under the concentration-time curve (AUC) from time zero to the last time point with a measurable concentration (AUC[0-tlast]) and maximum observed drug concentration (Cmax) were, respectively, 7300 ng?h/mL and 418 ng/mL after a single 130-mg evacetrapib dose and 21900 ng?h/mL and 954 ng/mL after QD dosing for 14 days. Evacetrapib median time of Cmax (tmax) and mean half-life were comparable for both treatments.
In Part 2, simva AUC from zero to 24 hours (AUC[0-24]) and Cmax increased, respectively, by 123% and 58%, and simva acid AUC(0-24) and Cmax increased by 108% and 79%, with evacetrapib. Evacetrapib did not affect simva tmax. Atorva AUC(0-24) and Cmax were 16% and 20% higher, respectively, and median tmax increased by 0.26 hours with evacetrapib.
After evacetrapib + simva, mean HDL-C increased 91%, mean LDL-C decreased 72%, and mean total cholesterol decreased 17% from baseline. Mean TG was within 10.5% of baseline. After evacetrapib + atorva, mean HDL-C increased 96%, mean LDL-C decreased 78%, and mean total cholesterol decreased 19% from baseline. Mean TG was within 11.5% of baseline.
Oral 130-mg evacetrapib single or QD doses were well-tolerated alone or with a statin. There were no safety concerns noted in clinical laboratory test, vital sign, and ECG data.
When coadministered with evacetrapib, simva exposure increased more than that of atorva. Simva and atorva are CYP3A4 substrates, while simva is also a substrate of CYP3A5, which is polymorphically expressed in Chinese. Evacetrapib weakly inhibited CYP3A4 in other clinical studies not conducted in China and it inhibited CYP3A5 in vitro. One hypothesis for the effect on simva exposure is that evacetrapib may inhibit CYP3A5 in vivo. CYP3A5 pharmacogenetic (PGx) expression could have elucidated these unexpected drug-drug interactions, but the samples were not collected for this study. The clinical interpretation of drug-drug interaction studies can be best informed in the context of data from in vitro, in vivo, and PGx sources.