Rifampin versus Rifapentine

Charles A. Peloquin, Pharm.D.DirectorInfectious Disease Pharmacokinetics LaboratoryProfessor, College of Pharmacy &The Emerging Pathogens InstituteUniversity of Florida

role: primary drug, along with INH

action: DNA - dependent RNA polymerase

dosage: oral, I.V. ( most countries ); m.w. 823 mu

dose: 600 mg QD // moving to 2400 mg QD ?

cleared: liver >> kidneys; t1/2 @ s.s. 2 hours

toxicity: hepatotoxicity, flu - like syndrome

Rifampin ( RIF )

Rifampin ( RIF )

0

1

2

3

4

5

6

7

8

9

10

0 4 8 12 16 20 24 28 32 36 40 44 48

RIFfree RIFLq. MIC

Rifampin plasma concentrations, 600 mg

role: primary drug, along with INH

action: DNA - dependent RNA polymerase

dosage: oral ( USA only ); m.w. 877 mass units

dose: 600 mg QD // moving to 1200 mg QD

cleared: liver >> kidneys; ~ 99% protein bound

toxicity: hepatotoxicity, flu - like syndrome

Rifapentine ( RPNT )

Rifapentine ( RPNT )

0

2

4

6

8

10

12

14

0 4 8 12 16 20 24 28 32 36 40 44 48

RPNTfree RPNTLq. MIC

Rifapentine plasma concentrations, 600 mg

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

0 4 8 12 16 20 24 28 32 36 40 44 48

RPNTfree RPNTLq. MIC

Rifampin versus Rifapentine

A tale of two Ferraris with different tails

Rifamycin Comparison ( 600 mg )

MIC * Cmax ^ Ratio t ½( µg / ml ) ( µg / ml ) ( hr )

Rifampin 0.25 12 48 2

Rifapentine 0.06 16 267 15

* 7H12 broth ^ total Rx ( free and bound )

Rifamycin Comparison ( 600 mg )

MIC * Cmax # Ratio t ½( µg / ml ) ( µg / ml ) ( hr )

Rifampin 0.25 1.8 7.2 2

Rifapentine 0.06 0.16 2.7 15

* 7H12 broth # free Rx ( only free is active )

Rifamycin Comparison

Serum albumin, 65,000 – 70,000 mass units

or about 80 x

larger than

RPNT

Rifapentine plus Albumin

PD: Sterilizing Activity of Rifampin

Jayaram et al, AAC 2003 ; 47: 2118

Mean value after 600 mg oral dose

R^2 = 0.95

PD: Sterilizing Activity of Rifampin

Jayaram et al, AAC (2003); 47:2118

Mean value after 600 mg oral dose

mg/liter resulted in a 2.5-log10 CFU/ml reduction in 7 days,thereby concluding that it is a concentration-dependent drug.In our studies, rifampin exhibited an Emax that resulted in a6-log10 CFU/ml reduction on day 1 to day 7. The EC50 de-creased from a Cmax/MIC of 158.5 on day 1 to a Cmax/MIC of4.89 on day 7, suggesting that rifampin showed a clear exposure(concentration ! time)-dependent killing. Thus, the concen-tration required to achieve a 6-log10 CFU/ml reduction on day1 was higher than the concentration required to achieve thesame reduction on day 7. This is in line with the observationmade by Jenne and Beggs (19), who they demonstrated thatthe 25% inhibition of M. tuberculosis by rifampin was depen-dent on the product of time and concentration, which is ameasure of exposure. It is pertinent that rifampin can rapidlykill 6 log10 CFU of nonreplicating bacilli within a single day,provided that a Cbroth/MIC of "1,000 is achieved.

Rifampin rapidly penetrates mammalian cells and accumu-lates to four- to fivefold higher levels in the intracellular envi-ronment than in the extracellular environment (5). One mightargue that this may be an apparent accumulation, since it isdifficult to separate that which entered the cell and that whichremained adherent to the cell surface due to the high lipophi-licity of rifampin. On the contrary, Dhillon and Mitchison (12)showed that the level of intracellular killing by rifampin is

lower in macrophages than it is in vitro under cell-free condi-tions. This is consistent with our observation that the Emax

obtained in the macrophage infection model is much lowerthan that observed under extracellular conditions. Carryn et al.(8) point out that intracellular accumulation and intracellularactivity are not necessarily the same. There may be severalfactors that separate the two, one of which could be the loca-tion of the bacilli within the mammalian cell. On the otherhand, protein binding does not explain this difference, sinceunder both the broth and macrophage culture conditions, theamount of albumin is less than or equal to 10%.

We were able to demonstrate that AUC/MIC showed thebest correlation with the bactericidal efficacy of rifampin. It ispertinent that this bactericidal effect was exerted against non-replicating organisms, since the onset of treatment in mice wasdelayed until after the onset of the stationary phase. TheAUC24/MIC ratios required for a 1-log10 CFU reduction invivo and inside macrophages were higher than those requiredin vitro. The difference in the level of exposure needed couldbe explained by the presence of barriers within the mammalianhost, either at the level of intracellular compartments or at thelevel of impermeable granulomas, where the bacilli are seques-tered from the drug.

Mitchison (27) argues that if the rifampin 600-mg dose rec-ommended at present was increased to 900 mg, it would sig-nificantly accelerate the sterilization process. We have pro-vided in our studies a PD basis to support this hypothesis, sincewe were able to achieve a culture-negative state (#30 CFU/lung) within 6 days of treatment when AUC/MIC ratios ofapproximately 50,000 were achieved following administrationof a 810-mg/kg dose. However, it is not practical to achievesimilar levels of exposure (AUC/MIC ratios) in humans with-out compromising safety. In our experiments a modest in-crease in the dose from 10 to 15 mg/kg reduces the duration oftreatment by one-third to achieve comparable AUC/MIC ra-tios. While it has long been recognized that rifampin is one ofthe best drugs in the directly observed therapeutic regimen

FIG. 6. Relationship between AUC24/MIC (A), Cmax/MIC (B), andT " MIC (C) of rifampin and log10 CFU per lung of M. tuberculosis(mean $ standard deviation) when the total dose was given as one,three, or six equally divided doses over 144 h.

VOL. 47, 2003 RIFAMPIN PHARMACOKINETICS-PHARMACODYNAMICS 2123

R^2 = 0.86

7.2 40

Mean value after 600 mg oral dose

PD: Sterilizing Activity of Rifampin

Jayaram et al, AAC (2003); 47:2118

Mean value after 600 mg oral dose

R^2 = 0.44

mg/liter resulted in a 2.5-log10 CFU/ml reduction in 7 days,thereby concluding that it is a concentration-dependent drug.In our studies, rifampin exhibited an Emax that resulted in a6-log10 CFU/ml reduction on day 1 to day 7. The EC50 de-creased from a Cmax/MIC of 158.5 on day 1 to a Cmax/MIC of4.89 on day 7, suggesting that rifampin showed a clear exposure(concentration ! time)-dependent killing. Thus, the concen-tration required to achieve a 6-log10 CFU/ml reduction on day1 was higher than the concentration required to achieve thesame reduction on day 7. This is in line with the observationmade by Jenne and Beggs (19), who they demonstrated thatthe 25% inhibition of M. tuberculosis by rifampin was depen-dent on the product of time and concentration, which is ameasure of exposure. It is pertinent that rifampin can rapidlykill 6 log10 CFU of nonreplicating bacilli within a single day,provided that a Cbroth/MIC of "1,000 is achieved.

Rifampin rapidly penetrates mammalian cells and accumu-lates to four- to fivefold higher levels in the intracellular envi-ronment than in the extracellular environment (5). One mightargue that this may be an apparent accumulation, since it isdifficult to separate that which entered the cell and that whichremained adherent to the cell surface due to the high lipophi-licity of rifampin. On the contrary, Dhillon and Mitchison (12)showed that the level of intracellular killing by rifampin is

lower in macrophages than it is in vitro under cell-free condi-tions. This is consistent with our observation that the Emax

obtained in the macrophage infection model is much lowerthan that observed under extracellular conditions. Carryn et al.(8) point out that intracellular accumulation and intracellularactivity are not necessarily the same. There may be severalfactors that separate the two, one of which could be the loca-tion of the bacilli within the mammalian cell. On the otherhand, protein binding does not explain this difference, sinceunder both the broth and macrophage culture conditions, theamount of albumin is less than or equal to 10%.

We were able to demonstrate that AUC/MIC showed thebest correlation with the bactericidal efficacy of rifampin. It ispertinent that this bactericidal effect was exerted against non-replicating organisms, since the onset of treatment in mice wasdelayed until after the onset of the stationary phase. TheAUC24/MIC ratios required for a 1-log10 CFU reduction invivo and inside macrophages were higher than those requiredin vitro. The difference in the level of exposure needed couldbe explained by the presence of barriers within the mammalianhost, either at the level of intracellular compartments or at thelevel of impermeable granulomas, where the bacilli are seques-tered from the drug.

Mitchison (27) argues that if the rifampin 600-mg dose rec-ommended at present was increased to 900 mg, it would sig-nificantly accelerate the sterilization process. We have pro-vided in our studies a PD basis to support this hypothesis, sincewe were able to achieve a culture-negative state (#30 CFU/lung) within 6 days of treatment when AUC/MIC ratios ofapproximately 50,000 were achieved following administrationof a 810-mg/kg dose. However, it is not practical to achievesimilar levels of exposure (AUC/MIC ratios) in humans with-out compromising safety. In our experiments a modest in-crease in the dose from 10 to 15 mg/kg reduces the duration oftreatment by one-third to achieve comparable AUC/MIC ra-tios. While it has long been recognized that rifampin is one ofthe best drugs in the directly observed therapeutic regimen

FIG. 6. Relationship between AUC24/MIC (A), Cmax/MIC (B), andT " MIC (C) of rifampin and log10 CFU per lung of M. tuberculosis(mean $ standard deviation) when the total dose was given as one,three, or six equally divided doses over 144 h.

VOL. 47, 2003 RIFAMPIN PHARMACOKINETICS-PHARMACODYNAMICS 2123

Rifampin PD

Rifampin PD clearly is linked to AUC / MIC

and somewhat less to Cmax / MIC.

It is not linked to % Time > MIC.

Therefore, what is the rationale for

a long half – life version of rifampin ?

Rifampin 600, 1200, 1500, 1800, 2100 mg

RIF log cfu TTP Cmax AUC ( mg / kg ) ( / ml / d )

10 0.18 0.02 7 2620 0.15 0.03 26 11325 0.16 0.03 25 13530 0.25 0.04 33 18935 0.25 0.04

Boeree M. et al, CROI 2013; Paper #148LB

Dose Ranging Trial to Optimize the Dose of Rifampin

Maximum tolerated dose study :RIF 10, 15, 20, 25, 30, 35 mg / kg for 14 daysin patients with drug – susceptible TB[ 70 kg * 35 mg / kg = 2,450 mg, round to 2,400 mg ]

More – than proportional increases in Cmaxand AUC occurred as doses increased.

Am J Respir Crit Care Med 2015; 191: 1058 - 1065.

Dose Ranging Trial to Optimize the Dose of Rifampin

Maximum tolerated dose study :High inter –individual variability in Cmax and AUC within any given dose ( an argument for TDM ).

Greatest reduction in sputum colony countsof Mtb were seen with the highest AUC.

Am J Respir Crit Care Med 2015; 191: 1058 - 1065.

High RPNT exposures (AUC) were associatedwith high levels of sputum sterilization at the completion of 8 weeks of treatment ( end of intensive phase )

Less – than proportional increases in Cmaxand AUC occurred as doses increased.

Am J Respir Crit Care Med 2015; 191: 333 - 343.

Daily Rifapentine for Treatmentof Pulmonary Tuberculosis

What is the “ Best “ Rifamycin ?

To truly answer “which is best” you would need to study escalating doses of rifapentineversus escalating doses of rifampin.

Otherwise, it will depend on who argues loudest( which is not very scientific ).

Tracer bullets -

visually guided dosing of Pb

Because only the bullets that hit their targets actually work … early TDM in 1945.

Acknowledgements