A Note on Power and Sample Size Calculations for the Kruskal–Wallis Test for Ordered Categorical Data

Although the Kruskal–Wallis test has been widely used to analyze ordered categorical data, power and sample size methods for this test have been investigated to a much lesser extent when the underlying multinomial distributions are unknown. This article generalizes the power and sample size procedures proposed by Fan et al. (2011 Fan , C. , Zhang , D. , Zhang , C. H. (2011). On sample size of the Kruskal-Wallis test with application to a mouse peritoneal cavity study. Biometrics 67:213–224.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) for continuous data to ordered categorical data, when estimates from a pilot study are used in the place of knowledge of the true underlying distribution. Simulations show that the proposed power and sample size formulas perform well. A myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmunce encephalomyelitis (EAE) mouse study is used to demonstrate the application of the methods.     

Pharmacokinetics and Pharmacodynamics of PEGylated IFN-β 1a Following Subcutaneous Administration in Monkeys

No HeadingPurpose. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of a new polyethylene glycol (PEG) conjugate formulation of interferon (IFN)- 1a following subcutaneous (SC) administration in monkeys.Methods. Single SC injections of 0.3, 1, and 3 million international units (MIU)/kg of PEG-IFN- 1a were administered to 3 groups of cynomolgus monkeys (n = 4 each). Plasma concentrations of drug and neopterin, a classic biomarker for IFN- PD, were measured at various time-points after dosing. PK/PD profiles were described by noncompartmental methods and pooled data by an integrated mathematical model, where fixed and delayed concentration-time profiles were used as driving functions in an indirect stimulatory response model.Results. PEG-IFN- 1a was rapidly absorbed, with peak concentrations observed at about 4–5 h. Compared to previous identical SC doses of IFN- 1a, administration of 1 and 3 MIU/kg of pegylated drug resulted in 27- and 16-fold increases in area under the concentration-time curves. Neopterin concentrations followed a typical dose-dependent biphasic pattern. Pooled PD profiles were well-described by the PK/PD model, and the neopterin elimination rate (0.0190 h^–1) is consistent with previous estimates.Conclusions. The PEG-modification of IFN- 1a provides enhanced drug exposure and similar pharmacodynamics of neopterin compared to the unmodified formulation.     

Multiple-Dose Safety, Pharmacokinetics, and Pharmacodynamics of the μ-Opioid Receptor Inverse Agonist GSK1521498

The endogenous opioid system and μ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a μ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.     

Evaluation of an alternative extended-infusion piperacillin–tazobactam dosing strategy for the treatment of gram-negative infections

Introduction To enhance the probability of pharmacodynamic target attainment, piperacillin–tazobactam can be administered as either a continuous or extended-infusion dosage regimen for the treatment of gram-negative infections. Four hour extended-infusions of piperacillin–tazobactam 3.375 g administered intravenously (IV) every 8 h have been widely studied as an alternative to conventional, intermittent dosage regimens with largely favorable outcomes. Objective To assess the clinical and economic impact of a novel 3-h extended-infusion piperacillin–tazobactam dosing strategy for the treatment of gram-negative infections. Setting 433-bed community hospital in Lexington, KY. Methods Retrospective cohort study before and after the implementation of an alternative dosing protocol using a 3-h infusion of piperacillin–tazobactam 3.375 g IV every 6 h. Main outcome measures The primary outcome was in-hospital mortality. Secondary outcomes include length of stay, ICU length of stay, 30-day all-cause hospital readmissions, total cost per admission, complications, and a composite of in-hospital mortality and readmission within 30 days of discharge. Results Readmission within 30 days of hospital discharge was significantly reduced in the extended-infusion arm (1.2 vs. 13.7 %, P = 0.002). A composite endpoint of death or readmission was lower among patients who received the extended-infusion dosing regimen [OR_adj 0.20; 95 % CI (0.07–0.57)]. However this was likely driven by reductions in readmission. Conclusion An alternative regimen of extended-infusion piperacillin–tazobactam resulted in a significant reduction in 30-day all-cause hospital readmission. These results indicate that 3-h infusions of piperacillin–tazobactam 3.375 g IV every 6 h may represent a clinically effective alternative to other commonly used regimens and results in fewer readmissions within 30 days.     

Evaluation of the cost-effectiveness of rifaximin-α for the management of patients with hepatic encephalopathy in the United Kingdom

Objective: Rifaximin-α 550?mg twice daily plus lactulose has demonstrated efficacy in reducing recurrence of episodes of overt hepatic encephalopathy (OHE) and the risk of hepatic encephalopathy (HE)-related hospitalizations compared with lactulose alone. This analysis estimated the cost effectiveness of rifaximin-α 550?mg twice daily plus lactulose versus lactulose alone in United Kingdom (UK) cirrhotic patients with OHE.

Method: A Markov model was built to estimate the incremental cost-effectiveness ratio (ICER). The perspective was that of the UK National Health Service (NHS). Clinical data was sourced from a randomized controlled trial (RCT) and an open-label maintenance study in cirrhotic patients in remission from recurrent episodes of OHE. Health-related utility was estimated indirectly from disease-specific quality of life RCT data. Resource use data describing the impact of rifaximin-α on hospital admissions and length of stay for cirrhotic patients with OHE was from four single-center UK audits. Costs (2012) were derived from published sources; costs and benefits were discounted at 3.5%. The base-case time horizon was 5 years.

Results: The average cost per patient was £22,971 in the rifaximin-α plus lactulose arm and £23,545 in the lactulose arm, a saving of £573. The corresponding values for benefit were 2.35 quality adjusted life years (QALYs) and 1.83 QALYs per person, a difference of 0.52 QALYs. This translated into a dominant base-case ICER. Key parameters that impacted the ICER included number of hospital admissions and length of stay.

Conclusion: Rifaximin-α 550?mg twice daily in patients with recurrent episodes of OHE was estimated to generate cost savings and improved clinical outcomes compared to standard care over 5 years.     

Pharmacokinetics–pharmacodynamics of antifungal agents in the central nervous system

Introduction: Mortality from invasive fungal disease involving the central nervous system (CNS) is excessive. Achieving therapeutic drug concentrations at the site of infection within the CNS is always difficult and its evaluation is complex due to anatomical barriers and variable pathophysiological lesions.

Areas covered: This review provides an updated summary of the CNS PK of antifungal therapies. It considers factors that influence the success of antifungal regimens for CNS infection as well as preclinical and clinical data that quantify antifungal pharmacokinetics (PK) in the CNS. Furthermore, it presents state-of-the-art technologies to enhance the clinical use of existing antifungal drugs, and introduces novel antifungal drugs in development.

Expert opinion: The antifungal drugs currently available are either suboptimal, or are being used suboptimally, for CNS disease. Therapeutic drug monitoring is mandatory to enhance their effectiveness. Novel drugs in development may offer more efficacious options. In all cases, contemporary technologies to assess CNS PK offer the opportunity to enhance our understanding and use of antifungal drugs for CNS fungal disease.     

Pharmacokinetics of theophylline in patients with COPD and its interference factors

AIM： To study the pharmacokinetics of theophylline in patients with chronic obstructive pulmonary diseases （COPD） and its interference factors. METHODS： Serum theophylline concentrations in 9 patients with COPD after oral administration of theophylline （200 mg, tid） for 5 consecutive days or combining with nifedipine （ 10 mg, tid） for 5 consecutive days were determined by high performance liquid chromatography（HPLC） with ultraviolet spectrophotometry. RESULTS： The pharmacokinetics of theophylline in COPD patients was one-compartment model after oral administration of theophylline （200 mg, tid） for 5 consecutive days. The significant difference in individual variation on pharmacokinetics of theophylline was observed in this study. The volume of distribution （ Vd ） was （0.50 ± 0.21） L/kg, the elimination half-life （ t1/2 ） was （5.4 ± 1.3） h and clearance （CL） was （0.07 ± 0.03） L·h^-1·kg^-1 in the patients with COPD. There was no significant difference in Vd, t1/2, and CL between COPD patients and healthy volunteers （ P 〉 0.05）. The values of k and C1 were faster and t 1/2 was shorter in the middleaged patients than those in old COPD patients （P 〈 0.05）.[第一段]     

Pharmacokinetics and concentration–effect relationship of adalimumab in rheumatoid arthritis

Aims

This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration–effect relationship of adalimumab using pharmacokinetic–pharmacodynamic (PK–PD) modelling in patients with rheumatoid arthritis (RA).

Methods

Adalimumab PK and PK–PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated.

Results

Thirty patients treated for RA were analysed. The following pharmacokinetic and PK–PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (V_d/F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day⁻¹ (17%); first-order absorption rate (k_a) = 0.28 day⁻¹; CRP input (k_in) = 22.0 mg l⁻¹ day⁻¹ (65%); adalimumab concentration leading to a 50% decrease in k_in (C₅₀) = 3.6 mg l⁻¹ (88%); baseline DAS28 (DAS₀) = 5.5 mg l⁻¹ (11%); and adalimumab concentration leading to 50% decrease of DAS₀ (IC₅₀) = 11.0 mg l⁻¹ (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection.

Conclusions

This is the first study to describe adalimumab pharmacokinetics and the concentration–effect relationship in RA. A 160 mg loading dose may lead to an increased benefit from treatment in RA patients.     

Development and validation of an HPLC–UV method for the quantification of carbamazepine in rabbit plasma

An isocratic simple rapid assay has been developed and validated for the determination of carbamazepine (CBZ) in both solution form and rabbit plasma using propylparaben as an internal standard. The assay was performed using a μ-Bondapak C₁₈ (150 mm × 4.6 mm i.d) with a mobile phase consisting of methanol and water (50:50), the flow rate was 1 ml/min and UV detection at 285 nm. The method was found to be specific for CBZ, no interfering peaks were observed with an overall analytical run time of 15 min. Accuracy reported as % recovery were found to be 98.37–100.45% and 97.53–103.58% for inter-day and intra-day accuracies, respectively. Inter-day precision (reproducibility) was found to be 0.53–2.75% RSD, while intra-day precision (repeatability) was found to be 1.06–3.7% RSD for the samples studied. The calibration curve was found to be linear with the equation y = 0.2847x + 0.0138, with a correlation coefficient of 0.9999 (R²) over a concentration range of 0.5–40 μg/ml. The limit of quantitation was the lowest concentration. The method is simple and rapid and does not require any preliminary treatment of the sample. The method was fully validated.     

Evaluation of the maternal–fetal transfer of granisetron in an ex vivo placenta perfusion model

The objective of this study was to estimate maternal–fetal transplacental passage of granisetron in an ex vivo placental perfusion model. Term human placentas (N = 8) were collected immediately after delivery. A single cotyledon from each placenta was perfused granisetron concentration to mimic systemic maternal peak plasma concentrations following either IV (50 ng/mL) or transdermal administration (5 ng/mL). To assess drug transfer and accumulation, samples were collected from maternal and fetal compartments.In the 50 ng/mL open model, the mean transport fraction was 0.21 ± 0.08 with clearance index of 0.53 ± 0.66. Fetal peak concentrations achieved was 5.6 ± 6.6 ng/mL with mean accumulation of 5.35 ± 6.4 ng/mL. No drug was detected in the fetal compartment with the 5 ng/mL models.Transplacental passage of granisetron was inconsistent at the 50 ng/mL concentration that achieved with IV dosing. However, there consistently was no detectable passage in all the placentas evaluated of the granisetron at 5 ng/mL concentration that would be achieved after transdermal patch administration.     

Compaction and measurement of tablets in liquids with different dielectric constants for determination of bonding mechanisms—Evaluation of the concept

In order to study bonding mechanisms in tablets, liquids with increasing dielectric constants have been used to filter out weak long range distance forces. The aim of this study was to further critically evaluate this concept.Tablets of sodium chloride, sodium bicarbonate, Avicel®, Emcompress®, lactose and sucrose were compacted in media with dielectric constants from 1 to 24 and the remaining tensile strength of tablets compacted in liquid was calculated. With increasing dielectric constant a continuos decrease in tensile strength was obtained and at a dielectric constant above approximately 10–15, a plateau level was reached for all materials except for Avicel®. This level was assumed to reflect the proportion of solid bridges in the compact and the values were consistent with previous data reported from our laboratory.The results also showed that by compacting particles suspended in a liquid a more effective reduction of long range distance forces was obtained, than if tablets were compacted in air followed by a soaking process in liquid.Compaction in liquids may be unsuitable for some materials due to swelling or changes in volume reduction behaviour. Nevertheless, the method appears to be favourable for studying bonding mechanisms, especially for tablets with a low porosity.     

Pharmacokinetics of omeprazole in rats with dextran sulfate sodium–induced ulcerative colitis

Omeprazole is a commonly used drug in patients with ulcerative colitis (UC). This study investigated the pharmacokinetics of omeprazole in rats with UC induced by dextran sulfate sodium (DSS). The pharmacokinetics of intravenously administered omeprazole (20 mg/kg) was investigated in normal and UC rats using LC-MS/MS. The formation of 5-OH omeprazole, a main metabolite of omeprazole, in rat liver microsomes (RLMs) from normal and UC rats was compared. The protein levels of CYP1A2, CYP2D1, and CYP3A1 in the liver were measured by Western blot. Compared with normal rats, UC rats had increased plasma concentrations of omeprazole, resulting in an increased AUC_0–240 min and decreased CL. DSS treatment decreased the formation rate of 5-OH omeprazole in RLMs but did not change the affinity of the enzymes. The V_max and CL_int of RLMs from UC rats were 62% and 48% those of RLMs from normal rats, respectively. The hepatic CYP1A2 and CYP3A1 protein levels in UC rats were 42.6 and 45.2% lower than those in normal rats, respectively; however, the protein levels of CYP2D1 in the two groups were similar. The activity and expression of some hepatic CYP450 isoforms were decreased by UC, leading to changes in the pharmacokinetics of omeprazole.     

Disease Progression and Pharmacodynamics in Parkinson Disease – Evidence for Functional Protection with Levodopa and Other Treatments

We have modelled the Unified Parkinson’s Disease Rating Scale (UPDRS) scores collected in 800 subjects followed for 8 years. Newly diagnosed and previously untreated subjects were initially randomized to treatment with placebo, deprenyl, tocopherol or both and, when clinical disability required, received one or more dopaminergic agents (levodopa (carbidopa / levodopa), bromocriptine, or pergolide). Using models for disease progression and pharmacodynamic models for drug effects we have characterized the changes in UPDRS over time to determine the influence of the various drug treatments. We have confirmed and quantitated the relative symptomatic benefits of the dopaminergic agents and provide model-based evidence for slowing of disease progression.     

The Pharmacokinetics of β-Cyclodextrin and Hydroxypropyl-β-cyclodextrin in the Rat

Hydroxypropyl--cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 µg/ml. The pharmacokinetics of -cyclodextrin and of hydroxypropyl--cyclodextrin were studied after intravenous administration to permanently cannulated rats. The pharmacokinetic behavior of both cyclodextrins was similar to that of inulin, showing rapid distribution over extracellular fluids. Elimination occurred through glomerular filtration. When a dose of 200 mg/kg -cyclodextrin was administered the elimination rate was decreased, probably as a result of nephrotoxicity of -cyclodextrin. Within 24 hr after administration most of the cyclodextrin dose was recovered unchanged in urine. After oral administration, only insignificant amounts of intact -cyclodextrin were absorbed from the gastrointestinal tract.     

Multivariate Mann–Whitney Estimators for the Comparison of Two Treatments in a Three-Period Crossover Study with Randomly Missing Data

This paper discusses the application of multivariate Mann–Whitney estimators to the comparison of two treatments for a strictly ordinal response variable in a crossover study with four sequence groups and three periods. Ways of managing randomly missing data and nonparametric covariance adjustment for no differences among groups for a baseline period have consideration as well. Estimators pertaining to treatment comparisons in linear logistic models for the Mann–Whitney estimators have determination through a Bradley–Terry model for dimension reduction and weighted least squares. These estimators can be the basis for both statistical tests and confidence intervals. The methods in this paper have their results presented for an example. Simulation studies for the methods show that they have reasonable control of type 1 error and power.