Personalized Drug Dosage – Closing the Loop

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Abstract

A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, computer-guided dosage using ‘dashboards’, and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her ‘virtual twin’ through the application of physiologically-based pharmacokinetic modeling is also discussed.

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Most cited references 36

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A randomized trial of genotype-guided dosing of warfarin.

Munir Pirmohamed, Girvan Burnside, Niclas Eriksson … (2013)

The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy. We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation. A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001). Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).

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A pharmacogenetic versus a clinical algorithm for warfarin dosing.

Stephen Kimmel, Benjamin French, Scott E Kasner … (2013)

The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

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Thinking outside the pillbox--medication adherence as a priority for health care reform.

David Cutler, Wendy Everett (2010)

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Author and article information

Contributors

Geoffrey T Tucker: g.t.tucker@sheffield.ac.uk

Journal

Journal ID (nlm-ta): Pharm Res

Journal ID (iso-abbrev): Pharm. Res

Title: Pharmaceutical Research

Publisher: Springer US (New York )

ISSN (Print): 0724-8741

ISSN (Electronic): 1573-904X

Publication date (Electronic): 9 December 2016

Publication date PMC-release: 9 December 2016

Publication date (Print): 2017

Volume: 34

Issue: 8

Pages: 1539-1543

Affiliations

ISNI 0000 0004 1936 9262, GRID grid.11835.3e, Department of Human Metabolism, Medical and Biological Sciences, , University of Sheffield, ; Sheffield, UK

Article

Publisher ID: 2076

DOI: 10.1007/s11095-016-2076-0

PMC ID: 5498646

PubMed ID: 27943015

SO-VID: a970d764-73ff-4466-af11-08ec305b4b73

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 31 October 2016

Date accepted : 29 November 2016

Funding

Funded by: University of Sheffield

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: drug dosage,personalized medicine,pharmacogenetics,physiologically-based pharmacokinetic modeling,therapeutic drug monitoring

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: drug dosage, personalized medicine, pharmacogenetics, physiologically-based pharmacokinetic modeling, therapeutic drug monitoring

Personalized Drug Dosage – Closing the Loop

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Abstract

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Drug Repurposing Research Collection

Most cited references 36

A randomized trial of genotype-guided dosing of warfarin.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

Thinking outside the pillbox--medication adherence as a priority for health care reform.

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