A supportive pharmaceutical care program consisting of review by patient and pharmacist of each patient's electronically compiled dosing history, plus educational reminders, improves patient adherence to the once-daily atorvastatin dosing regimen, mainly by extending persistence.
Electronic and chemical marker methods provide the first reliable measurements of drug exposure in ambulatory trials. These data contradict the usual claim in published drug trials of > 90% of patients having been satisfactorily compliant with the protocol-specified dosing regimen. Such exaggerated claims are based, usually, on count of returned dosing forms, which afford patients easy ability to manipulate by discarding or hoarding untaken doses. Electronic monitoring provides, for the first time, data on intervals between doses, revealing the 'drug holiday'--3 or more consecutive days without dosing--as a basis not only for lapsed therapeutic action, but as a pharmacodynamic trigger for hazardous rebound effects on recurrent first dose effects. Another new findings is the evident non-specificity of poor or partial compliance, the range and distributions of which appear to be hardly affected by drug, disease, prognosis, or symptoms. This finding contradicts often repeated but unsupported claims that noncompliance is a specific response to drug action, disease, prognosis or other treatment-related factors. New statistical methods are needed for trial design and analysis, to use drug exposure data as covariate information, to incorporate into drug labelling estimates of dose-related efficacy, holiday-related hazard, the limits of safe variation in dose-timing, and what one should best do when those limits are exceeded. Oral contraceptive labelling in the U.K. and U.S. is exemplar for this next step toward full-disclosure labelling.
The primary objective of this paper is to investigate the effect of adherence to prescribed antiretroviral therapy on virologic response measured repeatedly over time in HIV-infected patients. To this end observations on plasma viral load (HIV RNA) assessed in copies/ml are categorized into four clinically meaningful states, [0--50[, [50--400[, [400--2000[, [2000 and up. A time-dependent continuation ratio model is used to analyse longitudinal ordinal responses. The main challenge lies in modelling dependencies over time and using information contained in the data efficiently to establish a dynamic relation between observed patient adherence and viral load. Among the several measures of adherence investigated, two specifically account for long periods of time without intake. One is derived from the third moment of the inter-dose interval distribution, while the second reflects internal drug exposure using pharmacokinetic parameters. The approach is applied to a clinical trial involving 35 patients who were followed over 12 months. Results demonstrate a significant relation between patient adherence and virologic response.
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