The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.

Aims To characterize the absorption, metabolism and excretion of an oral and intravenous (IV) dose of radiolabelled [ 14 C]-sildena®l citrate in healthy male subjects. Speci®c objectives were to measure the cumulative amount of drug-related radiolabelled material excreted in the urine and faeces, to characterize urinary and faecal radioactivity as unchanged sildena®l or its metabolites, and to quantify blood and plasma total radioactivity and unchanged drug concentrations. Methods Six healthy male subjects between the ages of 45 and 58 years were enrolled in an open-label, parallel-group study; three subjects received the oral dose and three received the IV dose. Oral drug was administered as a single dose of 50-mg [ 14 C]-sildena®l, and IV drug was administered as a single dose of 25-mg [ 14 C]-sildena®l infused over 25 min. Each dosage form contained 50 mCi of radioactivity. For radioactivity assays, whole blood, plasma, urine and faeces samples were taken predose and at speci®ed intervals up to 5 days postdose. Plasma samples were assayed for sildena®l and the metabolites UK-103,320 and UK-150,564. Metabolite pro®ling was also performed in plasma, faeces and urine. Results Absorption of sildena®l after oral administration was rapid and approximately 92% whilst the absolute bioavailability was limited to 38%, due to ®rst-pass metabolism. Mean AUC t values showed that sildena®l accounted for about 60% of the total circulating radioactivity in the plasma after IV administration and for 32% after oral administration. Concentrations of radioactivity in whole blood were lower than in plasma, indicating limited penetration of sildena®l into blood cells. No unchanged sildena®l was detected in either urine or faeces, demonstrating that metabolism was the major mechanism of drug clearance. The principal routes of metabolism were N-demethylation, oxidation and aliphatic dehydroxylation. Sildena®l was well tolerated, with treatment-related adverse events reported by three subjects. Two of these were mild, and there was one case of moderate leg pain. Conclusions The pharmacokinetics of radiolabelled [ 14 C]-sildena®l were consistent with rapid absorption, ®rst-pass metabolism and primarily faecal elimination of N-demethylated metabolites.

cHepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n ‫؍‬ 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n ‫؍‬ 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUC) or maximum concentration in plasma (C max ) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R-and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUC for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUC was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments.

1. The pharmacokinetics and disposition of modipafant, a dihydropyridine PAF antagonist, were studied in rat and dog following intravenous and oral administration of the drug or its radiolabelled analogue. In addition, the pharmacokinetics were studied in man following single administration of escalating oral doses of the drug. Modipafant is a lipophilic weak base with log D(octanol) 7.4 and pKa of 4.3 and 5.3 respectively. 2. Following intravenous administration of [14C]-modipafant to rat, radioactivity is rapidly distributed throughout the body, except for the brain. A significant amount of radioactivity (probably modipafant) is rapidly distributed to the alimentary tract, particularly in the stomach. This is believed to be due to 'ion trapping' of modipafant in the acidic environment of the upper GI tract. The re-circulated modipafant may be subject to reabsorption and/or faecal excretion. 3. Following intravenous administration to rats, systemic clearance is five times greater in the male than female. The magnitude of this difference is in keeping with the clearance of other dihydropyridines such as nilvadipine. In dog, the clearance values are similar for both sexes, as expected. In this latter species, the systemic clearance decreases 6-fold with increasing dose size, indicative of saturation of a pathway of metabolism. 4. Following oral administration over a dose range of 1-12 mg/kg, modipafant is incompletely (27-67%) bioavailable in rat and dog. In the male dog, systemic exposure to drug (AUC/infinity) increased non-linearly with dose. Following oral administration to man, absorption was rapid with a mean value for Tmax of 1 h, and Cmax's ranging non-linearly from 90 to 2100 ng/ml following dosing at 12.5 to 150 mg respectively. 5. The elimination of modipafant is characterized by short half-life (mean values for t1/2 range from 1 to 3 h). However, the nature of the receptor kinetics of modipafant (slow offset) means that the drug shows a long duration of action in spite of short pharmacokinetics at pharmacologically relevant doses. 6. Following oral and intravenous administration of 14C-modipafant to rat and dog, the majority of radioactivity (mean 92%) is recovered in the faeces. The excretion of modipafant in rat and dog is characterized by metabolism, mostly to pyridine metabolites, accounting for between 38 and 75% of total clearance, the rest being cleared as unchanged drug.

Following major orthopaedic surgery, guidelines usually recommend continued thromboprophylaxis after hospitalisation. The availability of an effective oral anticoagulant with an acceptable safety profile that does not require routine clinical monitoring may lead clinicians to switch patients from subcutaneous to an oral therapy either during hospitalisation or at discharge. The purpose of this study was to assess the effect of enoxaparin on the pharmacokinetics, pharmacodynamics and safety of apixaban, an oral, direct inhibitor of coagulation factor Xa. In this four-period, crossover study, 20 healthy subjects were randomised to receive single doses of apixaban 5 mg orally; enoxaparin 40 mg subcutaneously; apixaban 5 mg and enoxaparin 40 mg concomitantly; and apixaban 5 mg followed 6 hours (h) after by enoxaparin 40 mg. Pharmacokinetics of apixaban were not affected by enoxaparin. Average peak pharmacodynamic effect, measured by anti-Xa activity, was 1.36 U/ml after administration of apixaban and was 0.42 U/ml after enoxaparin. Following co-administration of apixaban and enoxaparin, peak anti-Xa activity was 42% higher than for apixaban alone. Following administration of enoxaparin 6 h after apixaban, peak anti-Xa activity was 15% higher than for apixaban alone. In conclusion, enoxaparin had no effect on the pharmacokinetics of apixaban. The increase in anti-Xa activity after co-administration was modest and appeared to be additive. Peak anti-Xa activity increases are mitigated by separating administration of subcutaneous anticoagulation and apixaban when switching between therapies; the potential for pharmacodynamic interaction may be further mitigated by transitioning at the next scheduled dose (12 h).