Isoniazid and rifampicin exposure during treatment in drug-susceptible TB
Onno W. Akkerman, Regina Dijkwel, Huib A.M. Kerstjens, Tjip S. van der Werf, Shashikant Srivastava, Marieke G. G. Sturkenboom, Mathieu S. Bolhuis
Abstract
BACKGROUND: Observational real-world studies on therapeutic drug monitoring (TDM) in relation to pharmacokinetic (PK) target values are lacking. This study aims to describe the PK of rifampicin (RIF) and isoniazid (INH) in a real-world setting of patients with drug-susceptible TB in relation to frequently used threshold values. METHODS: A total of 116 patients with TB using standard doses of RIF and INH and who had TDM as part of clinical care were included. Maximum plasma concentration (C max ) and 24 h area under the concentration time curve (AUC 24 ) at standard and revised doses were described in relation to the threshold values (C max ≥8 mg/L for RIF and ≥3 mg/L for INH). RESULTS: For RIF (100 patients), median C max and median AUC 24 were respectively 7.9 mg/L (IQR 6.0–11.0) and 35.8 mg*h/L (IQR 27.4–57.3) at the first TDM measurement after a standard dose of 600 mg. For INH (90 patients), median C max and median AUC 24 were respectively 2.9 mg/L (IQR 1.3–2.5) and 12.5 mg*h/L (IQR 8.7–18.9) at the first TDM after a standard dose 300 mg. Overall, more than 50% of study participants had drug exposure below threshold values at the first TDM. CONCLUSION: Our study shows that the measured C max values for both RIF and INH were frequently below the pre-specified targets, emphasising the need for better justification of drug exposure targets. These TDM results highlight the need for validating PK targets of anti-TB drugs associated with clinically relevant outcomes.