Prakash Khadka1, Shubhra Sinha2, Ian G. Tucker1, Jack Dummer3, Philip C. Hill4, Rajesh Katare2 & Shyamal C. Das1
1School of Pharmacy, University of Otago, Adams Building, 18 Frederick Street, P.O. Box 56, Dunedin 9054, New Zealand
2Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 270 Great King Street, P.O. Box 913, Dunedin 9054, New Zealand
3Department of Medicine, Dunedin School of Medicine, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand
4Centre for International Health, Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand
Summary
Despite several studies on inhaled rifampicin in the literature, there have been no reports on the in vivo safety and pharmacokinetics of high-dose (>20 mg/kg) inhaled rifampicin. A high-dose of rifampicin is necessary to achieve drug high concentration in the lungs and the systemic circulation to treat both pulmonary and extra-pulmonary TB. While the use of high-dose of rifampicin from the oral route is associated with increased risk of toxicity including hepatotoxicity, the pulmonary delivery is an alternative approach to achieving higher drug concentration in the lungs and the systemic circulation with a lower dose than that from oral route. In this study, high-dose amorphous and crystalline powder formulations were prepared and characterized in vitro. Then, the safety and pharmacokinetics of rifampicin were studied after repeated administration to Sprague Dawley rats by intra-tracheal insufflation once daily for seven days. Among the powder formulations prepared, the amorphous and the crystalline dihydrate formulation showed better aerosolization stability compared to the crystalline pentahydrate formulations and were selected for further in vivo evaluations. Repeated intra-tracheal administration of high-dose rifampicin powder formulations (50 mg/kg) were well tolerated by laboratory rats and were safe to the lungs and the liver. The intra-tracheal administration of rifampicin achieved significantly higher area under the plasma concentration-time curve (AUC) compared to that from oral rifampicin at the same dose. Inhaled administration of high-dose rifampicin, therefore, has the potential to achieve higher systemic bioavailability than oral rifampicin and can be beneficial in improving TB treatment.
Key Message
Intra-tracheal administration of rifampicin results in significantly higher systemic drug bioavailability compared to the oral rifampicin at the same dose suggesting the potential of inhaled rifampicin in achieving better therapeutic effects in TB treatment.