Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). AIM: To use a population pharmacokinetic model that accounts for the time-varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. METHODS: Adults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline ≥ 100 points), remission (CDAI ≤ 150), C-reactive protein (CRP) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 µg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 µg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. RESULTS: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP ≤ 5 mg/L or FC ≤ 250 µg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 µg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 µg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. CONCLUSIONS: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.

Clinical and demographic characteristics predictive of treatment outcomes for certolizumab pegol in moderate to severe Crohn's disease: analyses from the 7-year PRECiSE 3 study.

BACKGROUND: Clinical factors were previously identified as predictors of short-term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short- and long-term clinical remission among CD patients treated with certolizumab pegol (CZP). AIM: To identify factors that influence long-term remission of CD with CZP treatment. METHODS: Patients who had completed placebo-controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey-Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI ≤4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used. RESULTS: Predictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P < 0.05 for all). Predictors for loss of remission (N = 437) included HBI, serum albumin concentration, haematocrit, smoking status and exposure. Predictors of maintenance of remission (N = 437) included haematocrit, IBD surgery, HBI, disease duration, serum albumin concentration and exposure. Significant predictors were confirmed with stepwise multivariate regression models. CONCLUSIONS: These analyses identified several influential parameters for short-and long-term remission of Crohn's disease with certolizumab pegol treatment. The data yield valuable hypotheses regarding factors that influence certolizumab pegol treatment. More investigation is needed. (ClinicalTrials.gov identifier NCT00552058).

Adverse drug reaction reporting system: developing a well-monitored program.

The spontaneous reporting of adverse drug reactions (ADRs) at the St. John's Hospital and Memorial Medical Center was well below that reported in the literature. After review of procedures for reporting of ADRs at these institutions, the authors developed a system that was approved by their joint P & T Committee. The ADR reporting program developed uses concurrent monitoring of most hospital inpatients and a retrospective review of all emergency room patients. In the year after program implementation, 162 ADR reports were documented. From this program, a group of serious ADRs to one agent was identified and reported, both to the Food and Drug Administration and to the manufacturer. A well-developed ADR monitoring program may lead to heightened physician and nurse awareness and early problem identification, possibly decreasing morbidity for hospitalized patients.

An exchange cart supply-distribution system employed on an institution-wide basis.

This paper describes a drug distribution system developed for replenishment of stock supplies for hospital patient-care units, ambulatory care areas, and clinical support service areas. The method employed, a modified exchange cart system in which duplicate sets of supplies are exchanged at regular and predetermined intervals, utilizes unit-of-use packaging whenever feasible and is an extension of our centralized unit dose drug distribution system. Various supply-distribution techniques and inventory surveillance and control techniques, as well as cost identification and charge recovery procedures, are discussed.

Hospital pharmacy indexes: a tool for assessing purchasing and inventory control performance.

The development and use of price and value indexes that differentiate between the effects of price and volume changes on a hospital's cost of drug products and related supplies are discussed. To construct a price index it is necessary to (1) compile a general list of drug products representative of a major portion of the institution's annual drug expenditure, (2) assign appropriate weights (quantity determinants) to these listed products, (3) select a base period that reflects normal hospital operations, and (4) select a suitable equation, the authors' choice being a fixed-weight aggregates method. The value index, which measures the combined effects of acquisition cost changes and volume changes, can be calculated when the acquisition cost change for the period is known. Information derived from the indexes can be used in (1) cost analysis and operational forecasts, (2) measurement and assessment of purchasing and inventory control, and (3) simplification of procurement and inventory processes.

Objective-focused approach for appraising the performance of institutional pharmacists.

The development of an objective-focused performance appraisal method applied to hospital pharmacy management is discussed. Objective-based performance appraisal techniques should match the pharmacy department's goals and management style and be a continuous process. Goals should be established and target dates set jointly by the individual and supervisor, emphasizing employee planning and departmental priorities. Standards by which to measure accomplishment of objectives should be set before the evaluation period begins. Appraisals and rewards should be related to achievement of goals. Objective-focused performance appraisals provide a better system for establishing priorities and improve coordination and integration of departmental plans and activities.

Use of fructose in the treatment of acute alcoholic intoxication.

The literature concerning the use of fructose to lower ethanol blood levels in acute alcoholic intoxication is reviewed. Studies indicate that 500 ml of a 40% infusion of fructose solution given over a 30-minute period can increase the rate of decline of ethanol blood levels by 25%. The recommended daily dosage is one to three liters of a 10% solution. Lactic acidosis is a potentially serious side effect of large doses of fructose. The lack of controlled clinical studies or other convincing evidence makes the routine use of fructose to treat acute alcoholic intoxication inadvisable.