Pharmacokinetics of rifapentine, a new long lasting rifamycin, in the rat, the mouse and the rabbit.

Assandri, Alessandro; Ratti, Bruno; Cristina, Tito

doi:10.7164/antibiotics.37.1066

Cited by 32 publications

(16 citation statements)

References 6 publications

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“…The corresponding pharmacokinetic parameters are presented in Table 5 along with those obtained after 1 wk of dosing with daily R and twice-weekly P. The 25-desacetyl metabolites of R and P were not detected at any time point, as described previously for rodents (23,24). After a single oral dose, the total drug mean peak serum concentration (Cmax) values were 12.1 Ϯ 1.3 g/ml for 10 mg/kg of rifampin and 19.2 Ϯ 1.0 g/ml for 15 mg/kg of P. The time to peak serum concentration (Tmax) values were 2 and 2.7 h for R and P, respectively.…”

Section: Pharmacokinetics and Pharmacodynamics Of Rifampin And Rifapementioning

confidence: 76%

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Rosenthal

Williams²,

Tyagi³

et al. 2006

Am J Respir Crit Care Med

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Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin. Methods: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid-or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single-and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined. Results: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid-or moxifloxacincontaining therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg). In the treatment of drug-susceptible pulmonary tuberculosis (TB), daily administration of a standardized 6-mo regimen including rifampin (R), isoniazid (H), and pyrazinamide (Z; collectively, RHZ) is highly effective in achieving cure (1). But, because supervision of daily treatment imposes a substantial burden on both patients and treatment programs (2, 3), intermittent regimens with predominantly twice-or thrice-weekly drug administration are recommended for supervised therapy (4, 5). Although at least one randomized clinical trial has shown that daily and thrice-weekly RHZ-based regimens have similar efficacy, more recent observational studies suggest intermittent therapy is not as effective as daily therapy, particularly in patients at high risk for relapse (6-8). Recent experience in the murine model of TB supports the latter observations. Daily administration of the 6-mo RHZ-based regimen is significantly more effective than the same regimen administered according to a predominantly twice-weekly schedule (9).The rifamycins are the key drugs in modern short-course therapy. Rifapentine (P) is a rifamycin with a lower minimum inhibitory concentration (MIC) against Mycobacterium tuberculosis and a much longer serum half-life compared with R (10). While P is approved for twice-weekly administration at a dose of 10 mg/kg during the initial phase of therapy (11), several influential clinical trials have focused attention on the use of once-weekly administration of P in combination with H during the continuation phase. In Tuberculosis Trials Consortium Study 22, once-weekly PH was less effective than twice-weekly RH, and was associated with rifamycin-resistant relapse among HIVinfected patients (12...

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Section: Pharmacokinetics and Pharmacodynamics Of Rifampin And Rifapementioning

confidence: 76%

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Rosenthal

Williams²,

Tyagi³

et al. 2006

Am J Respir Crit Care Med

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“…Subsequent studies have shown that the broth-determined MICs of RPT were two-to threefold lower than those of RMP (8,10). The elimination half-life of RPT in animals and humans was about five times longer than that of RMP, and the levels of RPT in plasma substantially exceeded the MICs for a period of up to 72 h after a single oral dose (1)(2)(3)12). The advantage of RPT over RMP has been shown in murine models (1,5,11,18).…”

mentioning

confidence: 99%

Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages

Mor

Simon

Mezo

et al. 1995

Antimicrob Agents Chemother

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The activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human monocytederived macrophages were determined. The MICs and MBCs of rifapentine for intracellular bacteria were twoto fourfold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. Nevertheless, the more favorable pharmacokinetics of rifapentine over rifampin was addressed in other experimental models. These models showed substantial differences after short pulsed exposures of the infected macrophages to the drugs and when the infected macrophages were exposed to changing drug concentrations that imitated the pharmacokinetic curves observed in blood. Once-a-week exposures to rifapentine concentrations equivalent to those attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and this decline was maintained at a minimal level for a period of four weeks. The results of this study have shown the suitability of rifapentine for intermittent-treatment regimens. The prolonged effect of rifapentine found in this study may be associated with high ratios of intracellular accumulation, which were four-to fivefold higher than those found for rifampin. Further studies on the intracellular distribution of rifamycins and on the sites of actual interaction between the drugs and bacteria residing in macrophages are necessary.The combined use of isoniazid, rifampin, and pyrazinamide provided the basis for a successful short course of tuberculosis therapy. The discovery of long-lasting rifamycins, particularly of rifapentine (RPT), created the possibility for intermittent drug regimens (5,7,18). In the early studies, RPT was reported to have an in vitro activity the same as or higher than that of rifampin (RMP) (19,20). Subsequent studies have shown that the broth-determined MICs of RPT were two-to threefold lower than those of RMP (8, 10). The elimination half-life of RPT in animals and humans was about five times longer than that of RMP, and the levels of RPT in plasma substantially exceeded the MICs for a period of up to 72 h after a single oral dose (1)(2)(3)12). The advantage of RPT over RMP has been shown in murine models (1,5,11,18). Besides its more favorable pharmacokinetic parameters in blood, RPT accumulates to higher concentrations than does RMP in polymorphonuclear leukocytes and macrophages (6,9,16).In anticipation of a controlled clinical trial for the comparison of RPT and RMP in the therapy of tuberculosis, the present study compares the potential activities of these rifamycins against extracellular and intracellular Mycobacterium tuberculosis. Inhibitory and bactericidal activities (MICs and MBCs) against intracellular bacteria in human monocyte-derived macrophages were determined and compared with MICs and MBCs against extracellular bacteria. The actual accumulation of these drugs in human monocytes was also determined. Special attention was given to the evaluation of the long-lasting effect of RPT after pulsed expo...

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“…Newer rifamycin analogs such as rifabutin (RBT), rifapentine (RPT), CGP 7040, CGP 29,861, and P/DEA (MDL 62,769) have greater intrinsic activities than rifampin against MAC in vitro (2,5,11,20) and offer pharmacokinetic advantages such as higher peak serum or tissue levels and longer plasma elimination half-lives than rifampin (1,21). The purpose of the present study was to determine the comparative in vivo activities of the newer rifamycin analogs against MAC and to evaluate the activities of newer rifamycins in combination with other antimycobacterial agents.…”

mentioning

confidence: 99%

In vivo activities of newer rifamycin analogs against Mycobacterium avium infection

Klemens

Cynamon

1991

Antimicrob Agents Chemother

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The comparative activities of newer rifamycin analogs and the activity of rifabutin or rifapentine in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J; bgilbg') mouse model of disseminated Mycobacterium avium infection. Rifabutin and rifapentine at 20 mg/kg of body weight had comparable activities. P/DEA and CGP 7040 at 20 mg/kg were less active. The combination of ethambutol at 125 mg/kg and rifabutin at 20 mg/kg resulted in a slight increase in activity beyond that seen with rifabutin alone against organisms in the spleens. The combination of ethambutol and rifapentine at 20 mg/kg resulted in a modest increase in activity beyond that seen with rifapentine alone against organisms in the lungs. The combination of ethionamide at 125 mg/kg and rifapentine resulted in a decrease in activity compared with that for rifapentine alone. The combination of clofazimine at 20 mg/kg and rifapentine resulted in increased activity in the mouse model. The combination of clofazimine and rifapentine (or rifabutin) appears to be an attractive regimen that should be evaluated for the treatment of human infections due to M. avium complex.Rifampin (RIF) has modest activity against Mycobacterium avium complex (MAC) in vitro and limited activity in murine models of disseminated MAC infection (3,17,18). Newer rifamycin analogs such as rifabutin (RBT), rifapentine (RPT), CGP 7040, CGP 29,861, and P/DEA (MDL 62,769) have greater intrinsic activities than rifampin against MAC in vitro (2, 5, 11, 20) and offer pharmacokinetic advantages such as higher peak serum or tissue levels and longer plasma elimination half-lives than rifampin (1, 21). The purpose of the present study was to determine the comparative in vivo activities of the newer rifamycin analogs against MAC and to evaluate the activities of newer rifamycins in combination with other antimycobacterial agents. MATERIALS AND METHODSDrugs. RBT was provided by Adria Laboratories, Dublin, Ohio. RPT was provided by Merrell Dow Pharmaceuticals, Cincinnati, Ohio. P/DEA (MDL 62,769)

show abstract

Pharmacokinetics of rifapentine, a new long lasting rifamycin, in the rat, the mouse and the rabbit.

Cited by 32 publications

References 6 publications

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages

In vivo activities of newer rifamycin analogs against Mycobacterium avium infection

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