A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Priftin Pharmacology, Pharmacokinetics, Studies, Metabolism - Rifapentine
Priftin Pharmacology, Pharmacokinetics, Studies, Metabolism - Rifapentine
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The absolute bioavailability of afapentine has not been determined.
The relative bioavailability (with an oral solution as a relavance of rifapentine
after a single 600 mg dose to healthy adult volunteers was 70 %. The maximum
concentrations were achieved from 5 to 6 hours after administration of the 600
mg utapentine dose. Food (850 total calories: 33 g protein, 55 g fat and 58
g carbohydrate) increased AUC (0-¥ ) and Cmax
by 43 % and 44%, respectively over that observed when administered under fasting
conditions. When oral doses of rifapentine were administered once daily or on
every 72 hours to healthy volunteers for 10 days, single dose AUC (0-¥
) value of rifapentine was similar to its steady-state AUCSS (0-24h)
or AUCSS (0-72h) values, suggesting no significant auto induction
effect on steady-state pharmacokinetics of rifapentine. Steady state conditions
were achieved by day 10 following daily administration of rifapentine (active
metabolite on day 10 following oral administration of 600 mg rifapentine every
72 hours to healthy volunteers are contained in the following table.
|
Parameter
|
Refapentine
|
25-desacetyl Rifapentine
|
| |
Mean ± SD (n=12)
|
|
Cmax (m g/mL)
|
15.45 ± 4.62
|
6.26 ± 2.06
|
|
AUC (0-72h)( m g*h/mL)
|
319.54 ± 91.52
|
215.88 ± 85.96
|
|
T ½ (h)
|
13.19 ± 1.38
|
13.35 ± 2.67
|
|
T max (h)
|
4.83 ± 1.80
|
11.25 ± 2.73
|
|
Clpo (L/h)
|
2.03 ± 0.60
|
--
|
Distribution
In a population pharmacokinet analysis in 351 tuberculosis
patients who received 600 mg rifapentine in combination with bomazid, pyrazinamide
and ethambutol, the estimated apparent volume of distribution was 70- 9: 1.
In healthy volunteers, rifapentine and 25-desacetyl rifapentine were 97.7% and
instead to plasma proteins, respectively. Rifapentine was mainly bound to albumin.
Since extent of protein binding was observed in healthy volunteers, asymptomatic
HIV-infected and hepatically impaired subjects.
Metabolism/Excretion
Following a single 600 mg oral dose of radiolabelled rifapentine
to healthy volunteers (n=4), 87% of the total 14C rifapentine was recovered
in the urine (17%) and feces (70%). Greater than 80% of the total 14C rifapentine
dose was excreted from the body within 7 days. Rifapentine was hydrolyzed by
an esterasenzyme to form a microbiologically active 25-desacetyl rifapentine.
Rifapentine and as desacetyl rifapentine accounted for 99% of the total radioactivity
in plasma. Plasma AUC (0-¥ ) and Cmax values
of the 25-desacetyl rifapentine metabolite were one-half and one-third those
of rifapentine, respectively. Based upon relative in vitro activities and AUC
(0-¥ ) values rifapentine and 25-desacetyl rifapentine
potentially contributes 62% and 38% to the actual activities against M. tuberculosis,
respectively.
Special Populations
Gender: In a population pharmacokmetics analysis of
sparse blood samples obtained from 351 tuberculosis patients who received 600
mg rifapentine in combination with isoniazid, pyrazinamide and ethambutol, the
estimated apparent oral clearance of rifapentine for males and females was 2.51
± 0.14 L/h and 1.69 ±
0.41 L/h, respectively. The clinical significance of the difference in the estimated
apparent oral clearance is not known.
Elderly: Following oral administration of a single 600
mg dose of rifapentine to elderly (³ 65 years)
male healthy volunteers (n=14), the pharmacokinetics of rifapentine and 25-desacetyl
metabolite were similar to that observed for young (18 to 45 years) healthy
male volunteers (n=20).
Pediatric (Adolescents): In a pharmacokinetic study
of rifapentine in healthy adolescents (age 12 to 15), 600 mg rifapentine was
administered to those weighing ³ 45 kg (n=10)
and 450 mg was administered to those weighing <45 kg (n=2). The pharmacokinetics
of rifapentine were similar to those observed on healthy adults.
Renal Impaired Patients: The pharmacokinetics of rifapentine
have not been evaluated in renal impaired patients. Although own about 17% of
an administered dose is excreted via the kidneys, the clinical significance
of impaired renal function on the disposition of rifapentine and its 25-desacetyl
metabolite is not known.
Hepatic Impaired Patients: Following oral administration
of a single 600 mg dose of rifapentine to mild to severe hepatic impaired patients
(n=15), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were
similar in patients with various degrees of hepatic impairment and to that observed
an another study for healthy volunteers (n=12). Since the elimination of these
agents are primarily via the liver, the clinical significance of impaired hepatic
function on the disposition of rifapentine and its 25- desacetyl metabolite
is not known.
Asymptomatic HIV-Infected Volunteers: Following oral
administration of a single 600 mg dose of rifapentine to asymptomatic HIV-infected
volunteers (n=15) under fasting conditions, mean Cmax and AUC (0-¥
) of rifapentine were lower (20-32%) than that observed in other studies in
healthy volunteers in SS. In a cross-study comparison, mean Cmax
and AUC values of the 25-desacetyl metabolite rifapentine, when compared to
healthy volunteers were higher (6-21%) in one study (n=20), but lower (15-16%)
in a different study (n=40). The clinical significance of this observation is
not known. Food (850 total calories: 33g protein, 55g fat, and 58 g carbohydrate)
increases the mean AUC and Cmax of rifapentine observed under fasting
conditions in asypromatic HIV-infected volunteers by about 51% and 53%, respectively.
Microbiology:
Mechanism of Action
Rifapentine, a cyclopentyl rifapentine, inhibits DNA-dependent
RNA polymerase in susceptible strains of Mycobacterium ruberculosis but not
in mammalian cells. At therapeutic levels, rifapentine exhibits bactericidal
activity against both intracellular and extracellular M. tuberculosis organisms.
Both rifapentine and the 25-desacetyl metabolite accumulate in human monocyte-derived
macrophages with intracellular/extracellular ratios of approximately 24:1 and
7:1, respectively.
Resistance Development
In the treatment of tuberculosis (see INDICATIONS
and USAGE), a small number of resistant cells present within large
populations of susceptible cells can rapidly become predominant. Rifapentine
resistance development in M. tuberculosis strains is principally due to one
of several single point mutations that occur in the rpoB portion of the gene
coding for the beta submit of the DNA-dependent RNA polymerase. The incidence
of rifapentine resistant mutants in an otherwise susceptible population of M.
tuberculosis strains is approximately one in 10’ to 10’ bacilli. Due to the
potential for resistance development to rifapentine, appropriate susceptibility
tests should be performed in the event of persistently positive cultures.
M.tuberculosisorganisms resistant to other rifamycins are likely
to be resistant to rifapentine. A high level of cross resistance between rifampin
and rifapentine has been demonstrated with M.tuberculosis strains. Cross resistance
does not appear berween rifapentine and non-rifamycin antimycobacterial agents
such as isoniazid and streptomycin.
In Vitro Activity of Rifapentine against M.tuberculosis
Rofapentine and its 25-desacetyl metabolite have demonstrated
in vitro activity against phagocytized M.tuberculosis organisms grown in activated
human macrophages.
In vitro results indicate that rifapentine MIC values for M.tuberculosis
organisms are influenced by study conditions. Rifapentine MIC values were substantially
increased employing egg-based medium compared to liquid or agar-based solid
media. The addition of Tween 80 in these assays has been shown to lower MIC
values for rifamycin compounds.
In mouse infection studies a therapeute effect, in terms of
enhanced survival time or reduction of organ bioburden, has been observed in
M.tuberculosis-infected animals treated with various intermittent rifapentine-containing
segmens. Animal studies have shown that the activity of rifapentine is influenced
by dose and frequency of administration.
Susceptibility testing for Mycobacterium tuberculosis
Breakpoints to determune whether clinical isolates of M.tuberculosis
are susceptible or resistant to rifapentine have not been established. The clinical
relevance of rifapentine in vitro susceptibility test results for other mycobacterial
species has not been determined.
CLINICAL TRIALS
A total of 722 patients were enrolled in Clinical Study 008,
an open label, prospective, randomized, parallel group, active controlled trial,
for the treatment of pulmonary tuberculosis. This population was mostly comprised
of Black (>60%) or Multiracial (>31%) patients and the mean ±
standard deviation age was 37 ± 11 years. Treatment
groups were comparable with respect to age and race. The percentage of male
patients was higher in the rifapentine combination group (80%) than in the rifampin
combination group (73%). The study was divided into two phases on the basis
of dosing frequency. For the first phase, designated as the Intensive Phase,
361 patients were randomized to receive rifapentine, isoniazid, Pyrazinamide,
and ethambutol for 60 days and 361 patients were randomized to receive rifampin,
isonized, pyrazinamide, and ethambutol for 60 days. (Ethambutol was to be discontinued
once baseline susceptibility test results were available). Rifapentine and isoniazid
were each administered at a fixed dose regardless of body weight rifampin, pyrazinamide,
and ethambutol were administered based on body weight according to Table 2-1.
Note: All drugs were administered daily in the Intensive Phase except for rifapentine
which was administered twice weekly.
During the second phase, designated as the Continuation Phase,
317 patients who had received rifapentine in the Intensive Phase continued to
receive rifapentine and isoniazid once weekly for upto 120 days. Three hundred
tour patients who had received rifampin in the Intensive Phase continued to
receive rifampin and isoniazid during the Continuation Phase twice weekly for
up to 120 days. Rifampin and isoniazid were administered based on body weight
according to Table 2-1.
Patients in either treatment group were scheduled to receive
study drug over a 180-day period with a subsequent 24-month follow-up. Additionally,
both treatment groups received pyridoxine (Vitamin B6) over the 180-day
treatment period.
The indication for treatment of pulmonary tuberculosis with
PRIFTIN is based on the 6 month follow-up treatment outcome observed
in Clinical Study 008 as a surrogate for the 2 year follow-up generally accepted
as evidence of efficacy in the treatment of pulmonary tuberculosis.
|
Table 2-1. Dose of Rifapentine,Rifampin, Isoniazid, Pyrazinamide,
and Ethambutol
|
|
Rifapentine Combination Treatment
|
|
Intensive Phase
|
Rifapentine (mg)
|
Isoniazid (mg)
|
Pyrazinamide (mg)
|
Ethambutol (mg)
|
| |
Twice Weekly
|
Daily
|
Daily
|
Daily
|
|
Patient Weight
<50 kg
³ 50 kg
|
600
600
|
300
300
|
1500 –
2000
|
800
1200
|
|
Continuation Phase
|
Rifapentine (mg)
|
Isoniazid (mg)
|
|
| |
Once Weekly
|
Once Weekly
|
|
|
Patient Weight
<50 kg
³ 50 kg
|
600
600
|
600
900
|
|
Rifapentine Combination Treatment
|
|
Intensive Phase
|
Rifapentine (mg)
|
Isoniazid (mg)
|
Pyrazinamide (mg)
|
Ethambutol (mg)
|
| |
Daily
|
Daily
|
Daily
|
Daily
|
|
Patient Weight
<50 kg
³ 50 kg
|
450
600
|
300
300
|
1500
2000
|
800
1200
|
|
Continuation Phase
|
Rifapentine (mg)
|
Isoniazid (mg)
|
|
| |
Twice Weekly
|
Twice Weekly
|
|
|
Patient Weight
<50 kg
³ 50 kg
|
450
600
|
600
900
|
* Ethambutol was to be discontinued once baseline susceptiblity test results
were available.
Priftin Proposed Text of the Labeling (Annotated)
Table 2-2 presents clinical outcome in study 008.
|
Table 2-2 presents clinical outcome in study 008.
|
| |
Rifapentine Combination
|
Rifapentine Combination
|
|
Status at End of Treatment:
|
|
|
|
Converted
|
67% (249/286)
|
81% (229/284)
|
|
Not Converted
|
1% (4/286)
|
3% (8/284)
|
|
Lost to Follow-up
|
12% (33/286)
|
17% (47/284)
|
|
Status in follow up.
|
|
|
|
Relapsed
|
10% (25/249)
|
5% (11/229)
|
|
Sputum negative, Still being followed
|
81% (201/249)
|
90% (205/229)
|
|
Lost to Follow-up
|
9% (23/249)
|
6% (13/229)
|
- All data through 8 July 1997 for patients with confirmed susceptible MTB
(rifapentine combination, n=286; rifampin combination, n=284).
Risk of relapse was higher in the rifapentine regimen. During
the Intensive Phase of treatment the rate of noncompliance with companion medications
was somewhat higher for the rifapentine regimen than for the rifampin regimen.
Most of the relapses occurred among those with poor compliance with these companion
medications and this group also had the largest risk of relapse for the rifapentine
regimen relative to the rifampin regimen. This factor appears to explain most,
but not all, of the higher relapse rate observed in the rifapentine arm. Failure
to convert sputum after two months of treatment (e., end of Intensive Phase)
was associated with a greater risk of relapse for both treatment regimens. Relapse
rates were also higher for males in both regimens. Relapse in the rifapentine
group was not associated with development of mono-resistance to rifampin.
In vitro susceptibility testing was conducted against initial
and subsequent M.tuberculosis isolates recovered from 620 patients enrolled
in the study. Rifapentine and rifampin MIC values were determined employed the
radiometric susceptibility testing method utilizing 7H 12 broth at pH 6.8 (NCCLS
procedure M24.T). Six hundred and fourteen patients with rifampin susceptible
(MIC £ 0.5m
g/mL) strains of M. tuberculosis had rifapentine MICs of £
0.125 m g/mL. The remaining six patients with
rifampin resistant (MIC > 8.0 m g/mL). M.tuberculosis
isolates had rifapentine MICs of >8.0 m g/mL.
Four of these represented baseline values for patients with multiresistant tuberculosis.
One rifampin resistant isolate was from a rifapentine relapse patient while
the remaining isolate was from a rifampin relapse patient. Restriction fragment
length polymorphism (RFLP) studies showed the rifapentine relapse isolate to
be genetically different from the baseline strain while RFLP data on the matched
rifampin isolate is pending. This information is provided for comparative purpose
only as rifapentine breakpoints have not been established.
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