Alfarisi 2017

Expert Review of Clinical Pharmacology
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
Rifampin vs. Rifapentine: What is the preferred

rifamycin for tuberculosis?
Omamah Alfarisi, Wael A. Alghamdi , Mohammad H. Al-Shaer , Kelly E.

Dooley & Charles A. Peloquin
To cite this article: Omamah Alfarisi, Wael A. Alghamdi , Mohammad H. Al-Shaer , Kelly E.
Dooley & Charles A. Peloquin (2017): Rifampin vs. Rifapentine: What is the preferred rifamycin for
tuberculosis?, Expert Review of Clinical Pharmacology, DOI: 10.1080/17512433.2017.1366311
To link to this article: http://dx.doi.org/10.1080/17512433.2017.1366311
Accepted author version posted online: 14

Aug 2017.
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Download by: [Mount Sinai Health System Libraries] Date: 14 August 2017, At: 21:06
Publisher: Taylor & Francis
Journal: Expert Review of Clinical Pharmacology
DOI: 10.1080/17512433.2017.1366311
Perspective
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Rifampin vs. Rifapentine: What is the preferred rifamycin for tuberculosis?
Downloaded by [Mount Sinai Health System Libraries] at 21:06 14 August 2017
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Omamah Alfarisi1, Wael A. Alghamdi2,3, Mohammad H. Al-Shaer2,3, Kelly E. Dooley1*, and
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Charles A. Peloquin2,3
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1
Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2University of Florida,
College of Pharmacy, Department of Pharmacotherapy and Translational Research, Gainesville,

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FL, USA, 3Infectious Disease Pharmacokinetics Laboratory, University of Florida, Gainesville,
FL, USA
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*Correspondence, Proofs, and Reprint Requests: Kelly E. Dooley, Johns Hopkins University
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School of Medicine, 600 N. Wolfe Street, Osler 527, Baltimore, MD 21287, USA. Email:
kdooley1@jhmi.edu, telephone: (443) 287-0517, fax: (410) 614-9978.
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Abstract
Introduction: One-third of the world’s population is infected with Mycobacterium tuberculosis
(M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading
cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique
sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis
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treatment?
Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics
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(PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for
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comparing them.
Expert commentary: Rifampin has shorter half-life, higher MIC against M.tb, lower protein
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binding, and better distribution into cavitary contents than rifapentine. Drug interactions for the
two drugs maybe similar in magnitude. For LTBI, rifapentine is effective as convenient, once-
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weekly, 12-week course of treatment. Rifampin is also effective for LTBI, but must be given
daily for four months, therefore, drug interactions are more problematic. For drug-sensitive
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tuberculosis disease, rifampin remains the standard of care. Safety profile of rifampin is better-
described; adverse events differ somewhat for the two drugs. The registered once-weekly
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rifapentine regimen is inadequate, but higher doses of either drugs may shorten the treatment
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duration required for effective management of TB. Results of clinical trials evaluating high-dose
rifamycin regimens are eagerly awaited.

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Keywords: tuberculosis, rifapentine, rifampin, rifamycin, pharmacokinetics, pharmacodynamics

1. INTRODUCTION
Rifamycins are macrocyclic antibiotics that are derived from Amycolatopsis mediterranei
and are most commonly known for their activity against Mycobacterium tuberculosis (M.tb) [1].
They demonstrate bactericidal activity by binding to the DNA-dependent RNA polymerase,
which results in inhibition of bacterial RNA synthesis. The current rifamycins used in the
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treatment of tuberculosis include rifampin, rifapentine, and rifabutin. Although rifabutin is
frequently used in the treatment of tuberculosis when patients are co-infected with HIV and
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receiving combination antiretroviral therapy [2], its therapeutic margin is narrow (limiting
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further optimization efforts), so the focus of this article is on rifampin and rifapentine for the
treatment of latent tuberculosis infection (LTBI) or active pulmonary tuberculosis and new
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studies investigating both drugs [2-4].
Rifampin was the first rifamycin approved by the Food and Drug Administration for the
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treatment of tuberculosis, in 1971 [5]. It is considered to be the most important drug for drug-
susceptible tuberculosis. Rifampin is widely available and has been used for over 45 years, and
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thus, it has the richest data among the rifamycins. Its pharmacokinetic and pharmacodynamic
profiles are well characterized [6]. The potent induction of hepatic cytochrome P450 (CYP)
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enzymes by rifampin can make its use quite challenging [2, 7], especially when the drug
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interaction affects the plasma concentrations of antiretroviral drugs used to treat HIV infection.
In this situation, rifabutin, a less potent CYP inducer, is often used instead of rifampin.
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Rifapentine differs structurally from rifampin, having a cyclopentyl ring as a side chain
instead of a methyl group [8, 9]. This structural change affects the pharmacokinetics of
rifapentine significantly. It has higher protein binding (around 99%), and because of that protein
binding, a longer elimination half-life compared to rifampin [10]. Rifapentine was approved by
the FDA in 1998 [11]. Because of its long elimination half-life, it can be dosed once weekly
(along with isoniazid) in the treatment of latent tuberculosis [12]. An ultra-short course regimen
of four weeks of daily rifapentine plus isoniazid is now being evaluated for treatment of LTBI
[13]. With regards to tuberculosis disease, current trials are assessing daily high-dose rifapentine
as a treatment shortening strategy [14]. Higher-dose rifampin is being explored in similar fashion
[15, 16]. The central questions are whether rifapentine can and should be used instead of
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rifampin in the treatment of active TB disease [3, 7, 17]. In this review, we will discuss some of
the main studies that were conducted to evaluate the pharmacokinetics and pharmacodynamics
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(PK/PD), efficacy, and tolerability of rifampin and rifapentine for the treatment of LTBI and
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pulmonary TB, providing an overview and comparison of the two drugs based on the findings in
these studies.
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2. RIFAMPIN
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2.1 Preclinical studies
Rifampin is bactericidal against M.tb. In vitro studies demonstrated that its activity is
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concentration dependent [4, 18]. Rifampin’s minimum inhibitory concentration (MIC) is 0.125-
0.25 µg/ml against drug-susceptible M.tb in 7H12 broth [19]. It has excellent sterilizing activity,
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which means it prevents post-treatment relapses by eliminating slowly- or non-replicating,

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persisting bacilli. Those compounds remained present in the necrotic lesions even after rifampin
plasma concentrations fell below the lower limit of detection. Rifampin also delayed recovery of
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log-phase growth in vitro due to its long post-antibiotic effect (PAE), which is defined as the
continuation of the bacterial suppression after a short exposure of an antibiotic even after the
cessation of the drug [20-22]. Gumbo et al. showed that PAE is associated with the ratio of peak
concentration divided by minimal inhibitory concentration (Cmax/MIC). In their experiments,
rifampin prevented regrowth for 5.2 to 19.3 days, depending on the rifampin concentration.
Rifampin’s sterilizing activity also is dependent on the concentration. Rosenthal et al.
demonstrated this relationship in a dose-ranging study in two murine models [4]. In this model of
in-bred animals, the authors established that there was a consistent relationship between
concentration and dose. As the rifampin dose was increased, a significant increase in bactericidal
activity was shown. A stable cure was achieved in 12 weeks when the rifampin dose increased to
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40 mg/kg. However, these findings of dose-sterilizing activity relationship have not yet been
utilized to optimize the dosing in routine clinical settings.
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2.2 Basic clinical PK/PD
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2.2.1 PK and exposure-response
Rifampin exhibits non-linear kinetics, especially at high doses [23-25]. A typical rifampin
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dose of 600 mg produces a maximum concentration (Cmax) of 8-24 mg/L, and this is observed
about two hours after the dose [26]. The Cmax/MIC ratio is positively correlated with resistance
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suppression, while the parameter most closely associated with bactericidal activity is the ratio of
the area under the curve (AUC) above MIC [20]. As growing evidence from in vitro studies
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suggested that higher doses produced faster sterilizing effects [4, 20], recent and current ongoing
studies are investigating the PK and safety of higher rifampin doses to shorten the treatment
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duration of TB [6, 15, 25, 27]. A recent study compared doses of 10, 15 and 20 mg/kg dosing
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regimens during the intensive phase of TB treatment [27]. These dosing regimens produced
slightly more than proportional increases in Cmax (median 6.20, 10.18, and 13.33 mg/L,
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respectively). The high rifampin doses were well tolerated across all groups. The PanACEA
African-European consortium reported similar supra-proportional PK with increasing doses up to
35 mg/kg daily given for 14 days [15]. They found that rifampin was tolerable and safe at the
highest studied dose (35 mg/kg). While a Cmax of 8 mcg/mL is generally considered to be
‘subtherapeutic’ for rifampin, this number is largely based on population means, and target
concentrations that maximize rifampin’s sterilizing effects have yet to be elucidated.
2.2.2 Absorption, distribution, metabolism, excretion (ADME)
Rifampin is absorbed relatively quickly compared to the other rifamycins and has a
bioavailability of 68% [2]. Cmax is achieved after ~2 hours (Tmax) [2, 28]. Food can
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significantly prolong rifampin absorption (Tmax ~4 hours) and reduce Cmax by 36%. Although
the extent of absorption is not significantly affected by food (AUC reduction of 6%), the Cmax
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reduction might compromise the drug’s efficacy by decreasing this drug’s suppression of
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resistance. Therefore, rifampin should be administered on an empty stomach, where possible.
Another consideration is rifampin-containing combination products [2]. The purpose of these

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formulations is to reduce the risk of drug resistance by preventing selective drug intake.
However, the absorption of rifampin is reduced modestly when combined with isoniazid and
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pyrazinamide; thus, the rifampin dose in the Rifatur® combination product is 720 mg to account
for the differences in absorption. In addition, some patients with diabetes mellitus, cystic fibrosis
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and HIV infection experience prolonged or reduced rifampin absorption [2, 26, 29-32].
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Therefore, in such patients, therapeutic drug monitoring may be helpful to ensure the adequacy
of drug absorption and to judge whether or not a dose increase is needed. Blood samples
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collected two and six hours after the dose provide the minimum data for a clinical assessment of
drug absorption [26]. These samples capture the usual peak concentration, even when absorption
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is delayed. Two samples allow one to distinguish delayed absorption from malabsorption.
Rifampin is widely distributed to most tissues in the body [28, 33]. It has a fairly large
volume of distribution (0.7 L/kg), with protein binding of ~80%. In humans undergoing
scheduled lung resection for TB who were dosed with rifampin prior to surgery, rifampin and its
main metabolite 25-desacetyl-rifampin appeared to accumulate a in the caseum of TB
granulomas after multiple doses [34]. Rifampin has an elimination half-life of two to five hours
initially, the shortest half-life amongst rifamycins [2]. It also undergoes autoinduction (separate
from effects on cytochrome P450), and at steady state, the half-life can be as short as 1-2 hours
in some patients. Less than 25% of rifampin is renally excreted as unchanged drug. The main
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pathway of elimination is through intestinal and hepatic esterases. It is metabolized to 25-O-
desacetylrifampin, which is a partially active metabolite. Both rifampin and its metabolites are
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excreted through the biliary system, a process that can be saturated and result in a relatively
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longer half-life and non-linear kinetics with high doses [23, 35]. With multiple dosing, most
autoinduction happens within 7 days, but true steady state may take up to 40 days [2, 36] (Table
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1).
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2.3 Drug interactions (enzyme induction)
Rifampin is a potent inducer of metabolizing enzymes, and it is well-known to cause
different clinically significant drug interactions. It induces both hepatic and intestinal
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cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) transporters [37]. Among CYP
enzymes, 3A4 and 2C8/9 are most affected by rifampin induction, and such effects approach a
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maximum within 7 days of starting rifampin, and this effect persists for 7-14 days after stopping
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the medication [2, 38]. Some of the drug classes that have clinically-significant reductions in
drug concentrations (and drug effects) include cardiovascular agents, lipid lowering agents,
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antidiabetic agents, analgesics, azole antifungals, macrolides antibiotics (e.g. clarithromycin),
antiretrovirals, antiplatelet/antithrombotic agents, anticoagulants, and anticonvulsants [37, 39,
40]. It is, thus, imperative to select companion drugs cautiously in patients taking rifampin for
TB treatment, selecting those with lesser drug interaction liability, easy monitoring for toxicity,
or available TDM.
2.4 Trials of rifampin for TB disease
• 2.4.1 Efficacy
The last 50 years have brought large advances in TB treatment. Regimen duration went down
from 18 to 6 months, with improved adherence, reduced relapse, and less risk of treatment
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failure. Rifampin proved its sterilizing capacity and reduced the relapse rate significantly [41-
47]. When first introduced, the rifampin dose was 600 mg because this dose produced a total
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concentration above the mycobacterial MIC, there was concern that higher doses might cause
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more adverse reactions, and, most importantly, it was an expensive drug to manufacture and the
need for it was great [48]. However, these arguments do not hold in the modern era now that
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rifampin is inexpensive and globally available
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In one systematic review, the authors included 14 randomized clinical trials, most of them
conducted before 1980, in which rifampin doses used were >10 mg/kg (i.e. >600 mg) as part of
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combination treatment for pulmonary tuberculosis. The authors concluded that historical trials
would suggest that a higher dose of rifampin results in better culture conversion rates [6]. In the
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trial cited above comparing rifampin at doses of 10, 15, or 20 mg//kg over eight weeks, the
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proportion of patients with sputum culture conversion by two months of treatment was similar
across arms (77%, 73%, and 75%, respectively), suggesting that an increase from 10 to 20 mg/kg
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may be insufficient to shorten TB substantially. Doses even higher than 20 mg/kg daily have also
been recently tested. An open-label, phase II, multiple dose-ranging study evaluated the safety,
tolerability, pharmacokinetics, and EBA of rifampin. Sixty-eight patients received different
doses of rifampin (10, 20, 25, 30, and 35 mg/kg) for 14 days. Isoniazid, pyrazinamide, and
ethambutol were added in the second 7 days of treatment, then all patients continued the standard
treatment. In the groups with 30 and 35 mg/kg doses, EBA was the highest, and there was
nonlinear increase in exposure to rifampin. None of the patients discontinued or withdrew from
the study, and no adverse events warranted stopping the treatment [15]. In South Africa and
Tanzania, a subsequent randomized controlled trial was conducted among 365 patients who
were assigned to either 35 mg/kg/day rifampin plus 15–20 mg/kg ethambutol, 20 mg/kg/day
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rifampin plus 400 mg moxifloxacin, 20 mg/kg/day rifampin plus 300 mg SQ109, 10 mg/kg/day
rifampin plus 300 mg SQ109, or a daily standard regimen (10 mg/kg rifampin, 5 mg/kg
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isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol) in a ratio of 1:1:1:1:2.
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Experimental treatments were given with 5 mg/kg isoniazid and 25 mg/kg pyrazinamide daily
for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampin daily.
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Recruitment was stopped in the arms containing SQ109 since the prespecified efficacy
thresholds were not met at the planned interim analysis. The 35-mg/kg rifampin group showed
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faster culture conversion in liquid media than the control group (median 48 vs. 62 days,
p=0.003), but not in the other experimental groups. However, no differences were observed
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between groups in the solid media. No recurrences were reported in 35 mg/kg rifampin and
moxifloxacin groups [16]. Other trials are still investigating the higher doses of rifampin, and
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their results should be expected soon.

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• 2.4.2 Safety
Regarding the safety, flu-like syndrome and hepatotoxicity are the main concerns. The flu-
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like syndrome is experienced most commonly with high, intermittent doses of rifampin (once or
twice weekly), and less than 5% of patients have increases in aminotransferases, phosphatases,
and bilirubin, most of which are modest and diminish spontaneously despite continuing the
regimen [49, 50].

2.5 Relapse and Resistance
Some of the common reasons to develop drug-resistant TB are large bacillary population
such as in cavitary lung disease, an inadequate regimen (inappropriate drug or insufficient dose),
or failure to take the regimen [51]. For mycobacteria, the primary mechanism for resistance to
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rifampin is mutation in the rpoB gene which encodes the beta subunit of the DNA-dependent
RNA polymerase [52]; altered permeability or efflux/influx mechanism are other mechanisms
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for resistance [53]. In order to prevent resistance, patients should be treated with multiple-drug
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regimens, since monotherapy is the highway to drug resistant TB. Gumbo et al. conducted an in
vitro experiment to test rifampin’s suppression of resistance, and found that it prevented
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resistance at Cmax/MIC ratio of 175 or more. Additionally, the activity was similar among once
daily, twice per week, and once a week dosing. Rifampin was associated with lower resistant
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strains with higher Cmax/MIC ratio [20].

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2.6 Treatment of LTBI
In a Cochrane review, ten trials and 10,717 patients (2% HIV-positive) were included and
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concluded that shortened prophylactic regimens using rifampin alone have not demonstrated
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higher rates of active TB when compared to longer regimens with INH, and rifampin regimen
had higher completion rates and fewer adverse events [54]. In HIV patients, however, rifampin
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may strongly induce the metabolism of antiretroviral therapy (ART) and there might be a risk of
treatment failure. As a result, regimens should be chosen wisely in such population.
3. RIFAPENTINE
3.1 Preclinical studies

Rifapentine is a semisynthetic cyclopentyl rifampin derivative with a similar spectrum of
activity to rifampin. However, its MIC against M.tb. is 2-4 fold lower than rifampin’s, ranging
from 0.01 to 0.06 µg/ml [55]. Like rifampin, rifapentine works by selective binding to M.tb.’s
DNA-dependent RNA polymerase, but not to the polymerase in mammalian cells. Rifapentine
binds even with low enzyme activity, which is the case in dormant mycobacteria, making
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rifampin attractive for LTBI treatment [56, 57].
Rifapentine is bactericidal against extracellular organisms, and also has important intracellular
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activity, accumulating in human granulomas with intracellular/extracellular ratios of 24:1 (and
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7:1 for its 25-desacetyl metabolite). This ratio of intracellular/extracellular penetration of
rifapentine is about four to five-fold higher than that of rifampin, and may enhance its suitability
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for LTBI, depending on the location of the relatively few “latent” infecting bacilli. The MIC and
MBC of rifapentine in human monocyte-derived macrophages were two to four folds lower than
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that of rifampin [58].

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3.2 Basic clinical PK/PD
3.2.1 PK and exposure-response

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In 1999, Keung estimated the PK of rifapentine given at doses of 150, 300, and 600 mg of
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rifapentine as a single dose, after multiple doses, or with intermittent dosing. The Cmax was
found to be dose-proportional over the range tested, whereas the increase in the AUC was found
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to be less than dose-proportional (different from rifampin which displays greater than dose-
proportional PK), which was subsequently confirmed in other trials employing even higher doses
[59, 60]. The time to Cmax was observed in 4-5 hours and the half-life of the drug was found to
be about 13-14 hours. The rifapentine Cmax at a dose of 600mg sufficiently exceeded the MIC
against M.tb. and the half-life was long, supporting testing of rifapentine in intermittent fashion
in treatment trials [60]. In addition to displaying decreased bioavailability with increasing dose,
rifapentine was also shown to have reduced half-life and increased clearance with repeated
dosing, consistent with autoinduction [59]. Drug exposures could be increased with splitting the
dose or giving the drug with a high fat meal, but high doses given in this fashion were associated
with poor tolerability [61]. With regards to PK-PD relationships, a combined analysis from two
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clinical trials assessing rifapentine doses ranging from 10 to 20 mg/kg showed that microbiologic
activity increased with higher AUC, with maximal efficacy likely achieved at a dose of 1200 mg
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daily. Lower concentrations were seen in men, persons of black race, or individuals with HIV
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infection [62].
3.2.2 ADME
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The absolute bioavailability of rifapentine is not known, but the relative bioavailability of 600
mg in patients with tuberculosis compared to healthy adults was found to be ~70%. The effect of
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food, however, significantly affects rifapentine’s bioavailability, as demonstrated in several
studies. Keung reported that fat increased rifapentine bioavailability by 51% when given as
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single doses in patients who were infected with HIV [63]. Zvada et al. showed that meal type
impacted absorption; high fat meals increased the oral bioavailability of rifapentine by 86%, bulk
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low-fat meal by 33%, bulk high-fat meal by 46%, and high fluid low-fat meal by 49% [64]. The
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effect of high fat food, increasing the bioavailability of rifapentine, was confirmed in subsequent
studies [59, 62]. This is of course quite different from rifampin, whose bioavailability is highest
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in a fasting state [28].
Rifapentine is 97-99% protein-bound, mainly to albumin [10, 65]. The volume of distribution if
rifapentine in adults ranges from 70.2 +/- 9.1 L [66] and 1.4 +/- 0.81 L/kg in children
[67].Rifapentine is metabolized by arylacetamine deacetylase [68].

Clearance of rifapentine increases with increasing duration of drug exposure [69]. Savic et al.
performed population pharmacokinetic modeling of rifapentine and its main metabolite in
healthy volunteers after single versus multiple doses, over a range of doses from 450 to 1800 mg.
Clearance was demonstrated to be time-dependent, but independent of the dose given [70], in
agreement with previous work [59] (Table 1).
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3.3 Drug interactions:
Important considerations when evaluating this literature are the rifapentine dose, the frequency
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of the rifapentine dosing, and the clearance pathway of the “victim” drug. It might be expected
that once weekly rifapentine may produce less induction of cytochrome P450 and other enzyme
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systems than would daily dosing.
In a phase I study, rifapentine was found to be a potent inducer of CYP3A activity [71]. A
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subsequent study showed that rifapentine at doses of 10-20mg/kg increased the clearance of
MDZ (a CYP450 3A probe drug) 8 folds, more than a 10 mg/kg dose of rifampin [59].
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While daily rifapentine reduces the concentrations of moxifloxacin, a drug metabolized by phase
2 enzymes, significantly, thrice-weekly rifapentine reduces moxifloxacin exposures only

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modestly [72, 73], and once-weekly rifapentine has a negligible effect on moxifloxacin
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exposures [74]. Rifapentine reduces the trough concentrations of raltegravir, a drug metabolized
by UGT1A1, by about 41% with daily dosing, but this reduction is not thought to be clinically
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significant [75]. Interestingly, a study that evaluated the effect of rifapentine and rifampin on the
concentration of bedaquline, showed that rifapentine 600 mg daily resulted in 3.96 folds increase
in the clearance of bedaquiline, while rifampin 600 mg daily produced a 4.78 folds increase in
the clearance of bedaquiline [76]. While rifapentine given once-weekly does not affect
concentrations of efavirenz, an HIV drug that is a CYP2B6 substrate, the effects of daily
rifapentine on efavirenz are still under study [77].
3.4 Trials of rifapentine for TB disease
• 3.4.1 Efficacy
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Following studies in the mouse model of TB disease that showed that replacing rifampin with
rifapentine and giving rifapentine daily allowed for substantial shortening of TB treatment [78,
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79], clinical evaluations of rifapentine were revived (Table 2).
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Disappointingly, an initial study comparing rifampin and rifapentine (each at a dose of 10 mg/kg,
given five days per week on an empty stomach, together with isoniazid, pyrazinamide, and
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ethambutol) showed no improvement in microbiologic activity of rifapentine compared to
rifampin over eight weeks [3]. A subsequent dose-ranging study including 334 patients with
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sputum smear-positive pulmonary TB compared the efficacy and safety of rifapentine 10, 15, or
20 mg/kg versus rifampin 10 mg/kg daily for 8 weeks. All patients also were treated with INH,
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PZA, and ethambutol. The authors found that there was lower culture conversion to negative in
the rifampin group as compared to the rifapentine group (81.3% in rifampin group versus 92.5%
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(89.4%, and 94.7% in 10, 15, and 20 mg/kg rifapentine groups, respectively). Better activity was
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associated with higher rifapentine exposures [3, 80]. These results also showed the potential of
higher rifapentine doses to shorten treatment duration [80]. Consistent with that, one study
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showed that moxifloxacin plus low-dose rifapentine (7.5 mg/kg) had similar but not better
activity to INH and rifampin (in the context of multidrug treatment) [73].
• 3.4.2 Safety
Similar to rifampin, rifapentine may have higher risk of adverse events when given intermittently
or at high doses. [81, 82]. Unlike rifabutin which has a unique side effect (uveitis), the adverse
effects of concern for rifampin and rifapentine appear to be similar in nature and include
hepatotoxicity and rifamycin hypersensitivity syndrome. In trials of daily treatment with
rifampin versus rifapentine for TB disease, safety and tolerability seemed similar across the
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doses tested [3, 80].
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3.5 Relapse and resistance:
However, even though there is evidence that rifapentine could be as safe and effective as
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rifampin in the treatment of active TB disease, the potential problem of higher relapse rates if the
drug is insufficiently dosed is important. In an early study involving HIV-seropositive patients

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taking 600 mg rifapentine plus 900 mg INH once weekly versus 600 mg rifampin plus 900 mg
INH twice weekly during the continuation phase of TB treatment, relapse in the rifapentine
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group was associated with monoresistance to rifamycins (perhaps because of PK mismatch or
low isoniazid levels on those patients) [83]. In the same trial, an analysis combining patients with
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and without HIV infection showed that the rate of failure or relapse was 9.2% in the participants
who were given 600 mg rifapentine plus 900 mg INH once weekly compared to 5.6% in
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participants who were given 600 mg rifampin plus 900 mg INH twice weekly (p=0.04) [84]. In
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the systematic review by Gao, once weekly of rifapentine was associated with a higher risk of
relapse compared with twice or thrice weekly of rifampin [85]. In a trial done in South Africa,
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Zimbabwe, Botswana, and Zambia, enrolling 827 HIV-positives patients with newly diagnosed
tuberculosis, patients were assigned to the three arms: a) control: 2 months of, INH, rifampin,
pyrazinamide, and ethambutol followed by 4 months of daily INH and rifampin, b) 4 months of
treatment in which INH was replaced by moxifloxacin daily for 2 months followed by
moxifloxacin and 900 mg rifapentine twice weekly for 2 months, and c) 6 months treatment in
which INH was replaced by daily moxifloxacin for the first two months and 1200 mg rifapentine
and moxifloxacin are given once-weekly for the last 4 months. The six-month experimental arm
was non-inferior to the control group, suggesting that rifapentine can be given once-weekly in
the continuation phase provided the dose is high enough and the companion drug has a
sufficiently long half-life to protect against emergency of rifamycin resistance [86].
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The emergence of resistance with rifapentine is associated with a single nucleotide mutation in
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the beta subunit of the RNA polymerase gene (rpoB) [87, 88]. The degree of the mycobacterial
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resistance to rifapentine is influenced by the type and site of the amino-acid substitution that are
involved in the composition of the B-subunit. Cross-resistance between rifampin and rifapentine
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is nearly complete [89].
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3.6 Treatment of LTBI
In animal models of LTBI, 3 months’ treatment with rifapentine given with either INH or
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moxifloxacin once weekly had similar activity to daily INH given for 6 to 9 months [90].
Following on these promising animal results, large clinical trials involving intermittently-dosed
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rifapentine were conducted. In a large clinical trial in Brazil, the efficacy of weekly rifapentine
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plus INH for 12 weeks versus daily rifampin plus pyrazinamide for 8 weeks was compared in
399 household contacts of patients diagnosed pulmonary TB [91]. The authors found that both
Ac
regimens afford good protection against development of TB disease. However, the study was
stopped early due to unacceptable hepatotoxicity that was observed in the rifampin plus PZA
group (10%) compared to 1% in the rifapentine group. Another trial conducted in South Africa in
2011 evaluated the efficacy, safety and adherence of different treatment strategy for the
prevention of TB in HIV positive patients. The study enrolled 1148 patients, who were randomly
allocated to four arms: rifapentine 900 mg and INH 900 mg once weekly for 12 weeks, rifampin
600 mg and 900 mg INH twice weekly for 12 weeks, 300 mg INH daily for up to 6 years, or 300
mg INH daily for 6 months. The study found that both rifapentine and rifampin groups were
comparable in their completion rate and in the rate of TB but the INH alone group had
significantly more study discontinuation due to adverse events [92]. In the PREVENT trial, a
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large trial conducted in US, Brazil, Spain, and Canada, 7731 participants who were at high risk
of TB were enrolled [93]. Participants were randomized to receive once weekly 900 mg
cr
rifapentine plus 900 mg of INH given at the clinic for 3 months, versus 9 months of self-
us
administered daily INH dosed at 300 mg. In the modified-intention-to-treat analysis, they found
that the cumulative rate of TB in the rifapentine group was 0.19% as compared to 0.43% in the
an
INH-only group. They also found that the rate of treatment completion was significantly higher
in the rifapentine group as compared to the INH-only group (82.1% vs 69.0% respectively,
M
p<0.001) with significantly lower hepatotoxicity associated with the rifapentine group (0.4% vs
2.7% p<0.00). The study concluded that short-treatment combination of rifapentine and INH was
ed
as effective as the 9 months INH only strategy with higher completion rate and lower
hepatotoxicity [93]. However, the rifapentine group was associated with more common flu-like,
pt
and some other systemic drug reactions, such as urticaria, flushing, chills, shortness of breath,
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vomiting, nausea, hypotension, angioedema, bronchospasm, conjunctivitis, weakness, fatigue,
headache, fever, aches, sweats, and dizziness as well as grade 3 and 4 adverse events [94].
Ac
Similar results were found in children population nested from the larger trial but no
hepatotoxicity was reported [95]. A systematic review to compare the efficacy and the
completion rate of rifapentine and INH given on different durations: INH + rifapentine once
weekly for 12 weeks, 6 and 9 months of daily INH, 3-4 months of daily INH and Rifampin, and
4 months of rifampin alone. It was found that there was no significant difference between the
different groups in the efficacy, however there was overall significance in the completion rate for
the shorter-term treatment duration [96].
4. CONCLUSION
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The decision to favor rifampin or rifapentine involves many factors. At this time, rifampin
remains the core drug for the treatment of tuberculosis. Both drugs appear to be under-dosed at
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600 mg. Higher doses of rifapentine are superior to rifampin at 600 mg, but so are higher doses
us
of rifampin. Rifapentine does have a long elimination half-life, but time>MIC is not the
pharmacodynamically linked variable. Rifampin has lower protein binding, and that seems to
an
allow for greater penetration into cavitary lesions, as far as it has been studied. Rifapentine is a
reasonably safe drug, but so is rifampin. The latter is more widely approved by governments, and
M
more widely available, including as inexpensive generic dosage forms. Thus, for now, rifampin
appears to remain the gold standard for the treatment of active TB disease, pending further
ed
studies. Much needed is a head-to head comparison of higher doses of both rifamycins.
Regarding LTBI, rifapentine seems to be an appealing alternative, with just 12 once-weekly

pt
doses (along with INH). Rifampin-based regimens for LTBI include 3 months of daily INH plus
ce
rifampin, or 4 months of daily rifampin. Whether shorter or less frequent rifampin-based
regimens might work is not known.

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5. EXPERT COMMENTARY
The key for the successful therapy of tuberculosis are regimens that are active against the
majority of mycobacterial strains encountered in clinical practice. The current strategy uses
combination therapy, with a 2-month intensive phase followed by a less intensive combination 4-
months phase. That said, patients very often take much longer than 6 months to complete their
“short course” regimen. In the US, only 88% of TB patients complete their scheduled doses by
12 months, and it takes nearly 18 months for that to reach the often quoted 95% (annual TB slide
set, CDC.gov). The regimen remains long and fairly complex, and this leads to a lack of
adherence and the emergence of resistance. Further, the doses of rifampin and rifapentine have
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not been optimized, and low intermittent doses of rifapentine are associated with the emergence
of resistance. Rifapentine has longer half-life than rifampin, it has a lower MIC for M.tb, and it
cr
has a higher intracellular/extracellular ratio. These could favor rifapentine as more effective
us
drug. However, rifapentine has higher protein binding than rifampin, lowering of concentrations
of the free, active form of the drug. Additionally, rifapentine’s higher intracellular penetration
an
may be an advantage for the LTBI. Rifapentine, however, showed lower cavitary penetration
than rifampin, and that may be a relative disadvantage in patients with cavitary pulmonary TB.
M
Both drugs are potent hepatic enzyme inducers, and both are prone to serious drug-drug
interactions. Both drugs appear to display autoinduction.

ed
The safety of rifapentine and rifampin, particularly at high doses, needs further comparison.
pt
Current trials that compared the safety and tolerability between rifampin and rifapentine
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indicated that rifapentine was less hepatotoxic than rifampin, but perhaps rifapentine more
commonly causes flu-like syndromes. Neither at current doses is particularly hepatotoxic or

Ac
producing serious hypersensitivity reactions.
6. FIVE-YEAR VIEW
Being the leading infectious killer, TB should be better treated and controlled in order to be
eliminated. Because developing new drugs will cost a lot and needs long time, current regimens
should be optimized. Rifamycins have unique and proven sterilizing activity against TB and their
optimization may be the key to TB treatment shortening.
Rifampin is an old, inexpensive, globally available, and less protein-bound drug that
penetrates well into cavitary lung lesions. Rifapentine has a longer half-life, can be taken more
intermittently, and has a lower MIC against M.tb. In order for rifapentine to replace rifampin in
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TB programs worldwide, it has to outdo rifampin, not just tie it.
Future clinical trials should assess the efficacy and safety of both drugs at high doses for
cr
shortened durations, head-to-head, for treatment of drug-sensitive TB disease. These trials should
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compare the outcomes we care most about (relapse, not early sputum culture conversion) and
explicitly evaluate PK-PD relationships. Ultimately, one may be the winner.

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7. KEY ISSUES
M
• Tuberculosis is a main infectious disease killer world-wide, but its treatment is complex
and long, and under-dosing is associated with relapse or drug resistance

ed
• Rifapentine is a drug with a long half-life, higher potency against Mycobacterium
tuberculosis, and is a good option for treatment latent TB infection because it can be
pt
given for a short time in intermittent fashion

ce
• Rifampin has better penetration into cavitary lung lesions, increasing the dose gives
supraproportional increases in drug exposures, it has a long track record of safety, it is

Ac
inexpensive and globally-available so it is currently first-line for treatment of TB disease
• At high doses, rifapentine and rifampin both outperform standard dose rifampin, but until
a head-to-head trial is done, it is unclear which will be most effective at reducing TB
treatment duration in all patient populations

Acknowledgments
The authors acknowledge academic support from King Khalid University for Wael Alghamdi
and Kuwait University for Omamah Alfarisi.
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Funding
This paper was not funded.
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Declaration of Interest
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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,
an
expert testimony, grants or patents received or pending, or royalties.TABLES
Table 1: Comparing features of rifampin versus rifapentine.
Rifampin Rifapentine
M
MIC 0.125-0.25 µg/ml 0.01-0.06 µg/ml
Half-life 2h 15 h
Protein binding 80-85% 97-99%
ed
Food requirement No Yes

Kinetic Nonlinear (Michaelis-Menten) Nonlinear (Saturable absorption)
Hepatic enzyme induction 3 fold 4.5 fold
Flat vs mg/kg dosing Mg/kg Flat
pt
Cavitary penetration Good Poor

Access Global Limited
ce
Efficacy Comparative efficacy at high doses is to be determined

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Table2: Studies evaluating the pharmacokinetics, microbiologic activity, efficacy or safety of rifapentine.
Study Population n Intervention Comparator Duration Outcome measure

Benator 2002 PTB 1004 600 mg RPT + 900 mg INH 600 mg RMP+ 900 mg 4 months Failure/relapse
[84] (502/group) once weekly INH twice weekly
Weiner 2003 PTB 133 (failure=4, RPT + INH once weekly RMP + INH twice 16 Weeks Association
t
[97, 98] Relapse=35, weekly between PK and
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Cure=94) failure or relapse
Weiner 2004 PTB 35 RPT 900, 1200 mg once RPT 600 mg + INH 15 16 Weeks NCA PK
cr
[98] weekly fasting mg/kg once weekly
fasting
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Langdon PTB 45 RPT 600, 750, 900 mg on Healthy volunteers: ----- NCA PK
2004 [99] day 1 & 5 900 mg RPT
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Schechter PTB 399 household RPT/INH (900/900 mg) RMP/INH (450-600 12 weeks Tolerance/safety
2006 [91] once weekly mg/750-1500 mg) daily
Dooley 2008 Healthy 13 900 mg RPT+ 400 mg MFX MFX 400 mg once 12 days (7 Effect of RPT on
M
[72] participants (thrice weekly) daily for 4 days. doses of RPT MFX PK
& 19 dose of
MFX)
d
Zvada 2010 Healthy 35 900 mg RPT with: A. high 900 mg RPT on fasting Single dose Effect of Food on
[64] males fat meal, B. bulk and low- state RPT RPT PK
te
fat meal C. bulk and high fat
meal, D. low fat meal
ep
Martinson PTB/HIV co- 1148 RPT/INH (900/900 mg) Up to 6 years TB incidence
2011 [92] infection once weekly (based on the rate, AE
group)
c
Sterling 2011 Patients with 7731 RPT/INH (900/900 mg) 300 mg INH daily for 6 Efficacy/safety
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[93] High risk of once weekly months

developing 3 months
TB
RMP/INH (600/900 mg)
twice weekly for 12 weeks
300 mg INH daily for 6 yrs
Dooley 2012 Healthy 33 RPT 5, 10, 15 & 20 mg/kg 10 mg/kg RMP 14 days Safety/PK
[59] participants daily
Dorman Patients with 531 10 mg/kg/dose RPT 10 mg/kg/dose RMP 5 days/week Efficacy/Safety
2012 [3] PTB For 8 weeks
Dorman Patients with 334 10,15, or 20 mg/kg RPT 10 mg/kg RMP daily 8 weeks Efficacy/Safety
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2015 [80] PTB daily
Winter 2015 Healthy 32 600 mg RPT 600 mg RMP 21 days Effect of RPT or
cr
[100] participants RMP on
bedaquiline PK
Svensson Healthy 32 Multiple-dose RMP or RPT 400 mg bedaquiline 23 days of Effect of RPT or
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2015 [76] participants with bedaquiline alone single dose RPT and RMP on the PK
RMP of bedaquiline
an
Villarino PTB children 905 RPT+INH once weekly for INH daily for 9 months 3 versus 9 Efficacy/Safety
2015 [95] and 3 months months
adolescents
M
Dooley 2015 Healthy 44 Arm1: 10 mg/kg twice daily Arm1: 20 mg/kg RPT 14 days for PK/Safety
[61] participants once daily each period.
Arm2: 15 mg/kg RPT once
d
daily with high fat meal Arm2: 15 mg/kg RPT
once daily with low-fat
Jindani 2014 PTB 827

te
4 months:INH replaced by
meal
2 months of 18 months of Safety/efficacy
ep
[86] MFX and RPT 900 mg ethambutol, INH, follow-up
twice weekly for 2 months RMP, PZA followed by
OR 4 months of daily INH
c
6 months: INH replaced by and RMP

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daily MFX and 1200 mg for

4 months
Conde 2016 PTB 121 7.5 mg/kg RPT + 10 mg/kg 10 mg/kg RMP + 8 weeks Safety/efficacy
[73] MFX daily ethambutol daily
Abbreviations: PTB (pulmonary tuberculosis); RMP (rifampin), RPT (rifapentine), INH (isoniazid), MFX (moxifloxacin)
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d
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c ep
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Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Rifampin vs. Rifapentine: What is the preferred

Omamah Alfarisi, Wael A. Alghamdi , Mohammad H. Al-Shaer , Kelly E.

To link to this article: http://dx.doi.org/10.1080/17512433.2017.1366311

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Journal: Expert Review of Clinical Pharmacology

College of Pharmacy, Department of Pharmacotherapy and Translational Research, Gainesville,

FL, USA, 3Infectious Disease Pharmacokinetics Laboratory, University of Florida, Gainesville,

Introduction: One-third of the world’s population is infected with Mycobacterium tuberculosis

Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics

rifamycin regimens are eagerly awaited.

Keywords: tuberculosis, rifapentine, rifampin, rifamycin, pharmacokinetics, pharmacodynamics

They demonstrate bactericidal activity by binding to the DNA-dependent RNA polymerase,

2.1 Preclinical studies

which means it prevents post-treatment relapses by eliminating slowly- or non-replicating,

concentration divided by minimal inhibitory concentration (Cmax/MIC). In their experiments,

utilized to optimize the dosing in routine clinical settings.

African-European consortium reported similar supra-proportional PK with increasing doses up to

concentrations that maximize rifampin’s sterilizing effects have yet to be elucidated.

2.2.2 Absorption, distribution, metabolism, excretion (ADME)

Another consideration is rifampin-containing combination products [2]. The purpose of these

Rifampin is a potent inducer of metabolizing enzymes, and it is well-known to cause

antidiabetic agents, analgesics, azole antifungals, macrolides antibiotics (e.g. clarithromycin),

antiretrovirals, antiplatelet/antithrombotic agents, anticoagulants, and anticonvulsants [37, 39,

tolerability, pharmacokinetics, and EBA of rifampin. Sixty-eight patients received different

their results should be expected soon.

regimen [49, 50].

strains with higher Cmax/MIC ratio [20].

2.6 Treatment of LTBI

treatment failure. As a result, regimens should be chosen wisely in such population.

3.1 Preclinical studies

that of rifampin [58].

3.2 Basic clinical PK/PD

3.2.1 PK and exposure-response

food, however, significantly affects rifapentine’s bioavailability, as demonstrated in several

in a fasting state [28].

[67].Rifapentine is metabolized by arylacetamine deacetylase [68].

performed population pharmacokinetic modeling of rifapentine and its main metabolite in

agreement with previous work [59] (Table 1).

2 enzymes, significantly, thrice-weekly rifapentine reduces moxifloxacin exposures only

rifapentine on efavirenz are still under study [77].

3.4 Trials of rifapentine for TB disease

hepatotoxicity and rifamycin hypersensitivity syndrome. In trials of daily treatment with

drug is insufficiently dosed is important. In an early study involving HIV-seropositive patients

group was associated with monoresistance to rifamycins (perhaps because of PK mismatch or

sufficiently long half-life to protect against emergency of rifamycin resistance [86].

3.6 Treatment of LTBI

vomiting, nausea, hypotension, angioedema, bronchospasm, conjunctivitis, weakness, fatigue,

the shorter-term treatment duration [96].

Regarding LTBI, rifapentine seems to be an appealing alternative, with just 12 once-weekly

rifampin, or 4 months of daily rifampin. Whether shorter or less frequent rifampin-based

regimens might work is not known.

interactions. Both drugs appear to display autoinduction.

commonly causes flu-like syndromes. Neither at current doses is particularly hepatotoxic or

producing serious hypersensitivity reactions.

optimization may be the key to TB treatment shortening.

explicitly evaluate PK-PD relationships. Ultimately, one may be the winner.

and long, and under-dosing is associated with relapse or drug resistance