SCY-078 is an orally bioavailable triterpenoid glucan synthase inhibitor in clinical development as an intravenous and oral treatment of fungal infections caused by Candida and Aspergillus species. This was a sequential, single-center, open-label phase 1 study to assess the drug-drug interaction potential between SCY-078 and tacrolimus during concomitant administration in healthy subjects. In cohort 1, period 1, subjects received a single oral dose of tacrolimus 2 mg in the fasted state. In period 2 after a ≥15 day washout, subjects received a single loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 through 8. On day 3 of period 2, subjects also received a single dose of tacrolimus 2 mg concurrent with SCY-078. In cohort 2, subjects received a loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 and 3. Pharmacokinetic (PK) parameters were compared to assess both the impact of steady-state SCY-078 on tacrolimus and the impact of tacrolimus on the PK of steady-state SCY-078. The concurrent coadministration of tacrolimus and SCY-078 had no effect on the maximum blood levels of tacrolimus, as evidenced by no change in maximum concentration of drug in blood plasma and a 1.4-fold increase in total area under the plasma drug concentration-time curve. The concurrent coadministration of tacrolimus and SCY-078 resulted in a weaker interaction than typically observed with the azole class of antifungals. The current data indicate that an initial dose adjustment for tacrolimus may not be warranted when combined with SCY-078, as the modest increase in exposure is less than the therapeutic window, although tacrolimus monitoring, as with addition of any new medication, is recommended. These results support the coadministration of SCY-078 and tacrolimus.

SCY‐078, the first in a new class of β 1,3‐glucan synthesis inhibitors, is being developed as an oral and intravenous antifungal treatment for Candida and Aspergillus species fungal infections. In vitro, studies indicated SCY‐078 is an inhibitor of cytochrome P450 (CYP) 2C8 with markedly lower effect over other CYP isozymes. To examine clinically relevant effects of th potential interaction with SCY‐078, this phase 1, open‐label, 2‐period crossover study evaluated the pharmacokinetic parameters of rosiglitazone, a sensitive substrate of CYP2C8 metabolism, in the absence and presence of SCY‐078 dosed to therapeutically relevant SCY‐078 concentration exposure after repeat dosing. Healthy adult subjects were randomized to 2 treatment sequences: a single oral 4‐mg rosiglitazone dose alone on day 1 or a 1250‐mg SCY‐078 loading dose on day 1 followed by a once‐daily 750‐mg SCY‐078 dose for an additional 7 days (reflecting the clinical regimen evaluated during phase 2 studies for infections by Candida species) and concurrent administration of a single oral 4‐mg rosiglitazone dose on day 3, before alternating following a ≥10‐day washout. The exposure to SCY‐078 observed in this study was in line with the intended exposure for treatment of invasive fungal infections. The 90% confidence intervals for rosiglitazone exposure geometric mean ratios were within the prespecified no effect interval of 0.70‐1.43. Additionally, maximum concentration values for rosiglitazone and its metabolite, N‑desmethylrosiglitazone, were not significantly affected by co‐administration with SCY‐078. Overall, rosiglitazone exposure was not impacted to a clinically meaningful extent with co‐administration of therapeutically relevant SCY‐078 concentration exposure after repeat dosing. The results are indicative of low risk for interaction of SCY‐078 with drugs metabolized via the CYP family of enzymes.

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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.

Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89.9%) when compared to increases in white subjects (108.0%). Similarly, the decrease in low-density lipoprotein cholesterol was 17.8% (absolute percentage points) less in blacks (-21.2%) relative to whites (-39.0%). In contrast, there were no apparent race-related differences in cholesteryl ester transfer protein mass or activity. Anacetrapib was generally well tolerated in this study. The results of this study suggest that there may be race-related differences in pharmacodynamics of anacetrapib independent of pharmacokinetics.