The quest to deliver high-dose rifampicin: can the inhaled approach help?

ABSTRACT

Introduction

Tuberculosis (TB) is a global health problem that poses a challenge to global treatment programs. Rifampicin is a potent and highly effective drug for TB treatment; however, higher oral doses than the standard dose (10 mg/kg/day) rifampicin may offer better efficacy in TB treatment.

Areas covered

High oral dose rifampicin is not implemented in anti-TB regimens yet and requires about a 3-fold increase in dose for increased efficacy. We discuss inhaled delivery of rifampicin as an alternative or adjunct to oral high-dose rifampicin. Clinical results of safety, tolerability, and patient compliance with antibiotic dry powder inhalers are reviewed.

Expert opinion

Clinical trials suggest that an approximately 3-fold increase in the standard oral dose of rifampicin may be required for better clinical outcomes. On the other hand, animal studies suggest that inhaled rifampicin can deliver a high concentration of the drug to the lungs and achieve approximately double the plasma concentration than that from oral rifampicin. Clinical trials on inhaled antibiotics suggest that dry powder inhalation is a patient-friendly and well-tolerated approach in treating respiratory infections compared to conventional treatments. Rifampicin, a well-known anti-TB drug given orally, is a good candidate for clinical development as a dry powder inhaler.

KEYWORDS:

• Rifampicin
• dry powder inhaler
• high dose rifampicin
• tuberculosis
• clinical trial
• safety
• tolerability
• DPI

Article highlights

• The current standard dose of oral rifampicin is not optimal for treatment of tuberculosis and higher oral doses have showed promising results in clinical trials.

• Higher oral doses of rifampicin, although promising in reducing treatment duration, have not been implemented in TB treatment regimens.

• Pulmonary delivery of rifampicin can be an adjunct or an alternative to oral standard rifampicin, and has the potential to achieve the goals of oral high-dose rifampicin with a smaller dose and possibly less systemic toxicity.

• A review of clinical studies on inhaled antibiotic dry powder formulations discusses the safety, tolerability and patient adherence of inhaled antibiotic therapy and the potential of inhaled rifampicin against TB.

Abbreviations

AUC	=	Area under the plasma concentration-time curve
Cmax	=	Maximum plasma concentration
CF	=	Cystic fibrosis
COPD	=	Chronic Obstructive Pulmonary Disease
DPI	=	Dry powder inhaler
FEV1	=	Forced expiratory volume in 1 sec
HIV	=	Human immunodeficiency virus
HV	=	Healthy volunteer
MDR-TB	=	Multidrug resistant TB
MIC	=	Minimum inhibitory concentration
MRSA	=	Methicillin resistant Staphylococcus aureus
Mtb	=	Mycobacterium tuberculosis
NCFB	=	Non-Cystic Fibrosis Bronchiectasis
NOAEL	=	No observed adverse effect level
PK/PD	=	Pharmacokinetics/Pharmacodynamics
Tmax	=	Time to Cmax
TB	=	TuberculosisXDR-TB: Extremely drug resistant TB
WHO	=	World Health Organization

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was funded by Health Research Council of New Zealand (ID: 22/184).