Comparison of a predefined dose increment nomogram with a percentage adjustment nomogram in patients receiving argatroban therapy

PURPOSE: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). PATIENTS AND METHODS: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m2 as a 3-hour infusion. RESULTS: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m2. Dose escalation of oral paclitaxel from 60 to 300 mg/m2 resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values ± SD after 60, 180, and 300 mg/m2 of oral paclitaxel were 1.65 ± 0.93, 3.33 ± 2.39, and 3.46 ± 1.37 μmol/L·h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 ± 3.26 μmol/L·h. CONCLUSION: The MTD of oral paclitaxel was 300 mg/m2. However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m2, the oral paclitaxel dose of 180 mg/m2 in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.

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Opioid Analgesics and Adverse Outcomes among Hemodialysis Patients

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.09910917 ◽

2018 ◽

Vol 13 (5) ◽

pp. 746-753 ◽

Cited By ~ 33

Author(s):

Julie H. Ishida ◽

Charles E. McCulloch ◽

Michael A. Steinman ◽

Barbara A. Grimes ◽

Kirsten L. Johansen

Keyword(s):

Confidence Interval ◽

Mental Status ◽

Oral Morphine ◽

Altered Mental Status ◽

Hazard Ratio ◽

Adverse Outcomes ◽

Dependent Manner ◽

Opioid Use ◽

Opioid Dose ◽

Dose Increment

Background and objectivesPatients on hemodialysis frequently experience pain and may be particularly vulnerable to opioid-related complications. However, data evaluating the risks of opioid use in patients on hemodialysis are limited.Design, setting, participants, & measurementsUsing the US Renal Data System, we conducted a cohort study evaluating the association between opioid use (modeled as a time-varying exposure and expressed in standardized oral morphine equivalents) and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture among 140,899 Medicare-covered adults receiving hemodialysis in 2011. We evaluated risk according to average daily total opioid dose (>60 mg, ≤60 mg, and per 60-mg dose increment) and specific agents (per 60-mg dose increment).ResultsThe median age was 61 years old, 52% were men, and 50% were white. Sixty-four percent received opioids, and 17% had an episode of altered mental status (15,658 events), fall (7646 events), or fracture (4151 events) in 2011. Opioid use was associated with risk for all outcomes in a dose-dependent manner: altered mental status (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.23 to 1.34; higher dose: hazard ratio, 1.67; 95% confidence interval, 1.56 to 1.78; hazard ratio, 1.29 per 60 mg; 95% confidence interval, 1.26 to 1.33), fall (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.21 to 1.36; higher dose: hazard ratio, 1.45; 95% confidence interval, 1.31 to 1.61; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.03 to 1.05), and fracture (lower dose: hazard ratio, 1.44; 95% confidence interval, 1.33 to 1.56; higher dose: hazard ratio, 1.65; 95% confidence interval, 1.44 to 1.89; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.04 to 1.05). All agents were associated with a significantly higher hazard of altered mental status, and several agents were associated with a significantly higher hazard of fall and fracture.ConclusionsOpioids were associated with adverse outcomes in patients on hemodialysis, and this risk was present even at lower dosing and for agents that guidelines have recommended for use.

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