Pharmacokinetics of Tedizolid and Pseudoephedrine Administered Alone or in Combination in Healthy Volunteers.

Therapeutic doses of tedizolid phosphate, an oxazolidinone antibiotic, lack monoamine oxidase inhibition in vivo, potentially resulting in an improved safety profile versus other oxazolidinones. This randomized, double-blind, placebo-controlled, 2-period, 2-sequence, crossover, phase 1 study (NCT01577459) assessed the potential for pharmacokinetic (PK) interactions between tedizolid and pseudoephedrine. Eighteen healthy volunteers (age: 18⁻45 years) were block-randomized to 1 of 2 treatment sequences containing 2 treatment periods (tedizolid phosphate or placebo once daily for 4 days; single dose of pseudoephedrine 60 mg on day 5) separated by a 2-day washout. Median time to maximum plasma concentration for tedizolid and pseudoephedrine ranged from 3 to 4 h, regardless of treatment coadministration. Steady-state tedizolid had no effect on the PK of pseudoephedrine; geometric mean ratio and 90% confidence interval remained within the no-effect 0.8 to 1.25 boundaries. The maximum observed concentration of tedizolid decreased by approximately 14% when pseudoephedrine was coadministered; no changes in the area under the plasma concentration-time curve or the minimum observed plasma concentration occurred. All adverse events (AEs) were mild, and there were no serious AEs or study drug discontinuations. No meaningful PK interactions occurred between tedizolid and pseudoephedrine, and tedizolid was well tolerated when administered in conjunction with pseudoephedrine.

Pharmacokinetics, Safety, and Tolerability of Tedizolid Phosphate in Elderly Subjects.

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We evaluated the pharmacokinetics of tedizolid in elderly subjects to guide dosing recommendations. In an open-label phase 1 study (ClinicalTrials.gov identifier NCT01496677), 14 elderly (≥65 years) and 14 younger control (18-45 years) subjects each received a single oral dose of tedizolid phosphate 200 mg. Blood samples were collected before dose and more than 72 hours after dose. The pharmacokinetic parameters of tedizolid after a single dose were similar in both age groups. Geometric mean ratios (elderly/younger controls) and corresponding 90% confidence intervals were maximum observed plasma concentration (Cmax ), 1.091 (0.917-1.297); AUC from time 0 extrapolated to infinity (AUC0-∞ ), 1.132 (0.954-1.343). Tedizolid plasma exposure was similar in elderly and younger control subjects. The findings indicated that after intravenous or oral administration of tedizolid phosphate 200 mg once daily, no dose adjustment was warranted in elderly subjects to achieve therapeutic levels.

Characterization of the haematological profile of 21 days of tedizolid in healthy subjects.

OBJECTIVES: Tedizolid is a novel oxazolidinone antibacterial. Oxazolidinones carry concerns for time-dependent myelosuppression. To further explore tedizolid's haematological tolerability, we analysed data from a 21 day study comparing safety and pharmacokinetics of tedizolid and linezolid. METHODS: This was a Phase 1 study in healthy volunteers comparing five treatments (each n = 8) over 21 days: tedizolid at 200, 300 or 400 mg once daily; linezolid at 600 mg twice daily; and placebo. Routine laboratory haematological parameters (platelet, absolute neutrophil, white blood cell, red blood cell and reticulocyte counts) were compared between groups. Adverse haematological outcomes were pre-specified as any parameter below the standard lower limits of normal (LLN), substantially abnormal (<50% LLN for neutrophils; <75% LLN for other parameters) or ≥50% below baseline (platelets only). ClinicalTrials.gov identifier: NCT00671814. RESULTS: During the 21 day study period, pre-specified adverse platelet outcomes were observed in the linezolid (n = 2), tedizolid 300 mg (n = 1) and tedizolid 400 mg (n = 3) groups. Mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with higher doses being similar to linezolid. The magnitude of platelet count decreases from baseline was influenced by unbound drug trough plasma concentrations, which were generally higher in subjects with at least a 20% decrease in platelet count. Substantially abnormal haematological parameters were only observed with linezolid and tedizolid 400 mg. One linezolid and two tedizolid 400 mg subjects discontinued due to meeting criteria for pre-specified adverse haematological outcomes. CONCLUSIONS: Although limited to small groups of healthy volunteers, these exploratory results support clinical study of extended treatment durations with tedizolid at 200 mg once daily.

Platelet profile in patients with acute bacterial skin and skin structure infections receiving tedizolid or linezolid: findings from the Phase 3 ESTABLISH clinical trials.

Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). The intent of this study was to characterize the platelet profiles of patients receiving tedizolid relative to linezolid over the course of treatment using pooled data from these two trials. The occurrences of clinically defined and statistical analysis plan-specified reduced platelet counts were assessed at the study days 7 to 9 visit, the study days 11 to 13 visit, and the posttherapy evaluation (PTE) visit. At the study days 7 to 9 visit, incidences of reduced platelet counts were low and largely similar between the groups. The only notable difference was a lower incidence of thrombocytopenia (platelet counts, <150,000 cells/mm(3)) among patients who received tedizolid (3.2%) relative to those who received linezolid (5.6%). At the study days 11 to 13 visit, patients who received tedizolid had lower incidences of platelet counts of <150,000 cells/mm(3) (-5.9%), <112,500 cells/mm(3) (-2.4%), and <100,000 cells/mm(3) (-1.9%) than patients in the linezolid group. Similar differences were noted at the PTE visit. Findings across the two phase 3 ABSSSI trials suggest that 6 days of 200 mg tedizolid daily confers a low potential for reduced platelet counts among patients with ABSSSIs. (The ESTABLISH-1 and ESTABLISH-2 trials have been registered at ClinicalTrials.gov under registration numbers NCT01170221 and NCT01421511, respectively.).

Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.

OBJECTIVES: Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. DESIGN: Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. SETTING: Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. PARTICIPANTS: Ninety healthy volunteers. INTERVENTION: Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. MEASUREMENTS AND MAIN RESULTS: A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 µg/ml) and the area under the concentration-time curve (17.4-58.7 µg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. CONCLUSION: These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes.

Pharmacokinetics of tedizolid following oral administration: single and multiple dose, effect of food, and comparison of two solid forms of the prodrug.

OBJECTIVES: The single- and multiple-dose pharmacokinetics (PK) of tedizolid were examined after oral administration of tedizolid phosphate disodium (TPD), including the effect of food on PK. The relative bioavailability of TPD to the free acid tedizolid phosphate was determined to bridge the results of these and other studies to the solid form of the prodrug selected for further development. DESIGN: Randomized placebo-controlled, double-blind single- and multiple-ascending dose studies and randomized open-label, crossover food effect and relative bioavailability studies. SETTING: Clinical Research Units. PARTICIPANTS: Healthy subjects. INTERVENTION: Study TR701-101 enrolled 40 subjects in single-ascending dose (200-1200 mg TPD or placebo) and 40 subjects in 21-day multiple-ascending dose (200, 300, or 400 mg TPD once/day; 600 mg linezolid twice/day; or placebo) arms. Study TR701-103 was a food-effect study in 12 subjects administered 600 mg TPD. Study TR701-108 was a relative bioavailability study in 12 subjects administered 150-mg tedizolid equivalents as TPD or tedizolid phosphate. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of the prodrug tedizolid phosphate, its active moiety tedizolid, and/or linezolid were collected. After administration of 200 to 600 mg TPD, tedizolid values increased approximately dose proportionally in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ). Tedizolid half-life values were approximately 2-fold greater compared with linezolid. TPD administration with food delayed tedizolid absorption and reduced Cmax relative to the fasted state but did not alter AUC. Minimal accumulation was predicted and observed for tedizolid, whereas observed accumulation of linezolid exceeded predictions based on single-dose PK. Comparable PK of tedizolid was observed following oral administration of either TPD or tedizolid phosphate. In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8 linezolid subjects (low reticulocyte count). CONCLUSIONS: Overall, tedizolid has a favorable PK profile, a half-life that supports once daily administration, and no nonlinearities at steady state. Tedizolid phosphate can be administered without regard to food.

A neuropsychological test battery for use in Alzheimer disease clinical trials.

OBJECTIVE: To report the psychometric properties of an alternative instrument to the cognitive subscale of the Alzheimer's Disease Assessment Scale, a neuropsychological test battery (NTB) for measuring drug efficacy in Alzheimer disease clinical trials. DESIGN: The NTB was evaluated in a randomized, double-blind, placebo-controlled trial of AN1792(QS-21) (synthetic beta-amyloid plus an adjuvant) (300 patients) and isotonic sodium chloride solution (72 patients). The test-retest reliability of the NTB was examined, and the NTB was correlated with other cognitive (cognitive subscale of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination) and functional (Disability Assessment Scale for Dementia and Clinical Dementia Rating Sum of Boxes) measures. In addition, a factor analysis was performed on NTB components. Finally, the sensitivity of the NTB to change was assessed as a function of Mini-Mental State Examination performance. RESULTS: The NTB had high test-retest reliability at 6 (Pearson product moment correlation [r] = 0.92) and 12 (r = 0.88) months. Internal consistency was high (Cronbach alpha = 0.84). The correlations between the NTB z score and scores on traditional measures of cognition and function were significantly different from 0 (P < .001). A factor analysis yielded "memory" and "executive function" factors. The NTB z score declined linearly over 1 year in patients receiving placebo and, in contrast to the Alzheimer's Disease Assessment Scale cognitive subscale, demonstrated similar declines in patients with high (21-26) and low (15-20) Mini-Mental State Examination scores at baseline. CONCLUSIONS: The NTB exhibits excellent psychometric properties and seems to be a reliable and sensitive measure of cognitive change in patients with mild to moderate Alzheimer disease. The psychometric properties of the NTB suggest that it may have particular utility in evaluating drug efficacy in clinical trials in which patients with mild Alzheimer disease are included.

An exact maternal-fetal genotype incompatibility (MFG) test.

The maternal-fetal genotype incompatibility (MFG) test can be used for a variety of genetic applications concerning disease risk in offspring including testing for the presence of alleles that act directly through offspring genotypes (child allelic effects), alleles that act through maternal genotypes (maternal allelic effects), or maternal-fetal genotype incompatibilities. The log-linear version of the MFG model divides the genotype data into many cells, where each cell represents one of the possible mother, father, and child genotype combinations. Currently, tests of hypotheses about different allelic effects are accomplished by an asymptotic MFG test, but it is unknown if this is appropriate under conditions that produce small cell counts. In this report, we develop an exact MFG test that is based on the permutation distribution of cell counts. We determine by simulation the type I error and power of both the exact MFG test and the asymptotic MFG test for four different biologically relevant scenarios: a test of child allelic effects in the presence of maternal allelic effects, a test of maternal allelic effects in the presence of child allelic effects, and tests of maternal-fetal genotype incompatibility with and without child allelic effects. These simulations show that, in general, the exact test is slightly conservative whereas the asymptotic test is slightly anti-conservative. However, the asymptotic MFG test produces significantly inflated type I error rates under conditions with extreme null allele frequencies and sample sizes of 75, 100, and 150. Under these conditions, the exact test is clearly preferred over the asymptotic test. Under all other conditions that we tested, the user can safely choose either the exact test or the asymptotic test.

A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11.

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is a common, highly heritable neurobehavioral disorder of childhood onset, characterized by hyperactivity, impulsivity, and/or inattention. As part of an ongoing study of the genetic etiology of ADHD, we have performed a genomewide linkage scan in 204 nuclear families comprising 853 individuals and 270 affected sibling pairs (ASPs). Previously, we reported genomewide linkage analysis of a "first wave" of these families composed of 126 ASPs. A follow-up investigation of one region on 16p yielded significant linkage in an extended sample. The current study extends the original sample of 126 ASPs to 270 ASPs and provides linkage analyses of the entire sample, using polymorphic microsatellite markers that define an approximately 10-cM map across the genome. Maximum LOD score (MLS) analysis identified suggestive linkage for 17p11 (MLS=2.98) and four nominal regions with MLS values >1.0, including 5p13, 6q14, 11q25, and 20q13. These data, taken together with the fine mapping on 16p13, suggest two regions as highly likely to harbor risk genes for ADHD: 16p13 and 17p11. Interestingly, both regions, as well as 5p13, have been highlighted in genomewide scans for autism.

Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism.

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism.