A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.

No abstract

Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P‐gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (Cmax), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2‐fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug‐drug interaction (DDI) with increasing RI severity, a similar 3.1‐fold to 4.4‐fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1‐fold to 4.7‐fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P‐gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst‐case scenario for clinically derisking P‐gp and BCRP substrates in the setting of RI.

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

No abstract