Pretomanid Treatment for Tuberculosis : A Review

1
Heryanti Pusparisa,1Fauna Herawati
1
Faculty of Pharmacy, Surabaya University

Abstract

Pretomanid, an oral nitroimidazooxazine antimycobacterial agent administered as part of the

BPaL (bedaquiline, pretomanid and linezolid) and BPaMZ (bedaquiline, pretomanid,
moxifoxacin and pyrazinamide) regimens, has been developed by the Global Alliance for TB
Drug Development (TB Alliance) under license from Novartis, for the treatment for tuberculosis
(TB). TB Alliance has licensed Mylan to manufacture and commercialize pretomanid for use as
part of the BPaMZ and BPaL regimens. The license is non-exclusive in low- and middle-income
countries and exclusive in high-income markets. Pretomanid, as part of the BPaL regimen, was
recently approved in the USA under the Limited Population Pathway for Antibacterial and
Antifungal Drugs (LPAD) pathway for the treatment of adults with pulmonary extensively drug-
resistant (XDR) or treatment-intolerant or non-responsive multidrug-resistant (MDR) TB.
Pretomanid is also under regulatory review in the EU. This article summarizes the milestones in
the development of pretomanid leading to this frst regulatory approval.
Keyword : Mycobacterium Tuberculosis. Pretomanid, Tuberculosis

INTRODUCTION

Tuberulosis (TB) is the infection of global disease caused by Mycobacterium

tuberculosis and the leading cause of death due to infection worldwide (Stover Ck, 2000). TBC
is associated with high mortality and morbidity (Alliance, 2019) and the emergence of strains
whih are potential to be multidrug-resistant or extensively drug resistant. It makes the disease
become difficult to manage (Gothi, 2011). In 2000, the Global Alliance for TB Drug
Development (TB Alliance) has formed to focus toward developing the new anti-T and well
tolerated, have a simple, shorter dosing schedule, have minimal interaction with antiretroviral
agents and are afordable (Murray, 2016). Pretomanid, an orally administered
nitroimidazooxazine antimycrobacterial agent, has been developed by TB Alliance under license
from Novartis, as the treatment to remedy TB (The Global Alliance for TB, 2019). Pretomanid
is indicated in the USA for use in a limited and specifc patient population (The Global Alliance
for TB, 2019).

Pretomanid shows in vitro activity against both drug-susceptible and drug-resistant

Mycobacterium tuberculosis and has in vivo activity in Animal Model of TB ( Tyagi et al.,
2005). The second phase of study has done to evaluate the early bactericidal activity (EBA) of
pretomanid for 14 days. Daily oral dosage demonstrates that the lowest dosage to result the
maximal effect of EBA is 100 mg/ day. On 14 August 2019, The Food and Drug Administration
has approved pretomanid as a tubercolusis treatment under Limited Population Pathway for
Antibcaterial and Antifungal Drugs (LPAD) pathway, as part of the BPaL combination regimen
for treatment of adult with pulmonary XDR or intolerant treatment or non-responsive MDR TB
(FDA, 2019).

The recommended dosage, administered in the form of combination bedaquiline and

linezolid, is 200 mg once daily for 26 weeks; the treatment with the combination regimen can be
prolonged more than 26 weeks if it is necessary (The Global Alliance for TB, 2019). In April
2019, EMA received a marketing authorization for pretomanid (Europian Medicine Agency,
2019). Pretomanid is just the second drug to be accepted in the USA under the LPAD pathway
and has also obtained the US FDA Qualified Infectious Disease Product (QIDP) designation
(FDA, 2019).

Figure 1. Timeline of development pretomanid as regimen to remedy Tuberculosis

METHOD

This study utilized a secondary data obtained from various references like scientific
journal, textbook, research report, and articles which were reliable relevant. In this review
process, we tried to seek a literature from science direct, PubMed, indian journal, research gate.
The keywords used in this review were prematoid, tuberculosis, and tuberculosis resistant. After
receiving numerous resources, we attempted to read, interpret, and compile the relevant data with
our topic. Figure 1 is presented to illuminate the review process.

Journals A review manuscript

Arranged
Textbooks
Interpreted with a relevant
Articles
Collected secondary data
Reports

Figure 2. The Illustration of Review Process

Result and Discussion

Pretomanid Structure
Pretomanid is the derivate of nitrimidazooxazin. Pretomanid is previously known as PA
824 which have the low KHM for Mycrobacterium tuberculosis. This drug is studied as the part
of the newly potential regimen. Diacon et all., (2015) assessed bactericidal activity in the first 14
days of a regimen containing pretomanid, moxifloxacin and pyrazinamide. The result has proved
that this regimen yields the higher activity compared to bedaquiline itself, a combination of
bedaquiline and pyrazinamide; and a combination of bedaquiline and pretomanid. Additionally,
that combination has yielded a comparable activity with standard regimen of therapy (isoniazid,
rifampin and pyrazinamide and streptomycin or ethambutol).Interestingly, the administration of
pyrazinamide elevate the activity of bedaquiline and pretomanid.

Figure 3. Pretomanid Structure (Hoagland et al., 2016)

Pretomanid Pharmacology

Pretomanid has a half-life up to 20 hours, is comprised of protein 94%, and has Vd 64.65;
PK is a propotional dosage up to 200 mg. CYP3A has a responsibility for 20% of its metabolism
(Lenaerts et al., 2005). In healthy volunteer, efavirenz and rifampicin can decrease pretomanid
through concentration 46% and 85% exposures (area under the curve) by 35% and 66%,
respectively, raising concerns for coadministration (Dooley dkk., 2014).

Pretomanid Pharmacokinetics

Pretomanid pharmacokinetics after oral, single-dose administration were approximately

dose proportional over a dose range of 50–200 mg and less than dose proportional over a dose
range>200–1000 mg. Administration of pretomanid with a high-fat, high calorie meal increased
exposure to pretomanid (mean Cmax increased by 76% and mean AUC∞ by 88%); the drug
should be taken with food. After a single 200 mg dose of pretomanid administered with food to
healthy adults, the mean Cmax of 2.0 μg/mL was achieved in a median 5.0 h and the mean
AUC∞ was 53.0 μg h/mL. Pretomanid is≈86.4% bound to plasma protein and the estimated
mean apparent volume of distribution is 97 L. Steady state was achieved≈4–6 days after repeated
administration of pretomanid 200 mg once daily under fasted conditions in the same population.
The accumulation ratio was≈2 under fasted conditions; the steady state mean Cmax (1.7 μg/mL)
was achieved in a median 4.5 h and the mean AUC24 was 30.2 μg h/mL (The Global Alliance,
2019).

Pretomanid is metabolized by multiple reductive and oxidative pathways, with no single

pathway dominating. In in vitro studies, CYP3A4 accounted for up to≈20% of pretomanid
metabolism. Pretomanid is excreted in urine (53% of a dose) and faeces (38%), predominantly as
metabolites;≈1% of a dose is excreted in urine as the unchanged drug. The estimated mean
apparent oral clearance of pretomanid after a single 200 mg dose under fed conditions in healthy
adults is 3.9 h and the estimated mean half-life is 17.4 h. Bodyweight, sex, race, HIV status and
pulmonary TB status (XDR, treatment intolerant or non-responsive MDR) has no clinically
signifcant efect on pretomanid pharmacokinetics. The impact of patient age (≥65 vs.<65 years)
and renal or hepatic impairment on pretomanid pharmacokinetics is not known (The Global
Alliance, 2019). Coadministration of pretomanid with the CYP3A4 inducers efavirenz and
rifampicin reduced pretomanid plasma concentrations (Dooley et al., 2014).

The Effect of Pretomanid on bacterial activity

Bactericid activity is defined as a decrease in the colony forming units (CFUs) of

Mycobacterium tuberculosis in the sputum of pulmonary TB patients who have positive smear
results in response to the drug given (Dawson et al., 2015). Bactericid activity was measured
based on the average daily reduction in CFU of M. tuberculosis (MTB) bacteria per ml. Two
inclusion studies (Diacon et al., 2012; Diacon et al., 2010; Diacon et al 2014) that compared the
effect of bactericidal activity for 14 days with pretomanid administration of 200 mg and standard
anti-tuberculosis (OAT) drugs showed better results with OAT administration standard.
However, it shows the simplifying effect of tuberculosis treatment withquite a draw. Three other
studies (Dawson et al., 2015; Diacon et al., 2015) showed better bactericidal activity in the
presence of pretomanids in the TB treatment regimen (for 14 days) (Diacon et al., 2015) as well
as at a dose of 200 compared to 100 mg (for 56 days) (Dawson et al., 2015).

The Safety Pretomanid on Tuberculosis Patient

Most of the adverse events (AE) reported were mild to moderate effects such as skin /
subcutaneous damage, headache, abdominal pain, hyperuricemia, nausea, vomiting and elevated
liver enzyme ALT / AST. There are four studies (Diacon et al., 2015, Traore et al., 2000) that
reported severe AEs with hemoptysis, pneumonia, and elevated grade 4 ALT liver enzymes.One
study (Traore et al., 2000) also reported participants who died during treatment, but the cause of
death was reported from pneumothorax and was thought to be unrelated to the treatment given.
In general, all inclusion studies concluded that pretomanid use in pulmonary TB patients was
safe and tolerable at doses of 200 mg / day.
Pretomanid Mechanism Against Tuberculosis Bacteria

A pretomanid (previously known as PA-824) is a molecule bicyclic nitroimidazole with a

dual action mechanism against MTB bacteria, namely blocking the synthesis of bacterial cell
walls (such as isoniazid), and in anaerobic conditions releasing intracellular nitric oxide which
causes respiratory poisoning in bacterial cells (such as cyanide) (Clain and Escalante, 2016).

Figure 4. Mechanism Action of Pretomanid

Conclusion

Pretomanid is the new invention to remedy tuberculosis and it does not have any adversity to
tuberculosis patient.

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