Journal of clinical pharmacology最新文献

At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty-eight patients were enrolled across the 3 drug-drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least-squares mean area under the plasma concentration-time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91-1.31) and was 1.11 (0.86-1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least-squares mean ratio of 0.26 [90%CI 0.18-0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least-squares mean ratio of 0.46 [90%CI 0.29-0.73]) in the presence of rifampin. The clinical drug-drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P-glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib.

We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (C_ss ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models. Blinatumomab mean ± SD C_ss was 621 ± 502 pg/mL (28 μg/day dose). Cytokines were transiently elevated in >50% of patients; B-cell levels decreased in most patients. Lower B-cell and bone marrow (BM) blast percentages and higher T-cell percentages were associated with higher CR/CRh (P < .001) in univariate analysis. Higher C_ss (OR, 1.90; 95%CI, 1.12-3.21), higher peak IL-10 level (1.59; 1.13-2.22), and lower BM blast percentage (0.78; 0.69-0.89) were associated with higher CR/CRh in multivariate analysis. Higher C_ss (HR, 1.40; 1.01-1.94) and lower B-cell level (0.90; 0.84-0.97) were associated with shorter time to NEs. Cytokine peaks were not associated with NEs or CRS. In conclusion, blinatumomab led to T cell-mediated depletion of target B cells in blood and blasts in the bone marrow. Immune system effectiveness was important for treatment responses.

Myocardial injury following elective percutaneous coronary intervention (PCI) occurs in about one-third of patients and is associated with mortality. Platelet aggregation, thrombosis formation, and inflammation are the main causes of cardiac injury during PCI. Vitamin D plays a key role in the cardiovascular system by exerting antiplatelet, anticoagulant, and anti-inflammatory properties. There is no published study that investigated the effect of vitamin D in the prevention of cardiac injury following elective PCI. In a randomized clinical trial, 99 patients admitted for elective PCI were randomized into vitamin D (n = 52) and control (n = 47) groups. The intervention group received 300 000 IU vitamin D orally 12 hours before PCI. The cardiac biomarkers were checked at baseline, 8 and 24 hours after PCI. hs-CRP was also measured at baseline and after 24 hours. The increase in CK-MB was documented in 20 patients (42%) in the control group and 18 patients (34.6%) in the intervention group (P = .417). Furthermore, the increase in cTnI occurred in 4 patients (8%) and 2 patients (3.3%) in the control and intervention groups, respectively (P = .419). No significant changes were noted in the level of cardiac biomarkers. In the vitamin D group, the mean difference in CK-MB between 8 and 24 hours was significantly lower (P = .048). The mean difference in hs-CRP was significantly lower in the vitamin D group (P = .045). This study could not show a clear effect of vitamin D in the prevention of cardiac injury during elective PCI. Further outcome-based studies are needed to describe the role of vitamin D in the prevention of periprocedural myocardial injury.

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.

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.

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.

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.

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.

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.