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In a single-dose bioavailability study of five RIFATER tablets (Treatment A, n=23) versus RIFADIN 600 mg, isoniazid 250 mg, and pyrazinamide 1500 mg (Treatment B, n=24) administered concurrently in healthy subjects, there was no difference in extent of absorption, as measured by the area under the plasma concentration versus time curve (AUC), of all three components. However, the mean peak plasma concentration of rifampin was approximately 18% lower following the single-dose administration of RIFATER tablets as compared to RIFADIN administered in combination with pyrazinamide and isoniazid. Mean (±SD) pharmacokinetic parameters are summarized in the following table.
|Parameter||Cmax (mcg/mL)||Half-life (hr)||Apparent Oral Clearance (L/hr)||Bioavailability (%)|
|Isoniazid||3.09 ± 0.88||3.14 ± 0.92||2.80 ± 1.02||2.80 ± 1.11||24.02 ±15.29||25.72 ±18.38||100.6 ±16.6|
|Rifampin||11.04 ± 3.08||13.61 ± 3.96||3.19 ± 0.63||3.41 ± 0.86||9.62 ± 3.00||8.30 ± 2.50||88.8 ±16.5|
|Pyrazinamide||28.02 ± 4.52||29.21 ± 4.35||10.04 ± 1.54||10.08 ± 1.29||3.82 ± 0.65||3.70 ± 0.59||96.8 ± 7.6|
The effect of food on the pharmacokinetics of RIFATER tablets was not studied.
Rifampin is readily absorbed from the gastrointestinal tract. Peak serum levels in healthy adults and pediatric populations vary widely from individual to individual. Following a single 600 mg oral dose of rifampin in healthy adults, the peak serum level averages 7 mcg/mL but may vary from 4 to 32 mcg/mL. Absorption of rifampin is reduced by about 30% when the drug is ingested with food.
In healthy adults, the biological half-life of rifampin in serum averages 3.35 ± 0.66 hours after a 600 mg oral dose, with increases up to 5.08 ± 2.45 hours reported after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2 to 3 hours. The half-life does not differ in patients with renal failure at doses not exceeding 600 mg daily and, consequently, no dosage adjustment is required. The half-life of rifampin at a dose of 720 mg daily has not been established in patients with renal failure. Following a single 900 mg oral dose of rifampin in patients with varying degrees of renal insufficiency, the mean half-life increased from 3.6 hours in healthy adults to 5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30-50 mL/min, less than 30 mL/min, and in anuric patients, respectively. Refer to the WARNINGS section for information regarding patients with hepatic insufficiency.
After absorption, rifampin is rapidly eliminated in the bile, and an enterohepatic circulation ensues. During this process, rifampin undergoes progressive deacetylation so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite has antibacterial activity. Intestinal reabsorption is reduced by deacetylation, and elimination is facilitated. Up to 30% of a dose is excreted in the urine, with about half as unchanged drug.
Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.
In one study, pediatric patients 6 to 58 months old were given rifampin suspended in simple syrup or as dry powder mixed with applesauce at a dose of 10 mg/kg body weight. Peak serum concentrations of 10.7 ± 3.7 and 11.5 ± 5.1 mcg/mL were obtained 1 hour after preprandial ingestion of the drug suspension and the applesauce mixture, respectively. After the administration of either preparation, the t1/2 of rifampin averaged 2.9 hours. It should be noted that in other studies in pediatric populations, at doses of 10 mg/kg body weight, mean peak serum concentrations of 3.5 mcg/mL to 15 mcg/mL have been reported.
After oral administration, isoniazid is readily absorbed from the GI tract and produces peak blood levels within 1 to 2 hours which decline to 50% or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). Isoniazid is not substantially bound to plasma proteins. The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. The plasma half-life of isoniazid in patients with normal renal and hepatic function ranges from 1 to 4 hours, depending on the rate of metabolism. From 50% to 70% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as metabolites.
Isoniazid is metabolized in the liver mainly by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50% of African Americans and Caucasians are “slow inactivators” and the rest are “rapid inactivators”; the majority of Eskimos and Asians are “rapid inactivators.” The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug, and thus, an increase in toxic reactions.
Pyridoxine (B6) deficiency is sometimes observed in adults with high doses of isoniazid and is probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.
Pyrazinamide is well absorbed from the gastrointestinal tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg/mL with doses of 20 to 25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs, and cerebrospinal fluid (CSF). The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges. Pyrazinamide is approximately 10% bound to plasma proteins. The plasma half-life of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The half-life of the drug may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydroxypyrazinoic acid.
Within 24 hours, approximately 70% of an oral dose of pyrazinamide is excreted in urine, mainly by glomerular filtration. About 4% to 14% of the dose is excreted as unchanged drug; the remainder is excreted as metabolites.
Mechanism of Action
inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase, but does not inhibit the mammalian enzyme.
Isoniazid inhibits the biosynthesis of mycolic acids which are major components of the cell wall of Mycobacterium tuberculosis.
The exact mechanism of action by which pyrazinamide inhibits the growth of Mycobacterium tuberculosis organisms is unknown.
Organisms resistant to rifampin are likely to be resistant to other rifamycins. β-lactamase production should have no effect on rifampin activity.
In the treatment of tuberculosis, the small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures.
Activity in vitro and in vivo
Rifampin, isoniazid, and pyrazinamide at therapeutic levels have demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms (see INDICATIONS AND USAGE).
Pyrazinamide alone is only active at a slightly acidic pH (pH 5.5) in vitro and in vivo. Isoniazid kills actively growing tubercle bacilli.
Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and in vitro susceptibility tests.
In vitro testing for Mycobacterium tuberculosis isolates
Two standardized in vitro susceptibility methods are available for testing isoniazid, rifampin, and pyrazinamide against Mycobacterium tuberculosis organisms. The agar proportion method (CDC or CLSI M24-A) utilizes Middlebrook 7H10 medium impregnated with isoniazid at 0.2 and 1.0 mcg/mL and rifampin at 1.0 mcg/mL for the final concentrations of drug. The final concentration for pyrazinamide is 25.0 mcg/mL at pH 5.5. After 3 weeks of incubation MIC99 values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug ≥ 1% of the control indicates resistance.
The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 0.2 and 1.0 mcg/mL of isoniazid and 2.0 mcg/mL of rifampin. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay. The radiometric broth method has not been approved for the testing of pyrazinamide.
Susceptibility test results obtained by the two different methods can only be compared if the appropriate rifampin or isoniazid concentrations are used for each test method as indicated above. Both test procedures require the use of Mycobacterium tuberculosis H37Rv, ATCC 27294, as a control organism.
The clinical relevance of in vitro susceptibility test results for mycobacterial species other than Mycobacterium tuberculosis using either the radiometric broth method or the proportion method has not been determined.
A total of 250 patients were enrolled in an open label, prospective, randomized, parallel group, active controlled trial, for the treatment of pulmonary tuberculosis. There were 241 patients evaluable for efficacy, 123 patients received isoniazid, rifampin and pyrazinamide as separate tablets and capsules for 56 days, and 118 patients received 4 to 6 RIFATER tablets based on body weight for 56 days. RIFATER tablets and the drugs dosed as separate tablets and capsules were administered based on body weight during the intensive phase of treatment according to the following table.
Dose of Isoniazid, Rifampin
and Pyrazinamide Administered as Separate Drugs
|Patient Weight||Isoniazid (mg)||Rifampin (mg)||Pyrazinamide (mg)|
|< 50 kg||300||450||1500|
|≥ 50 kg||300||600||2000|
Dose of Isoniazid, Rifampin
and Pyrazinamide Administered as RIFATER
|Patient Weight||Number of Tablets||Isoniazid (mg)||Rifampin (mg)||Pyrazinamide (mg)|
|≤ 44 kg||4||200||480||1200|
|45 to 54 kg||5||250||600||1500|
|≥ 55 kg||6||300||720||1800|
During the continuation phase, both treatment groups received 450 mg of rifampin and 300 mg of isoniazid per day for 4 months if the patient weighed < 50 kg or 600 mg of rifampin and 300 mg of isoniazid per day for 4 months if the patient weighed ≥ 50 kg. Patients were followed for occurrence of relapses for up to 30 months after the end of therapy.
There were no significant differences in the negative bacteriological sputum results (available in a subset of patients) between the two treatments at 2 and 6 months during the trial and during the follow-up period. See table below.
Negative Sputums/No. of
Patients (Percent Negative)
|Treatment||2 Months||6 Months||Follow-up Period*|
|RIFATER||91/96 (95%)||100/104 (96%)||99/101 (98%)|
|Separate†||99/108 (92%)||95/96 (99%)||105/106 (99%)|
|* The median follow-up time for all the RIFATER patients
was 756 days with a range of 42 to 1325 days and 745 days with a range of 50 to
1427 days for the patients dosed with separate tablets and capsules.
† Isoniazid, rifampin, and pyrazinamide dosed as separate tablets and capsules.
For adverse events, (See ADVERSE REACTIONS).
Last reviewed on RxList: 3/18/2013
This monograph has been modified to include the generic and brand name in many instances.
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