Effect of Missed Doses on the Therapeutic Effect of Methotrexate for Rheumatoid Arthritis: A Pharmacokinetic Modeling Study.

INTRODUCTION: Patients rarely, if ever, take their medications exactly as prescribed. The extent to which missed doses interfere with a drug's therapeutic effect remains unclear. METHODS: After weekly oral dosing of methotrexate (MTX) for rheumatoid arthritis, its polyglutamate derivatives (MTXglu) accumulate in red blood cells, where they are markers for the drug's therapeutic effectiveness. We used Medication Event Monitoring System data and pharmacokinetic modeling to analyze whether missing MTX doses causes the MTXglu level in red blood cells to fall below the range associated with the drug's clinical effect. RESULTS: For patients initiating oral MTX, the threshold for clinical effectiveness and the steady state level were reached in medians of 6 weeks and 22 weeks, respectively. For patients at steady state who discontinued MTX, the MTXglu level fell below the therapeutic threshold after a median of 3 weeks. After initiating MTX, single missed doses did not cause a loss of therapeutic effect in the median patient if they occurred after 10 weeks, while runs of ≥3 consecutive missed doses did cause the MTXglu level to fall below the therapeutic threshold. CONCLUSION: While there is considerable variation between patients, pharmacokinetic modeling indicates that instances of isolated single missed doses of MTX typically will not cause polyglutamated methotrexate levels in red blood cells to fall below the range associated with the therapeutic effect. Runs of ≥3 consecutive missed doses, however, are typically expected to result in a loss of the therapeutic effect.

Patterns of non-adherence to oral antiretroviral medication: frequencies of consecutively missed doses.

PURPOSE: The therapeutic effect of a once-daily oral drug will be maintained if there are no occurrences of consecutively missed doses that exceed the duration of the drug's effect. The durations of effect of antiretroviral drugs are typically in the range of 1-4 days. Here, we report the observed frequencies of ≥2, ≥3, and ≥4 consecutively missed doses for patients taking a once-daily oral antiretroviral drug for HIV infection. PATIENTS AND METHODS: Medication Event Monitoring System (MEMS) data were extracted from an electronic database of MEMS records, for a 30-day period for 555 patients taking once-daily oral HIV drug therapy. We recorded the number of days with missed doses and occurrences of ≥2, ≥3, or ≥4 consecutively missed doses. Distributions of the observed frequencies of ≥2, ≥3, and ≥4 consecutively missed doses as a proportion of number of missed doses were compared to calculated random distributions using the Wilcoxon signed-rank test. RESULTS: The frequencies of 0, 1, and ≥2 missed daily doses were 0.279, 0.312, and 0.409, respectively. The frequencies of ≥2, ≥3, and ≥4 consecutively missed doses were 0.184, 0.110, and 0.065, respectively. The probabilities that the observed frequencies of ≥2, ≥3, and ≥4 consecutively missed doses were as expected from random chance were P=0.345, P<0.01, and P<0.01, respectively. CONCLUSION: Observed runs of ≥3 and ≥4 consecutively missed doses - and hence loss of therapeutic effect for drugs of duration of action of <3 and <4 days, respectively - occurred more frequently than expected if missed doses were randomly distributed.

The Adherence Rate Threshold is Drug Specific.

INTRODUCTION: Patient adherence to a medication regimen is usually expressed as an adherence rate, defined as the proportion of prescribed doses actually taken. An adherence rate threshold, above which the therapeutic effect is maintained, is typically assigned an arbitrary value, commonly 0.8. OBJECTIVE: Here, we determined the value of the adherence rate threshold objectively in different drugs of the same class, using statins as an example. METHODS: We used pharmacokinetic/pharmacodynamic (PK/PD) modeling to predict serum levels of low-density lipoprotein cholesterol (LDL-C) in patients taking simvastatin 20 mg or atorvastatin 5 mg once daily for 30 days. LDL-C reduction was modeled for adherence rates of 1.0, 0.8, 0.6, 0.4, and 0.2. The results were expressed as the percentage of time spent at the LDL-C goal (< 70 mg/dL). The adherence rate threshold was defined as the minimum adherence rate that resulted in the same amount of time at goal as perfect adherence (i.e., a rate of 1.0). RESULTS: For simvastatin, an adherence rate of 0.8 resulted in a significant decrease in time at the LDL-C goal compared to perfect adherence (54.8% versus 85.1%; P < 0.001), and rates < 0.8 resulted in progressively less time at goal. For atorvastatin, the rates of 0.8 and 0.6 resulted in essentially the same amount of time at goal as perfect adherence (87.8% and 87.7%, respectively, versus 88.1%; P > 0.05 for both), with less time at goal only occurring at rates ≤ 0.4 (P < 0.001). Thus, the adherence rate thresholds are > 0.8 for simvastatin and between 0.4 and 0.6 for atorvastatin. CONCLUSION: These results indicate that a value of 0.8 cannot be applied universally.

Relationship Between Adherence Rate Threshold and Drug 'Forgiveness'.

The medication adherence rate (A) is the proportion of prescribed drug doses consumed within a given time period. It is often assumed that there is an adherence rate threshold (A th) at or above which the therapeutic effect of the medication is maintained. Drug forgiveness (F) is the number of consecutive doses that can be missed while still maintaining a therapeutic effect. At a given value for A, the therapeutic effect of the drug will be continuously maintained if there is no possibility of >F missed doses. Hence, for a once-daily drug prescribed for N days, A th and F are related by the formula, A th = (N - F)/N. At adherence rates below A th the probability of maintaining the therapeutic effect is equal to the probability of there being no instances of >F consecutive missed doses. Since F is a function of the duration of the drug effect (D) and D varies depending on the specific drug's pharmacokinetic/pharmacodynamic properties, there is no universal A th applicable to all drugs.

Conceptual framework for outcomes research studies of hepatitis C: an analytical review.

Hepatitis C virus infection is one of the main causes of chronic liver disease worldwide. Until recently, the standard antiviral regimen for hepatitis C was a combination of an interferon derivative and ribavirin, but a plethora of new antiviral drugs is becoming available. While these new drugs have shown great efficacy in clinical trials, observational studies are needed to determine their effectiveness in clinical practice. Previous observational studies have shown that multiple factors, besides the drug regimen, affect patient outcomes in clinical practice. Here, we provide an analytical review of published outcomes studies of the management of hepatitis C virus infection. A conceptual framework defines the relationships between four categories of variables: health care system structure, patient characteristics, process-of-care, and patient outcomes. This framework can provide a starting point for outcomes studies addressing the use and effectiveness of new antiviral drug treatments.

Defining medication adherence in individual patients.

BACKGROUND: The classification of patients as adherent or non-adherent to medications is typically based on an arbitrary threshold for the proportion of prescribed doses taken. Here, we define a patient as pharmacokinetically adherent if the serum drug levels resulting from his/her pattern of medication-taking behavior remained within the therapeutic range. METHODS: We used pharmacokinetic modeling to calculate serum drug levels in patients whose patterns of dosing were recorded by a medication event monitoring system. Medication event monitoring system data were from a previously published study of seven psoriasis patients prescribed 40 mg subcutaneous adalimumab at 14-day intervals for 1 year. Daily serum concentrations of adalimumab were calculated and compared with a known therapeutic threshold. RESULTS: None of the seven patients took adalimumab precisely every 14 days. Three patients who took adalimumab at intervals of 6-26 days could be classified as pharmacokinetically adherent, because their daily adalimumab serum concentration never fell below the therapeutic threshold. The four other patients, who took adalimumab at intervals of 7-93 days, could be classified as pharmacokinetically non-adherent, because their adalimumab serum concentration fell below the therapeutic threshold on 3.5%-71.3% of days. CONCLUSION: Patients with varying patterns of adalimumab dosing could be classified as pharmacokinetically adherent or non-adherent according to whether or not their serum drug concentrations remained within the therapeutic range.