Understanding the time course of pharmacological effect: a PKPD approach

Wright, Daniel F. B.; Winter, Helen; Duffull, Stephen B.

doi:10.1111/j.1365-2125.2011.03925.x

Cited by 78 publications

(65 citation statements)

References 38 publications

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“…Population analysis (also known as nonlinear mixed effects modeling) is the application of a pharmacostatistical modeling technique to describe the average response in a population as well as identify the sources of variability in response. [15][16][17][18] Response refers to either changes in the concentrations (PK) or pharmacological effect (PD) of the drug over time. A pharmacostatistical model consists of three components: a structural model that describes the response for a typical (average) individual; and two distinct statistical models that describe the variability between individuals and the remaining unexplained residual variability.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

Ravva

Gastonguay

Faessel

et al. 2014

Nicotine &Amp; Tobacco Research

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Introduction: Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2 mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2-compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response "kinetics. " Response was described as the net effect of the baseline, placebo, and drug responses. Results: Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time-course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. Conclusions: Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4 hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

Ravva

Gastonguay

Faessel

et al. 2014

Nicotine &Amp; Tobacco Research

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“…The sedating side effects of drugs used for PRNs are why the drugs are being used; patients are typically agitated, not psychotic or having anaphylaxis. The pharmacokinetic/pharmacodynamic models needed to explain drug onset of action are beyond the scope of this paper 29. Suffice it to say, the pharmacokinetic measure Tmax (time to maximum plasma level) is a reasonable metric to understand the timeline of drug side effects, given that a drug’s presence in plasma is a necessary precursor to drug effect.…”

Section: Discussionmentioning

confidence: 99%

What do we really know about PRN use in agitated children with mental health conditions: a clinical review

Baker

Carlson

2018

Evid Based Mental Health

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What is the evidence that ‘pro re nata’ (PRN) medication is effective for ending agitated outbursts in children and adolescents in psychiatric emergency rooms or inpatient units? Literature search was performed for studies of PRN medication use in children and adolescents that included an outcome measure. One randomised controlled trial, three prospective studies and six retrospective studies that included some outcome measure were identified. Outcome measures were heterogeneous, and frequently did not use standardised metrics assessing agitation level to measure effectiveness. The single small Randomized Controlled Trial (RTC) does not find a difference between placebo and medication, and outcomes of other studies do not control for potential placebo effect of the intervention itself as opposed to the medication. There is insufficient evidence to support the common practice of PRN medications for the management of acute agitation, and no data with which to inform clinical practice, such as which medicines and doses are helpful for specific populations or situations. Psychiatrists have no evidence-based medication interventions for acutely managing agitated outbursts in children and adolescents.

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“…There are numerous reviews available regarding the history of population PK, 7,8 current modeling practices, [9][10][11][12][13] and introductory material on conducting and reporting analyses. [14][15][16][17][18] An excellent review is also available on interpreting the results of population PK-PD studies. 19 This review consists of three parts: first, the reader is introduced to the theoretical and practical basics of population pharmacometrics; second, representative studies on analgesic agents are examined; and third, the use of optimal design methodology to plan future studies is introduced and discussed.…”

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confidence: 98%

Population pharmacometrics in support of analgesics studies

Välitalo

Ranta

Hooker

et al. 2014

Acta Anaesthesiol Scand

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Population pharmacometric modeling is used to explain both population trends as well as the sources and magnitude of variability in pharmacokinetic and pharmacodynamics data; the later, in part, by taking into account patient characteristics such as weight, age, renal function and genetics. The approach is best known for its ability to analyze sparse data, i.e. when only a few measurements have been collected from each subject, but other benefits include its flexibility and the potential to construct more detailed models than those used in the traditional individual curve fitting approach. This review presents the basic concepts of population pharmacokinetic and pharmacodynamic modeling and includes several analgesic drug examples. In addition, the use of these models to design and optimize future studies is discussed. In this context, finding the best design factors, such as the sampling times or the dose, for future studies within pre-defined criteria using a previously constructed population pharmacokinetic model can help researchers acquire clinically meaningful data without wasting resources and unnecessarily exposing vulnerable patient groups to study drugs and additional blood sampling.

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Understanding the time course of pharmacological effect: a PKPD approach

Cited by 78 publications

References 38 publications

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

What do we really know about PRN use in agitated children with mental health conditions: a clinical review

Population pharmacometrics in support of analgesics studies

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