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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., (© 2018, The American College of Clinical Pharmacology.)

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects., (© 2017, The American College of Clinical Pharmacology.)

Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5 mg (≥50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials., (© 2017, The American College of Clinical Pharmacology.)

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., (© 2014, The American College of Clinical Pharmacology.)

The underlying pathology of diabetic wounds, i.e. impairment of macro- and microcirculation, might also impact target site penetration of antibacterial drugs. To compare tissue concentrations of linezolid in infected and not infected tissue 10 patients suffering from type 2 diabetes with foot infection were included in the study. Tissue penetration of linezolid was assessed using in vivo microdialysis at the site of infection as well as in non-inflamed subcutaneous adipose tissue. All patients were investigated after receiving a single dose of linezolid and five patients in addition at steady state. After a single dose of linezolid significantly higher area under the concentration vs. time curve over 8 hours (AUC0-8 ) and maximum concentrations (Cmax )-values were observed in plasma (65.5 ± 21.2 mg*h/L and 16.4 ± 4.6 mg/L) as compared to inflamed (36.3 ± 22.9  mg*h/L and 6.6 ± 3.6 mg/L) and non-inflamed tissue (33.0 ± 17.7 mg*h/L and 6.7 ± 3.6 mg/L). Multiple administrations of linezolid led to disappearance of significant differences in Cmax and AUC0-8 between plasma, inflamed, and non-inflamed tissue. Approximately 2-fold increase of Cmax and AUC0-8 -values in tissue was observed at steady state as compared to the first administration. Penetration of linezolid is not impaired in diabetic foot infection but equilibrium between plasma and tissue might be delayed., (© 2014, The American College of Clinical Pharmacology.)

Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of anacetrapib (100 mg and 800 mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24 h following administration of single doses of anacetrapib 100 or 800 mg, moxifloxacin 400 mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between anacetrapib 800 mg and placebo in QTcF interval change from baseline were entirely <10 msec at every post-dose time point (1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 h). The upper bounds of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for anacetrapib 100 and 800 mg were <5 msec at every time point. In conclusion, single doses of anacetrapib 100 and 800 mg do not prolong the QTcF interval to a clinically meaningful degree relative to placebo and are generally well tolerated in healthy subjects., (© 2014, The American College of Clinical Pharmacology.)

Linezolid has antibacterial activity against aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high-performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) (ALT < 100 IU/L), Vd (L) = 1.310 × TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics., (© The Author(s) 2013.)

In vitro metabolism experiments have suggested a possible role for endogenous reactive oxygen species (ROS) in the in vivo clearance of linezolid, a synthetic antibiotic of the oxazolidinone class. This observation has resulted in the hypothesis that dietary antioxidant supplements might disturb the balance of ROS in vivo and thereby lower the clearance of linezolid. The purpose of this open-label, two-group parallel design study was to investigate whether continuous intake of widely used vitamin C or vitamin E will affect the pharmacokinetics of linezolid. A total of 28 healthy volunteers (27 male and 1 female), including 22 of Chinese origin, were administered a single oral dose of 600 mg linezolid on days 1 and 8. Half of the subjects received daily oral doses of 1000 mg vitamin C on days 2 through 9, whereas the other half were administered daily oral doses of 800 IU vitamin E during the same time period. Serial blood samples for assessment of the pharmacokinetic parameters of linezolid and its two inactive metabolites were collected on days 1 and 8, whereas vitamin concentrations were measured prior to and after the vitamin intake on these days. Urine was collected on days 1 and 8 to assess the fraction of dose excreted as linezolid and its major metabolites. All linezolid samples were analyzed according to validated HPLC/MS/MS methods. Linezolid was well tolerated in both groups with no reported clinically significant adverse events. No significant changes were found between the day 1 and day 8 AUC0- infinity and Cmax values of linezolid in either the vitamin C treatment group (p = 0.55 and p = 0.64, respectively) or the vitamin E treatment group (p = 0.06 and p = 0.49, respectively). Assessment of other pharmacokinetic parameters did not imply any change across the study groups. In conclusion, linezolid pharmacokinetics are not affected by concomitant administration with vitamins C and E. Therefore, no dose adjustment is necessary in patients taking vitamin C or vitamin E. These no-effect drug interaction data are in accord with current literature indicating that antioxidant vitamins have only subtle effects on overall ROS balance in vivo.

Linezolid is a novel oxazolidinone antibiotic with mild reversible monoamine oxidase inhibitor (MAOI) activity. The potential for interaction with over-the-counter (OTC) medications requires quantification. The authors present data evaluating the pharmacokinetic and pharmacodynamic responses to coadministration of oral linezolid with sympathomimetics (pseudoephedrine and phenylpropanolamine) and a serotonin reuptake inhibitor (dextromethorphan). Following coadministration with linezolid, minimal but statistically significant increases were observed in pseudoephedrine and phenylpropanolamine plasma concentrations; a minimal but statistically significant decrease was observed in dextrorphan (the primary metabolite of dextromethorphan) plasma concentrations. Increased blood pressure (BP) was observed following the coadministration of linezolid with either pseudoephedrine or phenylpropanolamine; no significant effects were observed with dextromethorphan. None of these coadministered drugs had a significant effect on linezolid pharmacokinetics. Minimal numbers of adverse events were reported. Potentiation of sympathomimetic activity by linezolid was judged not to be clinically significant, but patients sensitive to the effects of increased BP due to predisposing factors should be treated cautiously. No restrictions are indicated for the coadministration of dextromethorphan and linezolid.