Anti-TB drugs profile

Timeline for TB drugs discovery

2014
Delamanid and
Bedaquline
Grouping of Anti-tuberculosis agents
FLDs
Medicines for RR-MDR-TB
Isoniazid Group B: Injectable Group c: Other core Group D. Add-on agents
Group A:

Rifampcin Fluoroquinolones second-line agents2

D1
Ethambutol

Ofloxacin
Streptomycin Pyrazinamide
Pyrazinamide Ethionamide
Levofloxacin Ethambutol
Kanamycin
Prothionamide
Moxifloxacin High dose INH
Amikacin
Cycloserine
Gatifloxacin D2
Capreomycin
Terizidone
Bedaquiline
Viomycin
Linezolid (Lzd)
Delamanid
Clofazimine
D3
PAS
PAS

Amx-Clv

3
4
Delamanid Bedaquline
Inhibit ATP
synthesis

5
Isoniazid (H)
• Bactericidal
• The most active drug for the treatment of
tuberculosis caused drug susceptible strain
• MoA
o Inhibit synthesis of mycolic acids, which are essential
components of mycobacterial cell walls.
o Is a pro-drug metabolised to its active form by the
bacterial enzyme, catalase-peroxidase (KatG).
o forms complex with an acyl carrier protein (AcpM) and
KasA, a beta-ketoacyl carrier protein synthetase, which
blocks mycolic acid synthesis and kills the cell
• Dosage - 5 mg/kg/d or 300 mg for adult
 Isoniazid resistance
• Mutations in the gene katG that alter or eliminate
mycobacterial catalase-peroxidase activity
• Mutations resulting in overexpression of inhA, which
encodes an NADH-dependent acyl carrier protein
reductase
• Mutations in kasA
• Can prevent activation of the prodrug and induce
isoniazid resistance.

Lancet Infect Dis 2003; 3: 13–21 7

 Pharmacokinetics
 Absorption:
 readily absorbed from the GIT
Distribution:
 Penetrate all body tissue and fluids (including CSF, Placenta,
Meninges)
Metabolism:
 `Liver
 Excretion: 75 - 95% excreted in urine
• Dose adjustment is not required in Renal Failure
Contraindication
• Known hypersensitivity
• Acute hepatic disease

8
Adverse effects
• Peripheral neuritis
• Hepatitis
• Psychosis
Less
• Seizures common
• Anorexia
• GIT discomfort
• Fever
• Allergic reactions
Rifampin
• Bactericidal
• Acts both extra & intracellularly
• Good sterilizing property & resistance preventing action
• Bactericidal efficacy ≈ INH &>any other 1st line drug
• MoA
o Rifampin binds to beta subunit of DNA dependent RNA
polymerase and inhibits RNA synthesis in bacteria.

• Dosage - 10 mg/kg/d or 600 mg/d orally

10
 Rifampicin resistance
• Mutations in the rpoB gene – which encodes the beta
subunit of the bacterial RNA polymerase
• Cross-resistance other rifamycins:
– Rifapentine – +/- complete cross-resistance
– Rifabutin – 70-75% cross-resistance

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 Pharmacokinetics
• Absorption:
– Well absorbed from GIT
– PAS interferes with absorption
– Food also interferes with absorption
• Distribution:
– Widely distributed in body tissues and fluids
• Metabolism
– Liver
• Excretion
– Feces (60-65%), urine (30%)

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 Uses
TB & atypical
Prophylaxis in
mycobacterial Leprosy
H. influenza
infections

Resistant
Pneumococcal
staph Brucellosis
meningitis
infections

Prophylaxis of
latent TB
infection
 Adverse effects
• Staining of secretions
o Red or orange discoloration
• Hepatotoxicity
• Flu-like syndrome
• CNS symptoms
o drowsiness, ataxia, confusion, peripheral neuropathy etc
• GIT disturbances
• Hypersensitivity reactions
• strongly induces most cytochrome P450 isoforms
 Pyrazinamide (Z)
• Synthetic analogue of Nicotinamide
• Weak tuberculocidal
• Highly effective during 1st 2months
• Inactive at neutral pH
• Active in acidic medium
• Pyrazinamide is converted to pyrazinoic acid
– active form of the drug—by mycobacterial pyrazinamidase,
which is encoded by pncA
• MoA & drug target – not clearly known
• Resistance
– may be due to impaired uptake of pyrazinamide
– mutations in pncA that impair conversion to its active form

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Pyrazinamide (Z)
• Dose: 25mg/kg/D
• More effective against slow growing bacilli
• Active both intra & extracellularly
• Including Z in combination therapy:
o ↓Duration of treatment
o Has potent sterilizing action
o ↓ Risk of relapse
Pyrazinamide is essential for initial phase of TB treatment

100
80
Relapses (%)

60
Relapses
40
20 10.3%
3.4%
0
Pyrazinamide No Pyrazinamide

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 Pharmacokinetics
• Absorption:
• Well absorbed from GIT
• Distribution:
• Good penetration to all body tissue & CSF
• Metabolism:
• Liver
• Excretion
– Renal
– should be administered at 25–35 mg/kg three times weekly
• hemodialysis patients and CrCl is less than 30 mL/min
• Adverse effect
– Arthralgia
– Hepatotoxicity (1-5%)
– Nausea, vomiting, drug fever, and
– Hyperuricemia –lead to acute gouty arthritis
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 Ethambutol
• Tuberculostatic
• MoA
• Inhibit Mycobact. Arabinosyl
Transferase
• Also effective against atypical
mycobacterium.
• Dosage – 12-25 mg/kg/d
• Resistance
• due to mutations resulting in
overexpression of emb gene products
or within the embB structural gene,
• which encodes arabinosyl transferase

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Pharmacokinetics
• Absorption
o Well absorbed on oral administration
• Distribution
o Widely throughout body
o Concentrated in kidneys, lungs, saliva and RBCs
• Metabolism
o Liver
• Excretion
o Urine (50%), Feces (20%)
o Accumulates in renal failure
o Dose should be reduced in renal failure
o Dose should be reduced by half if CrCl is less than 10
mL/min
Adverse effect
• Optic neuritis requires withdrawal of the drug.
• Loss of visual acuity and red green color blindness
• Relatively contraindicated in children
o too young to permit assessment of visual acuity and red-
green color discrimination.
• Periodic visual acuity testing is desirable
o if 25 mg/kg/d dosage is used
 Levofloxacin (Lfx)
• MoA
• Acts by inhibiting the A subunit of DNA gyrase (topoisomerase II) and
topoisomerase IV
• Dose: 750 mg daily for <50 kg (1000 mg daily for > 75kg)
• A higher dose for tuberculosis is used than for other infections
• Resistance for fluoroquinolones
• due to one or more point mutations in the quinolone binding region of the
target enzyme or
• to a change in the permeability of the organism
• Pharmacokinetics
• Well absorbed orally
• Distributed widely in body tissues and fluids
• Side effects
• Generally well-tolerated
• GI upset, rash, headache and dizziness
• Adjust dose in renal failure
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 Moxifloxacin (Mfx)

• May be more active than earlier generation quinolones

• Dose: 400 mg daily
• Near complete cross-resistance with other
fluoroquinolones
• Moxifloxacin may have limited efficacy against some strains
resistant to ofloxacin
• No dose adjustment in renal failure
• Hepatically cleared

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 Kanamycin (Km)

• MoA
• Inhibit protein synthesis
• bind to specific 30S-subunit ribosomal proteins
• Dose: 1 g IM/IV (15-20 mg/kg)
• Resistance
• Production of a transferase enzyme or
• enzymes inactivates the aminoglycoside by adenylylation,
acetylation, or phosphorylation
• impaired entry of aminoglycoside into the cell
• receptor protein on the 30S ribosomal subunit may be deleted
or altered as a result of a mutation
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Km
• Pharmacokinetics • Adverse effects:
• Absorbed poorly from • Nephrotoxicity
the GIT • Ototoxicity
• Absorbed well form • Electrolyte wasting
IM/IV injection
• Adjust dose for renal
failure
Amikacin (Amk)
• Highly similar to kanamycin (can be essentially
considered the same drug)
• Side effects:
o Same as kanamycin; nephrotoxicity and ototoxicity
• High cross-resistance with kanamycin
• Adjust dose in renal failure (same as kanamycin)
 Capreomycin (Cm)
• Polypeptide
• MoA – protein synthesis inhibitor
• Structurally and functionally similar to
aminoglycosides
• Side effects
• Hypokalemia
• nephrotoxic and ototoxic.
• Tinnitus, deafness, and vestibular
disturbances occur
• Some cross-resistance with Km/Amk
• Adjust dose for renal failure
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 Cross Resistance between Injectables
(aminoglycosides and polypeptides)
• Isolates that acquire resistance to Streptomycin are
usually susceptible to kanamycin, amikacin and
capreomycin;
• Isolates that acquire resistance to Capreomycin are
usually susceptible to kanamycin and amikacin
• Isolates that acquire resistance to amikacin essentially
always have associated resistance to kanamycin and
capreomycin.

Source - International Union Against Tuberculosis and Lung Disease

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Prothionamide
• Is ethioamide derivate
• Replaces ethionamide
• MoA
• Inhibits mycolic acid synthesis – cell wall sysnthesis
• Side effects
• hypothyroidism
• GI upset
• peripheral neuropathy
• Partial cross-resistance with isoniazid,
• complete resistance with ethionamide
• Hepatically excreted
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Cycloserine (Cs)
• Structural analogue D-Alanine
• MoA
• Interferes with cell-wall proteoglycan synthesis
• by inhibiting the incorporation of D-alanine into
peptidoglycan pentapeptide
• by inhibiting alanine racemase, which converts L-alanine
to D-alanine, and D-alanyl-D-alanine ligase
• Effective CNS penetration
• Renal excretion
• Side effects:
• Psychosis
• Seizures, irritability, headache, peripheral neuropathy
• Co-administer B6
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Para-Aminosalicylic acid (PAS)
• folate synthesis antagonist
• Dosage
• 8–12 g/d orally for adults
• 300 mg/kg/d for children
• Readily absorbed from GIT
• Widely distributed in tissue and body fluids except CSF
• Hepatic metabolism,
• Excreted in the urine
• Side effects
• GI upset, hypothyroidism
• Hepatitis, electrolyte abnormalities
• Administer with food or drink
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New TB drugs(Two repurposed)
Class  New TB Drugs
Diarylquinolone Bedaquiline
Nitroimidazole Delamanid
PA-824

Oxazolidnone Linezolid
(also Stuezolid is in this class, but
development is stalled)

Riminophenazine Clofazimine

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Bedaquiline
• Is a new drug for the treatment of DR-TB
• Approved by the U.S. FDA in 2012
• WHO recommended BDQ for Rx of MDR-TB in 2013,
providing that it is used under optimal conditions
• MOA-
o Inhibit mycobacterial adenosine 5’ triphosphate (ATP) synthase
• Half life is 5.5 month
• Dosage form – 100 mg tablet
• Dosage
o 400 mg once daily for week 1&2
o 200 mg trice weekly for week 3-24

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Adverse drug reaction
• Increased mortality due to QT Prolongation
• Hepatotoxicity
• Arthralgia
• Nausea
• Headache
• Chest Pain
• Anorexia

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 Delamanide (Dlm)
• Recommended by WHO in 2014 providing that it is used
under optimal conditions.
• Dlm is a nitorimidazole agent that works by inhibiting
mycobacterium cell wall synthesis.
• Dosage –a dose of 100mg twice daily for 24 weeks,
o a phase III trial of the drug is evaluating a dose of 200mg once
daily.
• Dlm has been given to children as young as 13 years and is
considered safe in this population.
• The safety of the drug has not been established in
children under the age of 13 years

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 Adverse drug reaction
• Most frequent (> 10.0% of patients)
• nausea (38%), vomiting (33%), and dizziness (30%).
• Less common
• QT interval prolongation is a prominent safety concern,
• with hypoalbuminaemia (particularly below 2.8 g/dl) and
hypokalaemia shown to be major contributing factors.
• Very frequent monitoring of albumin levels, serum
electrolytes and ECG is required

36
Delamanid – contraindications to
start
• Serum albumin  <2.8 g/dL
• Serum potassium outside the normal range
• High risk for cardiac complications.
o Patient has a QT interval greater than 500 ms, history of
Torsade de Point or cardiac ventricular arrhythmias or
severe coronary artery disease

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 Clofazimine (CFZ)
Riminophenazine
MoA
 Not completely understood
 Inhibit mycobacterial growth
 Binds preferentially to mycobacterial DNA
Dosage form – 100 mg tablet
Dosage
 200 mg daily for two months
 100 mg daily for 18 months

It has a half-life of 70 days.

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Adverse drug reaction
• Two main classes of side effects:
o skin and gastrointestinal.
• skin pigmentation changes
o range from an orange color to a dark black/purple color.
o This skin changes are reversible over time.
• Abdominal pain
o as the drug accumulates in the wall of the GI tract.
• Also associated with QTc prolongation.

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Linezolid (LZD)
• Oxazolidinone:
• MoA
• inhibits protein synthesis,
• interacting with ribosomal RNA
• Dosage form – 600 mg tablet
• Dosage – 600 mg daily for 12 months

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Adverse drug reaction
• Common:
o diarrhea, nausea, headache, insomnia, and rash.
• More serious:
o myelosuppression (generally reversible with
discontinuation of the drug)
o optic neuropathy (usually resolved over time with drug
discontinuation)
o peripheral neuropathy (possibly irreversible).
• Rare: hypertension, lactic acidosis, pancreatitis

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