Rifapentine
Paula Mckenzie MDa, Kristen Fuhrmann Pharm Db, David Sotello MDc,
Vipul Desai MDd, Richard Winn MDd
Correspondence to Paula McKenzie MD.
Email: paula.mckenzie@ttuhsc.edu
+ Author Affiliation
- Author Affiliation
a a fellow in Infectious Disease at TTUHSC in Lubbock, TX.
b a resident in Internal Medicine at TTUHSC in Lubbock, TX.
c a pharmacist at University Medical Center in Lubbock, TX.
d infectious disease specialists at TTUHSC in Lubbock, TX.
SWRCCC 2014;2(7):46-48
doi: 10.12746/swrccc2014.0207.092
...................................................................................................................................................................................................................................................................................................................................
Overview
Tuberculosis (TB) continues to be a global burden,
and with its link to HIV and associated morbidity,
the search continues for effective and convenient
therapy. Traditional directly-observed therapy (DOT)
and self-supervised therapy are cumbersome and often
associated with poor completion and compliance
rates. Recent studies on intermittent treatment regimens
have better identified patient populations who
are appropriate candidates for once or twice-weekly
therapy.
1,2
Rifapentine (RPT), marketed under the brand
name Priftin, is a rifamycin-class antibiotic. Rifamycin
antimycobacterials include rifampin, rifabutin, and rifapentine,
which are often used in combination with
other antimicrobials to treat TB.
3 According to the Sanford
Guide the RPT dosage is 600 mg by mouth twice
weekly for two months in combination with isoniazid
(INH), pyrazinamide, and ethambutol in immunocompetent
patients and then 600 mg once weekly for four
months in combination with INH for drug susceptible
TB. The American Thoracic Society/Centers for Disease
Control/Infectious Diseases Society of America
(ATS/CDC/IDSA) recommend that it be used in the
continuation phase or for latent TB.
RPT should not be used as monotherapy for
treatment of TB disease since mutational resistance
can emerge quickly. It is not recommended in children
under 12, in pregnant or lactating women, in individuals with culture negative or extra pulmonary
tuberculosis, or in patients with cavitary TB.
3,4
Currently the CDC recommends INH-RPT
regimens for 12 weeks as DOT doses as an equally
effective alternative to nine months of daily self-supervised
INH treatment for treating latent TB infections
in patients older than 12 who have a high likelihood
of developing TB. This includes patients who
are HIV positive, otherwise healthy, and not on retroviral
therapy.
4 INH-RPT intermittent regimens are not
recommended for HIV-infected patients who are on
antiretroviral therapy, as drug interactions have not been studied.
2,4
Chang, et al. summarized three studies (two
retrospective cohort analyses and one systematic review
and meta-analysis) on the impact and efficacy
of intermittent dosing in HIV-related TB. They concluded
that intermittent treatment, in the initial phase
of the disease, was associated with a higher risk of
treatment failure, relapse, and acquired rifamycin resistance.
Therefore, intermittent dosing is not recommended
in the initial phase of HIV-related TB (IA recommendation).
5
Martinson and colleagues conducted an
open-label, randomized trial comparing RPT (900
mg) plus INH (900 mg) once weekly for 12 weeks,
rifampin (600 mg) plus INH (900 mg) twice weekly for
12 weeks, continuous INH (300 mg) daily for the duration
of the study (<6 years), and a control regimen
of INH (300 mg) daily for six months. The primary end
point was tuberculosis-free survival. The study concluded
that rifamycin-based preventive treatment has
similar, but not superior, efficacy to the six months of
INH.6 For both HIV positive and HIV negative patient
population, completion rates are higher in INH-RPT
intermittent treatment groups and permanent drug
discontinuation rates were also lower among those in
the INH-RPT treatment group. Discontinuation due to
hepatotoxicity was lower in the INH-RPT group compared
to INH (0.3% vs. 2.0%).
6
Adverse reactions, contraindications,
drug interactions
Significant adverse reactions include hyperuricemia,
hypertension, headache, nausea, diarrhea,
rash, hematuria, neutropenia, elevated liver enzymes,
arthralgia, and hemoptysis. Prolonged use may result
in fungal or bacterial super infection, including C. difficile
associated diarrhea. RPT may also worsen porphyria
and can redden secretions, including urine and
tears.2,4
RPT is contraindicated in HIV positive patients
for treatment of TB disease due to the unacceptable
high rate of failure due to acquired mutational
resistance and lack of studies with concurrent
anti-retroviral therapy. Patients should be counseled
that compliance is absolutely necessary. Rifapentine
is contraindicated if there is evidence or a history of
hypersensitivity to RPT, rifampin, rifabutin, or any rifamycin
analog. Caution should be used in patients with
hepatic impairment, and liver enzymes and bilirubin
should be measured prior to therapy in patients with
possible liver disease. Furthermore, liver enzymes
and bilirubin should be monitored every two- four
weeks during therapy, and if there is any evidence
of hepatitis or unacceptable elevation in the liver enzymes
or bilirubin, it should be discontinued immediately.
3,4
Similar to other rifamycins, RPT induces metabolism
of many medications, specifically medications
primarily metabolized by cytochrome P450 isoenzymes
3A4, 2C8 and 2C9.2 Careful monitoring of
drugs with narrow therapeutic windows (e.g., warfarin,
phenytoin) is important while patients are on rifapentine
therapy. Women who take hormonal birth control should be counseled to use a barrier back up method
while on RPT. It is contraindicated with concurrent
antiretroviral therapy, as these interactions have not
been studied. RPT is a pregnancy category C drug,
and teratogenic effects have been observed in animal
reproduction studies. The CDC does not currently
recommend rifapentine as part of the treatment regimen
due to insufficient data in pregnant woman.4
Mechanism of action
RPT inhibits the initiation of chain formation
for RNA synthesis by inhibiting DNA-dependent RNA
polymerase in susceptible strains of Mycobacterium
tuberculosis (MTB). It is bactericidal against both intracellular
and extracellular bacilli. MTB resistant to
other rifamycins, including rifampin, is almost always
resistant to rifapentine. Cross-resistance does not
appear between rifapentine and other non-rifamycin
anti-mycobacterial agents.2
Pharmacokinetics
RPT is well absorbed and attains a mean
area under the curve of 325 mcg/hr/ml after a 600
mg dose. It is highly protein bound (93-97%) and is
metabolized by the liver. It is excreted approximately
70% through the bile and 17% through the urine and
has a half-life of 16-19 hours. The time to peak concentration
in serum is five-six hours.2 In vitro studies
show that there is a significant post-antibiotic effect
(PAE) observed with the rifamycins, supporting their
use in intermittent treatment regimens. Due to this
PAE, intermittent exposure (a few hours) to RPT can
suppress mycobacterial growth for several days.4 The
free peak concentration (Cpeak) to the minimum inhibitory
concentration (MIC) ratio correlates best with the
PAE and the suppression of resistance. This concentration-
dependent activity suggests that high doses
given at longer intervals are likely more effective than
smaller doses given as daily therapy. RPT is metabolized
to an active metabolite 25-desacetyl rifapentine
which extends its activity profile.4,6
Recent large randomized controlled clinical trials
In 1995-1998 a randomized multicenter trial of
non-HIV infected patients with pulmonary tuberculosis
was done in South Africa and North America; one
group received RPT twice weekly (with INH, pyrazinamide
and ethambutol daily) and the other received
rifampin daily (with INH, pyrazinamide and ethambutol
daily). Although the relapse rate was slightly
higher in the RPT arm, the development of resistance
was lower.2 RPT is given with INH during the continuation
phase for treatment of drug susceptible pulmonary
tuberculosis after being treated with rifampin (or
rifabutin), INH, pyrazinamide and ethambutol for two
months. US national guidelines do not recommend
RPT use in the intensive phase.
In latent tuberculosis infections RPT plus INH
or moxifloxacin given for three months once weekly
was as effective as INH for six to nine months given
daily.3
Keypoints
- RPT is used in the continuation phase in noncavitary drug susceptible pulmonary tuberculosis.
- RPT is a long acting drug that can be administered
once weekly with INH for latent TB infection
and during the continuation phase of active
TB.
- Rifapentine is not recommended in HIV positive
patients with active TB infection due to its high
relapse rate, development of resistance, and the
lack of studies examining concurrent anti-retroviral
therapy.
References
- Weiner M, Burman W, Vernon A, Benator D, et al. Low isoniazid
concentrations and outcome of tuberculosis treatment with
once-weekly isoniazid and rifapentine. Am J Respir Crit Care
Med 2003; 167: 1341-1347.
- Bock N, Sterling T, Hamilton CD, et al. A prospective, randomized,
double-blind study of the tolerability of rifapentine
600, 900, and 1,200 mg plus isoniazid in the continuation phase
of tuberculosis treatment. Am J Respir Crit Care Med 2002; 165:
1526-30.
- Sterling TR, Villarino ME, et al. Three months of rifapentine
and isoniazid for latent tuberculosis infection. N Engl J Med 2011; 365: 2155-66
- CDC. Recommendations for use of an isoniazid-rifapentine
regimen with direct observation to treat latent Mycobacterium
tuberculosis infection. MMWR 2011; 60(48): 1650-3.
- Chang KC, Leung CC, Grosset J, Yew WW. Treatment of tuberculosis
and optimal dosing schedules. Thorax 2011; 66: 997-
1007.
- Martinson NA, Barnes GL, Moulton LH, et al. New regimens
to prevent tuberculosis in adults with HIV infection. N Engl J
Med 2011; 365: 11-20.
- Munsiff SS, Kambilli C, Ahuja SD. Rifapentine for treatment
of pulmonary tuberculosis. Clin Infect Dis. 2006; 43: 1468-75.
...................................................................................................................................................................................................................................................................................................................................
Received: 12/10/2014
Accepted: 07/11/2014
Reviewers: David Griffith MD
Published electronically: 07/15/2014
Conflict of Interest Disclosures: none
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