Objective assessment of nonadherence and unknown co-medication in hospitalized patients.

PURPOSE: The intake of medications (drugs) without the knowledge of the treating physician (unknown co-medication) and nonadherence strongly influence drug safety. The aim of our study was to objectively assess unknown co-medication and nonadherence in hospitalized patients by screening urine for a large number of drugs using highly sensitive full scan gas chromatograpy/mass spectrometry (GC/MS). Secondary objectives were to determine the relationship of co-medication and nonadherence to the number of drugs prescribed and to compare history-taking by a pharmacist versus a physician. METHODS: In 152 patients, the drug histories taken by physicians, patients' self-reported adherence, and information compiled during as many as three structured interviews conducted by a trained pharmacist on days 1-2, 3-4, and 7-11 of the hospital stay were compared with the GC/MS results from urine samples collected after each interview. RESULTS: In the interviews performed by the pharmacist, 235 additional drugs were identified that were not documented in the chart. Of all the drugs indicated in any interview, 16.9% were identified only by the physician, 24.1% only by the pharmacist, and 59% by both. Overall, in 78% of the patients at least one additional drug was identified by urine screening. The findings suggest overall nonadherence to at least one drug in 13.0% of patients on admission and in 23.3% of patients at any time during hospitalization. Nonadherence was less frequent for critical dose drugs and correlated with the number of prescribed drugs. CONCLUSIONS: The drug history among hospitalized patients is often incomplete, and nonadherence and unknown co-medication are alarmingly frequent. This lack of knowledge might impact the overall success of drug therapies in the hospital setting.

Assessment of levothyroxine sodium bioavailability: recommendations for an improved methodology based on the pooled analysis of eight identically designed trials with 396 drug exposures.

BACKGROUND: Assessment of dosage form performance in delivering endogenous compounds, such as hormones, in vivo requires a specific approach. OBJECTIVES: Assessment of relative bioavailability of levothyroxine sodium (L-T4) from eight solid preparations, compared with a liquid formulation, by using pharmacological doses, and critical evaluation of trial methodology based on the pooled analysis of individual data. DESIGN: Eight open-label, randomised, single-dose, crossover phase I studies using eight solid L-T4 dosage forms (25, 50, 75, 100, 125, 150, 175, 200 microg per tablet; administered total doses 600, 625 or 700 microg) and a liquid formulation; assessment of relative bioavailability by 90% confidence intervals for the relative area under the concentration-time curve (AUC) of total thyroxine (TT4), i.e. protein-bound plus free thyroxine, calculated by using the recommended log AUC four-way analysis of variance models for crossover designs. For the pooled analysis, general linear models were applied to assess the validity of model assumptions, to identify potential sources of effect modification, to discuss alternative modelling approaches with respect to endogenous hormone secretion and to give recommendations for future designs and sample sizes. PARTICIPANTS: One hundred and sixty-nine healthy males; 29 of these individuals participating in two studies. INTERVENTIONS: Single oral doses of L-T4 tablets and the liquid formulation administered after fasting, separated by at least 6 weeks; a total of 396 drug exposures. MAIN OUTCOME MEASURES: TT4 AUC from 0 to 48 hours and peak plasma concentration with and without baseline correction. RESULTS: Each study demonstrated equivalence of the tablets to the drinking solution, independent of the chosen analysis model. Sequence effects that could devalidate the chosen crossover approach were not found. Period effects with changing directions that could best be explained by seasonal variation were detected. While the pre-specified method of baseline correction of simply subtracting individual time-zero TT4 values was disadvantageous, the analysis of total AUC could be improved considerably by covariate adjustment for baseline TT4. With this approach, sample sizes could have been substantially reduced or, alternatively, the recommended equivalence ranges could be reduced to +/-6%. CONCLUSION: Using a single pharmacological dose of L-T4 in two-period crossover designs is a safe and reliable procedure to assess L-T4 dosage form performance. With an adequate statistical modelling approach, the design is efficient and allows general conclusions with moderate sample sizes.