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Quantification of the Forgiveness of Drugs to Imperfect Adherence.

ABSTRACT: The circumstance of how sensitive therapeutic success is under imperfect adherence is driven by the property known as forgiveness. To date, no studies have considered variability in the pharmacokinetic-pharmacodynamic process in conjunction with imperfect adherence patterns in order to develop a comparative criterion to determine the forgiveness of a drug. In this study, we have proposed a criterion to quantify forgiveness; illustrated the criterion for a theoretical example and evaluated the forgiveness of a motivating example, namely warfarin. A forgiveness criterion, relative forgiveness, is defined as the number of times more likely that a target is successfully attained under perfect adherence compared to imperfect adherence; or when comparing two drugs under a standard setting of imperfect adherence. The relative forgiveness criterion may have important implications for both drug development and clinical practice since the choice of drug can account for the likely influence of its forgiveness.

SUBMITTER: Assawasuwannakit P

PROVIDER: S-EPMC4394614 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Quantification of the Forgiveness of Drugs to Imperfect Adherence.

Assawasuwannakit P P Braund R R Duffull S B SB

CPT: pharmacometrics & systems pharmacology 20150304 3

The circumstance of how sensitive therapeutic success is under imperfect adherence is driven by the property known as forgiveness. To date, no studies have considered variability in the pharmacokinetic-pharmacodynamic process in conjunction with imperfect adherence patterns in order to develop a comparative criterion to determine the forgiveness of a drug. In this study, we have proposed a criterion to quantify forgiveness; illustrated the criterion for a theoretical example and evaluated the fo ...[more]

PMID: 26225235

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Project description:BackgroundPoor medication adherence contributes to increased morbidity and mortality in patients with epilepsy and may be under-addressed in clinical practice. Ethical concerns make it impossible to study the impact of medication nonadherence in clinical trials, but our previous work emphasizes the importance of using preclinical approaches to address these questions. With over 30 clinically available antiseizure medicines (ASM's), it remains an important question to understand the relationship between poor adherence and seizure incidence across mechanistically distinct ASM's, including the broad-spectrum ASM, perampanel (PER).MethodsWe formulated PER into chow pellets to deliver to rats in a 100% fully adherent or 50% variable nonadherent paradigm via our novel automated medication-in-food delivery system. Chronic oral dosing was initiated in male rats with chronic epilepsy while monitoring 24/7 for videoEEG evidence of seizures during a 4-week placebo baseline and 4-week treatment phase. PER concentrations were monitored in plasma at 1-week intervals and correlated with degree of seizure control. The relationship between missed doses and extended patterns of nonadherence were correlated with breakthrough seizures.ResultsFully adherent rats demonstrated a median reduction in seizure frequency of 50%, whereas nonadherent rats had a median increase of 54%. Plasma concentrations of PER were stable over the 4-week treatment period in both fully adherent and nonadherent groups, with levels being twice as high in fully adherent animals. There was no correlation between a single missed dose or series of missed doses and the incidence of breakthrough seizures. However, those animals in the nonadherent group that received PER for every meal during a 24-h period had a reduced likelihood of seizure incidence.ConclusionsIf our preclinical data is supported in the clinic, PER's favorable pharmacokinetic profile in humans, combined with a lowered risk of breakthrough seizures suggests that it may provide a certain forgiveness factor if a dose is missed within a 24-h window.

Project description:We quantified concomitant medication polypharmacy, pharmacokinetic and pharmacodynamic interactions, adverse effects and adherence in Australian adults on effective antiretroviral therapy.Cross-sectional.Patients recruited into a nationwide cohort and assessed for prevalence and type of concomitant medication (including polypharmacy, defined as ?5 concomitant medications), pharmacokinetic or pharmacodynamic interactions, potential concomitant medication adverse effects and concomitant medication adherence. Factors associated with concomitant medication polypharmacy and with imperfect adherence were identified using multivariable logistic regression.Of 522 participants, 392 (75%) took a concomitant medication (mostly cardiovascular, nonprescription or antidepressant). Overall, 280 participants (54%) had polypharmacy of concomitant medications and/or a drug interaction or contraindication. Polypharmacy was present in 122 (23%) and independently associated with clinical trial participation, renal impairment, major comorbidity, hospital/general practice-based HIV care (versus sexual health clinic) and benzodiazepine use. Seventeen participants (3%) took at least one concomitant medication contraindicated with their antiretroviral therapy, and 237 (45%) had at least one pharmacokinetic/pharmacodynamic interaction. Concomitant medication use was significantly associated with sleep disturbance and myalgia, and polypharmacy of concomitant medications with diarrhoea, fatigue, myalgia and peripheral neuropathy. Sixty participants (12%) reported imperfect concomitant medication adherence, independently associated with requiring financial support, foregoing necessities for financial reasons, good/very good self-reported general health and at least 1 bed day for illness in the previous 12 months.In a resource-rich setting with universal healthcare access, the majority of this sample took a concomitant medication. Over half had at least one of concomitant medication polypharmacy, pharmacokinetic or pharmacodynamic interaction. Concomitant medication use was associated with several adverse clinical outcomes.

Project description:Although the personality correlates of dispositional interpersonal forgiveness (forgiveness of others) have been well characterized, those of dispositional self-forgiveness are less well understood. Moreover, when the personality correlates are examined for both types of forgiveness, the comparison has been based on participants' self-report ratings on questionnaires. The current study sought to address these gaps in the literature by adopting a scenario-based approach, which has been used less frequently, especially in self-forgiveness research. A total of 160 participants read six fictional scenarios, each describing a severe transgression, from the perspective of the transgressor (self-forgiveness, n = 78) or the victim (interpersonal forgiveness, n = 82) of the transgression, and then responded to several items assessing different facets of forgiveness (avoidance, revenge, and benevolence). Participants' personality (Big Five) and explanatory style were also assessed. Consistent with prior literature, agreeableness and neuroticism generally predicted different facets of interpersonal forgiveness. These two personality traits also predicted facets of self-forgiveness, but, additionally, conscientiousness and one's tendency to internalize failure (the personal component of explanatory style) uniquely predicted self-forgiveness, especially avoidance motivations. These results point to both similarities and differences in the personality correlates of interpersonal and self-forgiveness. As a secondary, more exploratory aim, the current study compared the results from our scenario-based assessment of forgiveness to those based on a commonly used questionnaire, the Other and Self subscales of the Heartland Forgiveness Scale (HFS). As expected, the Other subscale of the HFS were associated with levels of interpersonal forgiveness assessed with our transgression scenarios, but, surprisingly, the HFS Self subscale was more strongly related to interpersonal than self-forgivess assessed with scenarios. Moreover, the Self subscale was not associated with levels of self-forgiveness assessed with transgression scenarios, except for avoidance motivations. These results suggest that scenario-based and questionnaire-based methods may capture different facts of forgiveness and cannot be used interchangeably, especially for the assessment of self-forgiveness. More generally, the current study illustrates the importance of conducting direct within-study comparisons of interpersonal and self-forgiveness as well as of different assessment methods to better understand the similarities and differences between the two types of forgiveness.

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Quantification of the Forgiveness of Drugs to Imperfect Adherence.

Publications

Quantification of the Forgiveness of Drugs to Imperfect Adherence.

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