Bridging to Paediatric Dosing: Relative Bioavailability of Suspended Rifapentine and Isoniazid in an Open-Label Randomized Trial in Adults on Tuberculosis Preventive Therapy.

BACKGROUND AND

OBJECTIVES

The use of the 12-dose, once-weekly, rifapentine-based (3HP), short-course tuberculosis preventive treatment (TPT) in children has been limited due to a lack of child-friendly rifapentine formulations. In this study, we compared the relative bioavailability of rifapentine and isoniazid when suspended in water versus whole tablets, using generic adult formulations.

METHODS

We assessed the relative bioavailability of non-dispersible rifapentine and isoniazid adult tablets suspended in water compared with whole tablets. Adults with a positive tuberculosis infection test were randomized 1:1:1 to receive two of three rifapentine/isoniazid formulations in separate treatment sequences, including two generic brands of fixed-dose combinations and standalone tablets of rifapentine and isoniazid. Participants received either whole tablets swallowed or tablets suspended in water at a dose of 900 mg for each drug once weekly over 12 weeks with intensive pharmacokinetic sampling up to 48 h post-dose. Nonlinear mixed-effects modelling was used to compare the relative bioavailability of suspended versus whole tablets, with 90% confidence intervals (CI) evaluated against the standard bioequivalence range (80-125%).

RESULTS

In 24 participants, a one-compartment model described rifapentine data well. A two-compartment model with a mixture component for fast/intermediate and slow acetylators best described isoniazid. Rifapentine and isoniazid demonstrated similar bioavailability across all dosing forms, meeting formal bioequivalence criteria. The absorption rates for suspended tablets were faster than those for whole tablets by 22.2% (90% CI 12.4-30.8) for rifapentine and 35% (90% CI 26.1-42.6) for isoniazid.

CONCLUSION

Both rifapentine and isoniazid, whether in fixed-dose combinations or as standalone, showed similar bioavailability when administered as whole tablets or suspended in water. These findings support dosing in children and other populations without the need to adjust rifapentine or isoniazid doses, thereby supporting broader access to the 3HP regimen.

PAN AFRICAN CLINICAL TRIALS REGISTRY: PACTR202306775627089, registration date June 15, 2023.