Archives of Drug Information最新文献

Objective. This study was designed to investigate the pharmacokinetic effects of coadministration of saquinavir/ritonavir with efavirenz at steady state.

Methods. Healthy volunteers in this open-label, two-arm, one-sequence, two-period crossover study (planned enrollment of 40 participants) were randomized to one of two treatment arms: those in Arm 1 were scheduled to receive saquinavir/ritonavir 1,000/100 mg orally twice daily for 29 days and efavirenz 600 mg orally once daily starting on day 15 and continuing through day 29; participants randomized to Arm 2 were to receive efavirenz once daily for 29 days and saquinavir/ritonavir 1,000/100 mg twice daily starting on day 15 through day 29. Assessments included vital signs, laboratory analyses, electrocardiography, and blood levels of total saquinavir, ritonavir, and efavirenz. Pharmacokinetic parameters included C_max (maximum observed plasma concentration), t_max (time to reach the maximum observed plasma concentration), (apparent elimination half-life), and AUC_0-τ (area-under-the-plasma-concentration-time curve over one dosing interval).

Results. Eight participants (four in each arm) were enrolled; only two (one from each treatment arm) reached day 15 of the study and received the concurrent initial doses of saquinavir/ritonavir and efavirenz. The study was terminated prematurely after these two participants experienced nonserious adverse events. The participant in Arm 1 experienced mild abdominal discomfort, diarrhea, sleep disorder, and headache and the participant in Arm 2 experienced moderate-intensity abdominal pain and mild vomiting with leukocytosis accompanied by elevated pancreatic and hepatic enzymes (aspartate aminotransferase and alanine aminotransferase values of 2-fold and 3.5-fold the upper limit of normal, respectively). Both participants recovered completely following treatment discontinuation. Only limited pharmacokinetic data were generated on these two participants.

Conclusions. The early termination of this study precluded drawing any definitive conclusions regarding the pharmacokinetics at steady state of coadministered saquinavir/ritonavir and efavirenz.

Purpose. Statistical models for predicting hematologic toxicity were evaluated based on UGT1A1 polymorphisms and baseline serum bilirubin.

Methods. Blood DNA samples were collected from 113 patients with untreated metastatic colorectal cancer receiving irinotecan (FOLFIRI, n = 36; mIFL, n = 41; CapeIRI, n = 36). The primary endpoint was absolute neutrophil count nadir during first treatment cycle. Linear regression models, with increased R² implying important additional predictive power, sequentially added age, sex, baseline bilirubin level, and UGT1A1 genotype.

Results. All models demonstrated low R², suggesting unaccounted variables. UGT1A1 genotype added ∼8–9% during cycle 1 and from ∼7% [mIFL regimen] to 26% [CapeIRI regimen] after cycle 1. Correlation between genotype and overall ANC nadir without regard to treatment was low (R = −0.201, P = 0.035). Patients with genotype 7/7 may have increased risk for severe neutropenia, but data are insufficient to characterize this. Contribution of baseline bilirubin level was negligible.

Conclusions. Ability of UGT1A1 or baseline bilirubin to predict neutropenia is low and depends on regimen.

Introduction. Recombinant granulocyte colony-stimulating factor (G-CSF) may aid engraftment post high-dose chemo-/radiotherapy in patients with haematological malignancies undergoing allogeneic bone marrow transplantation (BMT); however, the effects of G-CSF on graft-versus-host disease (GvHD), relapse, and survival are not well defined.

Methods. In this double-blind, randomized, placebo-controlled, multicentre, phase 3 study, the effects of the G-CSF Filgrastim on neutrophil and platelet recovery, and on clinical outcomes were evaluated. Patients (12–55 years) receiving an allogeneic BMT for a haematological malignancy were randomized to receive Filgrastim 5 µg/kg or placebo. Study treatment was continued until patients achieved an absolute neutrophil count (ANC) ≥0.5 × 10⁹/L, or until day 42.

Results. Fifty-one patients (Filgrastim, N = 25; placebo, N = 26) were evaluable. Patients treated with Filgrastim had significantly faster engraftment with ANC ≥0.5 × 10⁹/L being achieved after a median (range) of 15.0 (1.0–22.0) days vs. 19.0 (15.0–28.0) days for placebo (P < 0.0001). The incidence of GvHD was comparable for both groups. During the limited follow-up (2 years), Filgrastim had no adverse effect on mortality and possibly reduced the rate of relapse.

Background and Aims. Tegaserod is a selective serotonin receptor (5-HT₄) agonist that relieves dysmotility symptoms associated with constipation. Here we explore its effects on functional dyspepsia symptoms and heartburn during continued proton pump inhibitor (PPI) treatment.

Methods. In this multicenter pilot study, following a 2-week screening/baseline period, women with functional dyspepsia and persisting heartburn treated with PPIs received add-on open-label tegaserod 6 mg twice daily (bid) for 4 weeks. Treatment responders were then randomized 1:1 to continue double-blind tegaserod or placebo therapy for 6 weeks. Efficacy variables included the proportion of days with satisfactory relief of dyspepsia symptoms (early satiety, postprandial fullness and bloating) as well as the change in individual symptom severity scores for these three cardinal dyspepsia symptoms. Health-related quality of life was evaluated using a validated questionnaire, the Nepean Dyspepsia Index. Adverse events (AEs) were monitored.

Results. Of 101 women enrolled, 71 completed open-label treatment, and 70 responders were randomized to double-blind treatment. The proportion of days with satisfactory relief of dyspepsia symptoms (least squares mean, LSM) increased with tegaserod and placebo, to 0.69 and 0.62, respectively at study end (P = 0.366). Similarly, both groups showed improvements in the composite daily symptom severity score (overall LSM change from baseline of 1.55 and 1.57, P = 0.934), and the Nepean Dyspepsia Index (overall LSM change of −39.0 and −37.8, P = 0.537). Tegaserod was well tolerated. Diarrhea was the most common AE (8.1% tegaserod, 0% placebo). There were no serious AEs or deaths.

Conclusions. A significant treatment effect was not demonstrated in this study using a treatment-withdrawal methodology. In future studies of functional dyspepsia patients with heartburn, a more rigorous parallel-group study design should be considered.

Objectives. Patients with cancer who are treated with chemotherapy report adverse events during their treatment, which can affect their quality of life and increase the likelihood that their treatment will not be completed. In this study, patients’ perceptions of the physician-patient relationship and communication about cancer-related issues, particularly adverse events were examined.

Methods. We surveyed 508 patients with cancer concerning the occurrence of adverse events and their relationship and communication with their physicians regarding cancer, treatment, and adverse events.

Results. Most individuals surveyed (>90%) discussed diagnosis, treatment plan, goals, and schedule, and potential adverse events with their physicians before initiating chemotherapy; approximately 75% of these individuals understood these topics completely or very well. Physician-patient discussions of adverse events were common, with tiredness, nausea and vomiting, and loss of appetite discussed prior to chemotherapy in over 80% of communications. These events were also the most often experienced (ranging in 95% to 64% of the respondents) along with low white blood cell counts (WBCs), which were experienced in 67% of respondents. Approximately 75% of the individuals reported that their overall quality of life was affected by adverse events.

Conclusions. These findings suggest that discussions alone do not provide patients with sufficient understanding of the events, nor do they appear to adequately equip patients to cope with them. Therefore, efforts to improve cancer care should focus on developing tools to improve patients’ understanding of the toxicities of chemotherapy, as well as providing resources to reduce the effects of adverse events.

Objective. This study was conducted to assess the dose proportionality, safety, and tolerability of fentanyl buccal tablet (FBT) in Japanese volunteers.

Methods. Healthy, opioid-naive Japanese adults received single-dose FBT 100, 200, 400, and 800 µg in a randomized, open-label, crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Peak serum fentanyl concentration (C_max), time to C_max (t_max), area under the serum fentanyl concentration-time curve (AUC) from time 0 to infinity (AUC_0–∞), and AUC from 0 to the last quantifiable concentration (AUC_0–last) were summarized using descriptive statistics. Dose proportionality was claimed if the ln-ln plots of C_max, AUC_0–∞, and AUC_0–last vs. dose were linear and the 90% confidence intervals (CI) of the slopes were within 0.8927 and 1.1073. The safety population comprised volunteers who received ≥1 FBT.

Results. Twenty-five volunteers were enrolled, 23 were included in the safety population (mean age 35.3 years), and 19 completed the study. The assessment of dose proportionality did not meet the statistical criteria (slope [90% CI]: 0.9118 [0.8601, 0.9635] for C_max, 1.0756 [1.0377, 1.1136] for AUC_0–∞, and 1.0992 [1.0677, 1.1307] for AUC_0–last). However, the increase in systemic exposure with dose appeared linear, and a post hoc analysis of partial AUCs from time 0 to 8, 12, 18, and 24 hours supported dose proportionality. Median t_max of 90 minutes (range 30–180 minutes) was independent of dose. Adverse events (AEs) were mild or moderate. The most frequent AEs were nausea (N = 9), dizziness (N = 8), headache (N = 6), somnolence (N = 6), dyspepsia (N = 5), and vomiting (N = 3). No application-site or serious AEs were reported.

Conclusions. Systemic exposure to FBT was approximately dose proportional across the range 100 µg to 800 µg in healthy Japanese adults. Adverse events were mild or moderate.

Background. Controlled trials have demonstrated the efficacy of antihistamines in the treatment of chronic idiopathic urticaria. Second-generation antihistamines are recommended as first-line therapy for chronic idiopathic urticaria. The purpose of this study was to determine the effect of desloratadine, a newer, nonsedating, second-generation antihistamine, on symptoms of chronic idiopathic urticaria, disease severity, and quality of life (QoL).

Methods. In an open-label, observational, multicenter study, 348 subjects with chronic idiopathic urticaria were given 5 mg of desloratadine once daily for 2 weeks. Outcome measures included change from baseline at Day 14 using the Aerius Quality of Life Questionnaire (AEQLQ); change from baseline in pruritus score, number and maximum size of hives, sleep quality, and activity impairment; and subjects' response to therapy.

Results. Desloratadine significantly decreased subjects' overall condition and symptom scores from baseline to Day 14 (2.19 ± [SD] 0.66 and 1.14 ± 0.89, respectively; P < 0.0001). Desloratadine treatment significantly improved all 10 AEQLQ domain scores from baseline to Day 7 and Day 14 (P < 0.0001). Sleep disturbance scores decreased 40% from baseline to Day 7 (1.42 ± 1.03 to 0.85 ± 0.89, respectively), and interference with daily outdoor activity scores showed a 41% decrease from baseline to Day 7 (1.11 ± 0.98 to 0.66 ± 0.90) (P < 0.0001 for both). There were significant reductions in itching, size of hives, and hive score at both Days 7 and 14. Treatment resulted in moderate, marked, or complete relief of symptoms in 76.2% of subjects. Desloratadine was well tolerated, with no adverse events reported.

Conclusion. In an open-label, observational study, desloratadine 5 mg once daily significantly decreased symptoms of chronic idiopathic urticaria and improved subject QoL.

Background. Fentanyl buccal tablet (FBT; FENTORA^®, Cephalon, Inc., Frazer, PA, USA) is indicated in the US for breakthrough pain in patients with cancer who are already receiving and are tolerant to around-the-clock opioid therapy for underlying persistent cancer pain. For each individual patient, FBT should be titrated to the effective dose.

Objective. The primary objective was to characterize the pharmacokinetic parameters of FBT 400 µg administered as a single 400 µg tablet (regimen A) or as two 200 µg tablets given simultaneously (regimen B) and determine whether these are bioequivalent in healthy Japanese volunteers. Regimen C (two 200 µg tablets 30 minutes apart) was also compared as a secondary objective.

Methods. Healthy Japanese adults received regimens A, B, and C in a crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Serum fentanyl concentrations were determined in venous blood collected through 36 hours post dose. Regimens were declared bioequivalent with respect to bioavailability (as reflected by AUC_0–∞, AUC_0–last, and C_max) if the 90% confidence interval (CI) of the regimens' ratio fell within 0.80–1.25 (80%–125%).

Results. Twenty-nine volunteers (13 men, 16 women) were enrolled; 24 completed the study. Regimens A and B had bioequivalent systemic exposure parameters (B/A [90% CI]: AUC_0–∞108.4 [103.4, 113.7], AUC_0–last 106.1 [100.7, 111.7], and C_max 92.3 [83.2, 102.4]). Regimen C was bioequivalent to both A and B for AUCs, but only to B for C_max. Median time to C_max was 45 minutes for regimen A and 60 minutes for regimens B and C. The most frequent AEs were dizziness, application-site erythema, headache, somnolence, nausea, and vomiting. All AEs were mild or moderate.

Conclusions. Bioavailability of fentanyl after FBT 400 µg administered as a single tablet was bioequivalent to that after 2 simultaneously administered 200 µg tablets in healthy Japanese volunteers. AEs were mild or moderate.

Objective. This study was conducted to characterize the pharmacokinetics, including extent of accumulation, and safety and tolerability of fentanyl following multiple doses of fentanyl buccal tablet (FBT) in healthy Japanese volunteers.

Methods. Healthy Japanese adults received 10 successive doses of open-label FBT 400 µg at 6-hour intervals. Naltrexone was given to minimize the opioid effects of fentanyl. FBT was placed above a molar tooth between the gum and cheek. Peak serum fentanyl concentration (C_max), time to C_max (t_max), and area under the serum fentanyl concentration-time curve from 0 to 6 hours (AUC_0–6) were summarized using descriptive statistics. Accumulation ratio was calculated as C_max for dose 10/C_max for dose 1, and was calculated similarly for AUC_0–6.

Results. Fourteen volunteers (mean age 33 years) were enrolled, and 13 completed the study. After doses 1 and 10, respectively, mean (SD) C_max was 1.70 (0.49) ng/mL and 1.97 (0.42) ng/mL, AUC_0–6 was 4.46 (1.14) ng·h/mL and 6.81 (0.90) ng·h/mL, and median (range) t_max was 50 (30–110) minutes and 30 (15–120) minutes. Following 10 successive doses, systemic exposure (AUC_0–6) was 55% higher than after dose 1, and C_max was 23% higher. Steady state was achieved within 3 days of dosing at 6-hour intervals, i.e., prior to dose 10. The most frequent adverse events (AEs) were somnolence (N = 9), decreased oxygen saturation (N = 4), headache (N = 3), application-site pain (N = 8), application-site erythema (N = 6), and application-site reaction (N = 5). All AEs were mild or moderate.

Conclusions. Following administration of FBT at 6-hour intervals to healthy Japanese volunteers, at steady state, fentanyl exposure was higher by 55% (AUC_0–6) and 23% (C_max) than after a single dose of FBT. Adverse events were mild or moderate.

Aim. To investigate the influence of probiotic pre-treatment on the permeation of the antidiabetic drug gliclazide in healthy and diabetic rats.

Methods. Wistar rats (age 2–3 months, weight 350 ± 50 g) were randomly allocated into one of 4 groups (N = 16 each group): healthy control, healthy probiotic, diabetic control, and diabetic probiotic. Probiotics (75 mg/kg, equal quantities of Lactobacillus acidophilus, Bifidobacterium lactis, and Lactobacillus rhamnosus) were administered twice a day for three days to the appropriate groups after diabetes had been induced with alloxan i.v. 30 mg/kg. Rats were sacrificed, ileal tissues mounted in Ussing chambers and gliclazide (200 µg/mL) was administered for the measurement of the mucosal to serosal absorption Jss^(MtoS) and serosal to mucosal secretion Jss^(StoM) of gliclazide.

Results. Treatment of healthy rats with probiotics reduced Jss^(MtoS) of gliclazide from 1.2 ± 0.3 to 0.3 ± 0.1 µg/min/cm² (P < 0.01) and increased Jss^(StoM) from 0.6 ± 0.1 to 1.4 ± 0.3 (P < 0.01) resulting in net secretion while, in diabetic tissues, treatment with probiotics increased both Jss^(MtoS) and Jss^(StoM) fluxes of gliclazide to the comparable levels of healthy tissues resulting in net absorption.

Discussion. In healthy rats, the reduction in Jss^(MtoS) after probiotics administration could be explained by the production of bacterial metabolites that upregulate the mucosal efflux drug transporters Mrp2 that control gliclazide transport. In diabetic rats, the restored fluxes of gliclazide after probiotic treatment, suggests the normalization of the functionality of the drug transporters resulting in a net absorption.

Conclusion. Probiotics may alter gliclazide transport across rat ileal tissue studied ex vivo.