Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors

Caffeine citrate is the drug of choice for the pharmacological treatment of apnea of prematurity. Factors such as maturity and genetic variation contribute to the interindividual variability in the clinical response to caffeine therapy in preterm infants, making the optimal dose administered controversial. Moreover, the necessity for therapeutic drug monitoring (TDM) of caffeine is still worth discussing due to the need to achieve the desired target concentrations as well as concerns about the safety of higher doses. Therefore, we reviewed the pharmacokinetic profile of caffeine in preterm infants, evidence of the safety and efficacy of different doses of caffeine, therapeutic concentration ranges of caffeine and impact of genetic variability on caffeine therapy. Whereas the safety and efficacy of standard-dose caffeine have been demonstrated, evidence for the safety of higher administered doses is insufficient. Thus, preterm infants who lack clinical response to standard-dose caffeine therapy are of interest for TDM when dose optimization is performed. Polymorphisms in pharmacodynamics-related genes, but not in pharmacokinetics-related genes, have a significant impact on the interindividual variability in clinical response to caffeine therapy. For preterm infants lacking clinical response, how to develop individualized medication regimens for caffeine remains to be explored.

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Therapeutic Drug Monitoring of Risperidone Using a New, Rapid HPLC Method: Reappraisal of Interindividual Variability Factors

Therapeutic Drug Monitoring ◽

10.1097/00007691-199902000-00017 ◽

1999 ◽

Vol 21 (1) ◽

pp. 105-115 ◽

Cited By ~ 91

Author(s):

Androniki E. Balant-Gorgia ◽

Marianne Gex-Fabry ◽

Chantal Genet ◽

Luc P. Balant

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Interindividual Variability ◽

Hplc Method ◽

Therapeutic Drug

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The Effect of Therapeutic Drug Monitoring on Safety and Efficacy of Voriconazole in Invasive Fungal Infections: A Randomized Controlled Trial

Clinical Infectious Diseases ◽

10.1093/cid/cis599 ◽

2012 ◽

Vol 55 (8) ◽

pp. 1080-1087 ◽

Cited By ~ 211

Author(s):

Wan Beom Park ◽

Nak-Hyun Kim ◽

Kye-Hyung Kim ◽

Seung Hwan Lee ◽

Won-Seok Nam ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Fungal Infections ◽

Controlled Trial ◽

Invasive Fungal Infections ◽

Therapeutic Drug ◽

Safety And Efficacy ◽

Randomized Controlled

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Use of Saliva in Therapeutic Drug Monitoring of Caffeine in Preterm Infants

Therapeutic Drug Monitoring ◽

10.1097/00007691-200106000-00011 ◽

2001 ◽

Vol 23 (3) ◽

pp. 250-254 ◽

Cited By ~ 24

Author(s):

Saskia N. de Wildt ◽

Katja T. M. Kerkvliet ◽

Muriël G. A. Wezenberg ◽

Sabine Ottink ◽

Wim C. J. Hop ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Preterm Infants ◽

Drug Monitoring ◽

Therapeutic Drug

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Interindividual variability in TPMT enzyme activity: 10 years of experience with thiopurine pharmacogenetics and therapeutic drug monitoring

Pharmacogenomics ◽

10.2217/pgs.14.32 ◽

2014 ◽

Vol 15 (6) ◽

pp. 745-757 ◽

Cited By ~ 38

Author(s):

Laurent Chouchana ◽

Celine Narjoz ◽

Denis Roche ◽

Jean-Louis Golmard ◽

Brigitte Pineau ◽

...

Keyword(s):

Enzyme Activity ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Interindividual Variability ◽

Therapeutic Drug ◽

Years Of Experience

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The First WHO International Standard for Adalimumab: Dual Role in Bioactivity and Therapeutic Drug Monitoring

Frontiers in Immunology ◽

10.3389/fimmu.2021.636420 ◽

2021 ◽

Vol 12 ◽

Author(s):

Meenu Wadhwa ◽

Chris Bird ◽

Eleanor Atkinson ◽

Isabelle Cludts ◽

Peter Rigsby

Keyword(s):

Life Cycle ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Life Cycle Management ◽

World Health ◽

Therapeutic Drug ◽

Expert Committee ◽

Safety And Efficacy ◽

International Standard ◽

Tnf Α

The expanded availability of adalimumab products continues to widen patient access and reduce costs with substantial benefit to healthcare systems. However, the long-term success of these medicines is highly dependent on maintaining consistency in quality, safety and efficacy while minimizing any risk of divergence during life-cycle management. In recognition of this need and demand from global manufacturers, the World Health Organization (WHO) Expert Committee on Biological standardization established the WHO 1st International standard (IS) for Adalimumab (coded 17/236) in October 2019 with a defined unitage ascribed to each of the individual bioactivities evaluated in the study namely, TNF-α binding, TNF-α neutralization, complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity. For development of the IS, two candidate standards were manufactured as per WHO recommendations. Analysis of extensive datasets generated by testing of a common set of samples including the candidate standards by multiple stakeholders including regulatory agencies using their own qualified assays in a large international collaborative study showed comparable biological activity for the tested candidates for the different activities. Use of a common standard significantly decreased the variability of bioassays and improved agreement in potency estimates. Data from this study clearly supports the utility of the IS as an important tool for assuring analytical assay performance, for bioassay calibration and validation, for identifying and controlling changes in bioactivity during life-cycle management and for global harmonization of adalimumab products. In addition, in a separate multi-center study which included involvement of hospital and clinical diagnostic laboratories, the suitability of the adalimumab IS for therapeutic drug monitoring assays was examined by analysis of data from testing of a common blind coded panel of adalimumab spiked serum samples representative of the clinical scenario along with the IS and in-house standards in diverse immunoassays/platforms. Both commercially available and in-house assays that are routinely used for assessing adalimumab trough levels were included. Excellent agreement in estimates for adalimumab content in the spiked samples was observed regardless of the standard or the method with inter-laboratory variability also similar regardless of the standard employed. This data, for the first time, provides support for the extended applicability of the IS in assays in use for therapeutic drug monitoring based on the mass content of the IS. The adalimumab IS, in fulfilling clinical demand, can help toward standardizing and harmonizing clinical monitoring assays for informed clinical decisions and/or personalized treatment strategies for better patient outcomes. Collectively, a significant role for the adalimumab IS in assuring the quality, safety and efficacy of adalimumab products globally is envisaged.

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Systematic Therapeutic Drug Monitoring for Linezolid: Variability and Clinical Impact

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00687-17 ◽

2017 ◽

Vol 61 (10) ◽

Cited By ~ 9

Author(s):

Alicia Galar ◽

Maricela Valerio ◽

Patricia Muñoz ◽

Luis Alcalá ◽

Xandra García-González ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Adverse Events ◽

Hospital Mortality ◽

Drug Monitoring ◽

Interindividual Variability ◽

Clinical Impact ◽

Therapeutic Drug ◽

Serum Trough ◽

Trough Levels ◽

Wide Interindividual Variability

ABSTRACT Linezolid serum trough (C min) and peak (C max) levels were determined prospectively in 90 patients. Adequate exposure was defined as a C min of 2 to 8 mg/liter. Therapy was empirical (73.3%) or targeted (26.7%). Wide interindividual variability in linezolid C min levels was recorded (0.1 to 25.2 μg/ml). Overall, 65.5% of the patients had out-of-range, 41.1% had subtherapeutic, and 24.4% had supratherapeutic trough levels. We did not find a correlation between abnormal levels and adverse events, in-hospital mortality, or overall poor outcome.

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Prospective investigations of concentration–clinical response for immunosuppressive drugs provide the scientific basis for therapeutic drug monitoring

Clinical Chemistry ◽

10.1093/clinchem/44.2.381 ◽

1998 ◽

Vol 44 (2) ◽

pp. 381-387 ◽

Cited By ~ 1

Author(s):

Leslie M Shaw ◽

Bruce Kaplan ◽

Kenneth L Brayman

Keyword(s):

Therapeutic Drug Monitoring ◽

Clinical Response ◽

Drug Monitoring ◽

Immunosuppressive Drugs ◽

Scientific Basis ◽

Therapeutic Drug ◽

Controlled Clinical Trial ◽

Target Drug ◽

Drug Concentrations ◽

The Individual

Abstract The performance of prospective concentration–clinical response investigations during the early stages of the development of new therapeutic agents can provide a more rigorous basis for therapeutic drug monitoring than the traditional retrospective review of drug concentrations vs clinical outcome. Here we discuss the application of the multicenter randomized concentration-controlled clinical trial study design, and related study designs, as applied to older commonly used and monitored drugs and to two new immunosuppressant drugs, mycophenolate mofetil and tacrolimus. Such studies can provide a more rigorous basis for assessing the risk/benefit associated with a target drug concentration in the individual patient and for designing future prospective pharmacokinetic and therapeutic drug monitoring investigations.

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