Theophylline TDM more necessary for elderly patients
发布日期:
2025-05-30
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Theophylline has anti-inflammatory and bronchodilatory effects and is a commonly used drug for pulmonary disorders such as chronic obstructive pulmonary disease (COPD), asthma and emphysema. However, when the concentration of theophylline drug exceeds 25 ug/ml, it can easily cause toxic symptoms such as nausea, vomiting, and cardiac arrhythmia [1]. In a Japanese survey of elderly people over 80 years of age, it was shown that the risk of toxicity caused by theophylline therapy was higher in the elderly population due to age and physiologic changes caused by combined medications [2]. It is evident that TDM should be used to control poisoning events during theophylline therapy.


This study analyzed existing Japanese database information using database and modeling and simulation (M&S) methods to investigate theophylline prescribing and side effect profiles, and assessed the effects of age, gender, drug formulation, and concomitant medications on theophylline exposure based on pharmacokinetic M&S.


Theophylline TDM more necessary for elderly patients

Methods and results

Theophylline TDM more necessary for elderly patients


This study was based on a sample from the 2020 National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), taking 1% of these patients with a clear ID number (the ID number was used to obtain information of the patient's prescription) and ensuring that the patients were balanced in terms of gender.


A total of 3973 patients were enrolled in the study and analyzed for data on gender, dosage forms, and concomitant medication by five years age group. Among the 1148 patients who had confirmed theophylline prescriptions, only 13 had ever been monitored for TDM. And, as shown in Figure 1, the most commonly administered dosage form was not 400 mg/day as a usual rule (<30.8% 200="" of="" but="" rather="" day="">53.8% of patients).

Theophylline TDM more necessary for elderly patients

Figure 1, Daily dose of theophylline in therapeutic drug monitoring and unknown group


In the association analysis of theophylline and concurrent drugs in a cohort of elderly patients over the age of 80 years, 174,172 prescriptions were studied, and 1,476 prescriptions for theophylline. Of these, fluvoxamine was reported to have the most increase in theophylline exposure (AUCR=2.38), and it was confirmed that theophylline was used concurrently in 0.31% of the patients. Among patients taking allopurinol, 2.60% were taking theophylline concurrently, and theophylline had the highest lift value of 3.03 among the precipitant drugs examined in the association analysis. 0.0687% of patients were using famotidine and theophylline concurrently, which had the highest supportive value of the precipitating drugs examined as shown in table 1.


Table 1 Association analysis of drugs influencing theophylline exposure (over 80 years old)

Theophylline TDM more necessary for elderly patients


Plasma concentrations of theophylline were analyzed in three age groups: 30, 65, and 80 years of age, in people who took fluvoxamine, or allopurinol, or famotidine at the same time as theophylline. The results showed that theophylline trough concentrations and AUCR were 1.82-fold and 1.65-fold higher, respectively, in 80-year-old patients, and 1.50-fold and 1.39-fold higher, respectively, in 65-year-old patients, compared with 30-year- young patients. The trough concentration and AUCR were 1.35 times higher in female than in male. As shown in Figure 2.


Theophylline TDM more necessary for elderly patients

Figure 2 Simulated plasma theophylline concentration–time profile in 30-, 65-, and 80-years patients. Red, AUCR = 2.38 (fluvoxamine); orange, 1.56 (famotidine); green, 1.34 (allopurinol); and blue, 1. AUCR: area under the concentration–time curve ratio. Shaded region: target range (5–20 µg/mL).


Theophylline TDM more necessary for elderly patients

Discussion

Theophylline TDM more necessary for elderly patients


This study utilizes real-world data and M&S methods to provide information on the rational use of theophylline. Since theophylline has been on the market for a long time, this provides a wealth of data on the rational use of the drug at a later stage.

Firstly from the data collected, the number of people who have explicitly been tested for TDM is only 1.13%, indicating low use in practice. This may be due to the fact that in practice, observation of clinical symptoms is usually used to adjust the dose. If symptoms are stable then TDM is not used, but in practice the various side effects of theophylline are atypical, making it difficult for long-term users to recognize the onset of side effects. Therefore TDM remains necessary.

In elderly patients there is usually a combination of medications. Any of these drugs that inhibit theophylline metabolizing enzyme (CYP1A2) may lead to high theophylline concentrations. This study lists eight commonly used comorbid drugs, all of which are inhibitors of CYP1A2. Fluvoxamine was the one that caused the highest AUCR and was the most avoided in medical practice (confidence level 0.31), but the other 7 drugs were all used more frequently (confidence level greater than 1 for all). In the study of fluvoxamine alone alone, it was seen that concomitant administration of fluvoxamine can lead to toxic plasma concentrations in patients over 80 years of age, even with low-dose theophylline use (200 mg/day). In practice, patients may even be taking multiple CYP1A2 drugs simultaneously, which necessitates vigilant testing for the risk of elevated plasma concentrations.


Theophylline TDM more necessary for elderly patients

Automated Therapeutic Drug Monitoring Platformfor Chemicals and Biologics

Theophylline TDM more necessary for elderly patients


Theophylline TDM more necessary for elderly patients


Theophylline TDM more necessary for elderly patients

Theophylline TDM more necessary for elderly patients

Reference:

1. Jenne, J.W., et al., Pharmacokinetics of theophylline. Application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther, 1972. 13(3): p. 349-60.

2. Okada, A., et al., Analysis of drug adverse events in elderly patients based on the Japanese Adverse Drug Event Report Database. J Clin Pharm Ther, 2022. 47(8): p. 1264-1269.




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