Rifampicin, a key drug in tuberculosis (TB) treatment, can be tolerated at
much higher doses than used in current clinical practice – suggesting that much
higher drug levels may lead to a more rapid treatment response, allowing the
treatment course to be shortened without the need for new drugs in first-line
treatment, according to findings presented at the 20th Conference on
Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta this week.
Rifampicin is used at a dose of 600mg per day throughout the six-month TB treatment course. Yet the maximum-tolerated dose of rifampicin has
never been defined. When the drug was being developed in the 1960s, it was
extremely expensive to synthesise, and on the basis of anecdotal reports it was
also assumed at the time that the toxicities of the drug were likely to be
dose-related. This led investigators to settle on a dose of 600mg as adequate
to achieve minimum inhibitory concentrations for 24 hours. Indeed, early
studies of short-course treatment either limited the dose and duration of
rifampicin treatment, or avoided use of the drug altogether, in order to test
regimens that would be affordable in low-resource settings.
A literature review
by Martin Boeree and colleagues at the St Radboud University, Nijmegen,
subsequently found that there was little evidence to support assumptions about
dose-related toxicity. Furthermore, they argued that previous investigators had
made the wrong assumption about the most relevant pharmacokinetic parameter for
assessment in studies of rifampicin as a TB treatment. Rather than looking at
the ratio of the trough level (Cmin) to the minimum inhibitory
concentration, which shows whether adequate blood levels are maintained
throughout a 24-hour period, Boeree and colleagues argued that what mattered
was the total drug exposure achieved during a 24-hour period. Higher total drug
exposure would be more likely to reduce bacterial load, and higher peak
concentrations would be needed to inhibit bacterial replication in epithelial
fluids within the lungs.
The study, conducted by Boeree and colleagues in the PanACEA
consortium in South Africa, recruited people with smear-positive TB in five
consecutive groups, each of which received a higher dose of rifampicin for the
first seven days of TB treatment, after which isoniazid, pyrazinamide and
ethambutol were added for a further seven days. The first group received a dose
of 10mg/kg, and subsequent groups received 20, 25, 30 or 35 mg/kg doses. Dose
increments were approved after reviewing data on adverse events in each cohort
of patients. All participants received rifampicin in combination with standard
doses of isoniazid, ethambutol and pyrazinamide.
The study measured rifampicin levels at days 7 and 14 of
treatment. Mycobacterium tuberculosis colony-forming units were measured by
culture on solid media at baseline and days 1 to 7, and days 12 and 14. Time to
culture positivity was measured in liquid media at the same time intervals.
Rifampicin was well-tolerated at higher doses, with no grade
4 adverse events and only four grade 3 adverse events reported, with no
association between increasing dose and incidence of grade 3 events. On the
basis of these results, the researchers concluded that they had failed to
identify a maximum tolerated dose, and research will now go forward to test a
35mg dose for safety and efficacy in a phase II study, and to test doses of 40
and 45mg for safety.
There was also a significant trend towards a reduced
number of colony-forming units of m.TB at higher doses, and a sevenfold increase
in total rifampicin exposure at the highest dose when compared to the standard
dose. This increase in exposure was disproportionate to the increase in dose.
However, very substantial variations in exposure were seen between individuals
at each dose, indicating that pharmacogenomic factors such as genetic markers
for rapid clearance of rifampicin will require attention in future research
into the optimisation of TB regimens.
Another factor that will require attention is the
interaction between rifampicin and the anti-HIV drug efavirenz (Sustiva, Stocrin, also in the combination drug Atripla). At a dose of 600mg, the effect of
rifampicin on efavirenz levels is enough to persuade US physicians that the
efavirenz dose should be increased to 800mg. What is unclear at present is
whether the increase in rifampicin exposure is accompanied by a corresponding increase
in the induction of efavirenz metabolism, or whether this effect hits a plateau
at some point, beyond which the efavirenz dose would not need to be increased