Limited sampling strategy for predicting isoniazid exposure in patients with extrapulmonary tuberculosis

Area of Science:

• Pharmacokinetics and Therapeutic Drug Monitoring
• Tuberculosis Treatment and Management
• Population Pharmacokinetics

Background:

• Limited sampling strategies (LSS) are valuable for predicting drug exposure, specifically the area under the concentration-time curve (AUC).
• Isoniazid pharmacokinetics and LSS development are scarce in South-Mediterranean populations, particularly for extrapulmonary tuberculosis.
• Accurate prediction of isoniazid AUC is crucial for optimizing treatment efficacy and minimizing toxicity.

Purpose of the Study:

• To develop and validate a convenient and accurate limited sampling strategy (LSS) for predicting isoniazid's 24-hour AUC.
• To evaluate the performance of different LSS models in Tunisian patients with extrapulmonary tuberculosis.
• To establish a practical method for therapeutic drug monitoring of isoniazid in this specific population.

Main Methods:

• Pharmacokinetic data were collected from 25 Tunisian patients with extrapulmonary tuberculosis, with six blood samples drawn per 24-hour dosing interval.
• Area under the curve (AUC) was calculated using the linear trapezoidal rule, and isoniazid concentrations were correlated with AUC via linear regression.
• Predictive performance of various LSS models was assessed using error indices (e.g., %MAE, %RMSE) and Bland-Altman/mountain plot analyses.

Main Results:

• A 1-time-point LSS using C3 concentration (isoniazid level at 3 hours) showed high correlation (r² = .906) with measured AUC.
• A 2-time-point LSS combining C2 and C6 concentrations yielded the highest correlation (r² = .960) and lowest prediction error.
• The C0/C3 LSS model demonstrated satisfactory accuracy (r² = .930), and a 3-time-point model (C0, C1, C6) achieved the best prediction (r² = .992).

Conclusions:

• The C0/C3 limited sampling strategy (LSS) provides a reliable, accurate, and practical method for estimating isoniazid AUC in Tunisian extrapulmonary tuberculosis patients.
• A single-time point LSS using C3 concentration is a viable alternative for clinical practice due to its acceptable accuracy and practicality.
• The findings support the implementation of LSS for therapeutic drug monitoring of isoniazid, enhancing treatment management in similar populations.