Influence of renal and hepatic impairment on the pharmacokinetics of anacetrapib

Abstract

Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment (assessed by Child-Pugh criteria) or severe renal impairment (CrCl <30 mL/min/1.73 m(2)). In both studies, patients were matched (race, age, sex, BMI) with healthy control subjects. Twenty-four subjects were randomized in each study (12 with either moderate hepatic or severe renal impairment and 12 matched healthy controls). In the hepatic insufficiency study, the geometric mean ratio (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% CIs for the area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and the maximum concentration of drug in plasma (C(max)) were 1.16 (0.84, 1.60) and 1.02 (0.71, 1.49), respectively. In the renal insufficiency study, the GMRs (mean value for the group with severe renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC(0-∞) and Cmax were 1.14 (0.80, 1.63) and 1.31 (0.93, 1.83), respectively. Anacetrapib was generally well tolerated and there was no clinically meaningful effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of anacetrapib.

Assessment of the persistence of anacetrapib and evacetrapib concentrations using two pharmacokinetic modeling approaches

“…The predicted C last,168 hours was 17.7 ng/mL (90%CI:4.15–44.3 ng/mL), whereas the observed mean was 30.8 ng/mL (90%CI not available). The geometric mean C max was under‐predicted: The predicted C max was 243 ng/mL (90%CI: 230–257 ng/mL), whereas the observed value was 1084 ng/mL (90%CI: 771–1536 ng/mL) . The predicted/observed ratios of geometric mean AUC 0‐∞ , C max , and C last,168 hours following a single 100 mg dose were 0.65, 0.22, and 0.57, respectively.…”

“…The reported mean CL/F of anacetrapib (100 mg p.o. SD) in healthy volunteers following a low‐fat meal is 7.3 L/h CnormalLint⁡,u=CL/FnormalFnormalanormalFnormalG−CnormalLnormalrnormalfu,p(1+CnormalLnormalrB:PnormalQnormalh)…”

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

“…With the impaired subject treated as the reference subject, the control is matched for demographic and anthropometric measures such as race, age, body weight and/or BMI to be within some reasonable range of the reference individual. Neither the EMA nor FDA guidelines codify a particular range for age and weight; however, our experience matching controls to the reference impaired age ±10 years and BMI ±5-20% is reasonable to recruit and have supported labeling [32,66] Use of tobacco products, when permitted by protocol, should also be considered when matching control subjects to impaired, as smoking in particular, has been demonstrated to influence GFR in both healthy and renal impaired individuals, as address in Section 6.4.…”

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects

“…Anacetrapib is primarily metabolized by cytochrome P450 (CYP) 3A and is affected by strong inhibitors and inducers of CYP3A . Anacetrapib exposure is not meaningfully impacted by age, weight, sex, moderate hepatic impairment, and severe renal impairment . Food increases anacetrapib exposure .…”

“…[11][12][13] Anacetrapib exposure is not meaningfully impacted by age, weight, sex, moderate hepatic impairment, and severe renal impairment. 9,14 Food increases anacetrapib exposure. 15 Anacetrapib does not prolong the QTc interval and does not increase blood pressure.…”