Journal of clinical pharmacology最新文献

Haloperidol is an antipsychotic with well-known antiemetic potential. It is underutilized for postoperative nausea vomiting due to reported corrected QT interval (QTc) prolongation. This meta-analysis evaluates its safety and efficacy as an antiemetic in the perioperative period. Trials comparing haloperidol to 5-HT₃ -receptor antagonists (5-HT₃ -RA) for 24 postoperative vomiting incidences published up to May 2017 were searched in the medical database. Comparisons were made for antiemetic efficiency variables (vomiting incidence, rescue antiemetic need, and patients with complete response) during early (until 6 hours) and late postoperative phases. Eight randomized controlled double-blinded trials were included in the final analysis. Twenty-four-hour vomiting incidence was similar in groups (fixed effects, P = 0.52, I² = 0%). Trial-sequential analysis confirmed noninferiority of haloperidol over 5-HT₃ -RAs (α = 5%, β = 20%, δ = 10%), with "information size" being 859 (required > 812). Pooled results did not demonstrate superiority/inferiority of 5-HT₃ -RAs over haloperidol in all other antiemetic efficacy variables (early and delayed). Negligible heterogeneity was found in all the comparisons made. Pooled Mantel Haenszel odds ratio for QTc prolongation was equivalent in both groups (fixed effects, P = 0.23, I² = 0%). The mean dose of haloperidol used was 1.34 mg, and no trial reported extrapyramidal side effects. Trial-sequential analysis showed statistical equivalence (α = 5%, β = 20%, δ = 10%), with information size being 745 (required > 591). Publication bias was unlikely (Egger test, X-intercept = 2.07, P = 0.10). We conclude that haloperidol is equivalent to the well-established 5-HT₃ -RAs in preventing vomiting during the first day after surgery. The incidence of QTc prolongation with haloperidol is statistically equivalent to 5-HT₃ -RAs and thus should not be the factor that discourages its use for treatment/prophylaxis of postoperative nausea vomiting.

Istradefylline, a selective adenosine A_2A inhibitor, is under development for the treatment of Parkinson's disease. The effect of oral steady-state rifampin 600 mg/day, a potent cytochrome P450 (CYP) 3A4 inducer, on the disposition of a single oral dose of istradefylline 40 mg was determined in a crossover study in 20 healthy subjects by measuring plasma concentrations of istradefylline and its M1 and M8 metabolites and their derived pharmacokinetic parameters. Based on the geometric mean ratio of log-transformed data, rifampin reduced istradefylline exposure: C_max , 0.55 (90%CI, 0.49-0.62); AUC_last , 0.21 (90%CI, 0.19-0.22); and AUC_inf , 0.19 (90%CI, 0.18-0.20), indicating nonequivalence. These changes were primarily because of the effect of rifampin on the elimination parameters of istradefylline; mean CL/F was increased from 4.0 to 20.6 L/h, and mean t_1/2 was reduced from 94.8 to 31.5 hours. The effect of rifampin coadministration on the disposition of the istradefylline M1 and M8 metabolites was inconsistent and variable. Furthermore, as exposure of the istradefylline M1 and M8 metabolites in plasma was generally <9% of total drug exposure, it would be expected to have a negligible impact on the pharmacodynamic effect of istradefylline. Caution should be exercised when istradefylline is administered concurrently with strong CYP3A4 inducers and dose adjustment considered.

Modafinil therapy, a nonamphetamine cognition-enhancing agent, holds the potential to improve recovery from cognitive impairment after intensive care unit (ICU) admission. To date, however, there is a paucity of data on modafinil use in the ICU setting. The purpose of this study was to explore the role of modafinil for improvement in cognition in ICU patients. This retrospective cohort study evaluated a total of 60 ICU patients with any ventilatory support who started on modafinil during their ICU stay from January 1, 2010, to March 19, 2016. The requirements of opioids and sedatives, as well as the lowest and average scores of the Glasgow Coma Scale (GCS) and Riker Sedation-Agitation Scale (SAS), were recorded during 48 hours before and after the start of modafinil therapy in 6-hour periods. The average daily modafinil dose of 170 mg was given for a median duration of 9 days. Modafinil administration was associated with a small, nonsignificant increase in GCS by 0.34 points after controlling for age, baseline severity of illness, and changes in sedation and analgesia over time (95%CI, -0.34 to 0.73 points; P = .0743). No major modafinil-associated adverse effects were observed. Modafinil administration did not significantly improve cognitive function in ICU patients within 48 hours of initiation. However, because of lack of robust evidence, the impact of modafinil on overall patient outcomes in the ICU remains unclear and needs further investigation.

Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using ¹ H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

Veliparib (ABT-888) is a novel oral poly-ADP-ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib have been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics (PK) of chronically dosed single-agent veliparib in patients with either BRCA 1/2-mutated cancer or PARP-sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly-ADP-ribose (PAR) level observed in peripheral blood mononuclear cells (PBMCs). Seventy-one subjects contributed with veliparib plasma concentrations, M8 plasma concentrations, and PAR levels in PBMCs. Veliparib and M8 concentrations were modeled simultaneously using a population PK approach. A 2-compartment model with delayed first-order absorption and the elimination parameterized as renal (CL_R /F) and nonrenal clearance (CL_NR /F) adequately described veliparib pharmacokinetics. The pharmacokinetics of the M8 metabolite was described with a 2-compartment model. Creatinine clearance(CL_CR ) and lean body mass (LBM) were identified as significant predictors of veliparib CL_R /F and central volume of distribution, respectively. For a typical subject (LBM, 48 kg; CL_CR , 95 mL/min), total clearance (CL_R /F + CL_NR /F), and central and peripheral volume of distribution for veliparib were estimated as 17.3 L/h, 98.7 L, and 48.3 L, respectively. At least 50% inhibition of PAR levels in PBMCs was observed at dose levels ranging from 50 to 500 mg.

Several studies have reported constipation, abdominal pain, or diarrhea as common adverse events for statins. Statins are among the most commonly prescribed medications, and the impact on the prevalence of these conditions was rarely studied as main outcomes. The aim of this study is to determine if statin therapy is associated with constipation, abdominal pain, diarrhea, or colitis. This was a retrospective cohort study using a regional military health care data from October 1, 2003, to March 1, 2012. A propensity score-matched cohort of statin users and nonusers was created based on 82 variables. The primary analysis evaluated the odds ratios of the following diagnoses: constipation, ≥3 encounters for constipation; abdominal pain, ≥3 encounters for abdominal pain; diarrhea, ≥3 encounters for diarrhea; colitis, ≥3 encounters for colitis; and endoscopy of the lower gastrointestinal tract, ≥3 endoscopies of the lower gastrointestinal tract. After propensity score matching of 6342 statin users and 6342 nonusers, there was no statistically significant difference in constipation (OR, 0.96; 95%CI, 0.87-1.05; P = .33), abdominal pain (OR, 0.95; 95%CI, 0.88-1.02; P = .15), or colitis (OR, 1.02; 95%CI, 0.91-1.14; P = .73). However, there was an association between statin therapy and endoscopy of the lower gastrointestinal tract (OR, 1.14; 95%CI, 1.04-1.26; P = .002) and decreased odds of diarrhea (OR, 0.88; 95%CI, 0.80-0.97; P = .01). In this retrospective cohort study, an association between statin therapy and increased likelihood of being diagnosed with lower gastrointestinal conditions could not be demonstrated, contrary to some statins package inserts.

Biologicals are a rapidly expanding class of medications used in the treatment of many different conditions. This article reviews the common characteristics of this class and the requirements for safe and effective use in patients. Several vignettes are included to illustrate common challenges.

Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (C_trough ) of macitentan and its active metabolite,  ACT-132577,  were obtained at steady state in 242 patients, indicating that mean C_trough of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577,  a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN.  A cross-study comparison showed that although C_trough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (C_max ) or area under the plasma concentration-time curve over a dosing interval (AUC_τ ). Geometric mean ratios for C_max and AUC_τ were 1.08 and 1.22, respectively, for macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.

Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semimechanistic manner. A total of 21 healthy subjects enrolled in an open-label phase 1 pilot study and provided continuous electrocardiogram monitoring and plasma glucose and insulin concentrations associated with a 24-hour baseline assessment. The data revealed a transient decrease in QTc, with peak suppression occurring approximately 3 hours after the meal. A semimechanistic modeling approach was applied to evaluate temporal delays between meals and subsequent changes that might influence QT measurements. The food effect was incorporated into a model of heart rate dynamics, and additional delayed effects of the meal on QT were incorporated using a glucose-dependent hypothetical transit compartment. The final model helps to provide a foundation for the future design and analysis of QT studies that may be confounded by meals. This study has significant implications for QT study assessment following a meal or when a cohort is receiving a medication that influences postprandial glucose concentrations.

Peginterferon beta-1a reduced annualized relapse rate as compared with placebo and was approved to treat multiple sclerosis patients. A population pharmacokinetic and an exposure-efficacy model were developed to establish the quantitative relationship between pharmacokinetics and annualized relapse rate. The pharmacokinetics was well described by a 1-compartment model with first-order absorption and linear elimination kinetics. Body mass index was the most significant covariate that impacted both clearance and volume of distribution, which in turn impacted area under the curve and maximum serum concentration. Cumulative monthly area under the curve and annualized relapse rate were best described by a Poisson-gamma (negative binomial) model, demonstrating that the improved efficacy of every-2-weeks dosing was driven by greater drug exposure. The results supported the superior efficacy of the every-2-week dosing regimen compared with the every-4-weeks dosing regimen.