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PK and Drug Interactions in a Changing World:
New Drugs for TB and New Regimens for TB-HIV Co-infection
Charles Flexner, MDCharles Flexner, MD
Johns Hopkins UniversityJohns Hopkins University
What have we learned about TB pharmacology?
Drug concentrations matter!
Association of rifabutin AUC with TBC treatment response
Weiner et al., CID 2005; 40: 1481
What have we learned about TB pharmacology?
Drug interactions can - and will - occur!
HIV Drug Interactions in the Global CommunityHIV Drug Interactions in the Global Community New diseasesNew diseases
TuberculosisTuberculosis New culturesNew cultures
Traditional and herbal medicinesTraditional and herbal medicines New formulationsNew formulations
Impact of generics, co-formulationsImpact of generics, co-formulations New familiesNew families
Drug interactions and contraceptivesDrug interactions and contraceptives New populationsNew populations
Do genetics and ethnicity matter?Do genetics and ethnicity matter?
Treatment of the TB/HIVCo-infected Patient
Treatment of the TB/HIV co-infected patient
The problem:The problem: Rifampin, rifapentine, or rifabutin are key Rifampin, rifapentine, or rifabutin are key
components of most anti-TB regimens.components of most anti-TB regimens. All three drugs are inducers of drug metabolizing All three drugs are inducers of drug metabolizing
enzymes.enzymes. How broad is their potential for producing clinically How broad is their potential for producing clinically
significant drug-drug interactions?significant drug-drug interactions?
ExampleExample::
Possible metabolic drug Possible metabolic drug interactions involving interactions involving
rifapentine and moxifloxacinrifapentine and moxifloxacin
Rifapentine: the Drug Only new drug approved for the treatment of TB Only new drug approved for the treatment of TB
in the U.S. in the past 30 yearsin the U.S. in the past 30 years Inhibits bacterial DNA-dependent RNA Inhibits bacterial DNA-dependent RNA
polymerase polymerase inhibits RNA transcription inhibits RNA transcription Rifamycin derivative with MICRifamycin derivative with MIC5050 and MIC and MIC9090 1-2 1-2
fold dilutions lower than rifampin (i.e. more fold dilutions lower than rifampin (i.e. more potent)potent)
Half-life 5 times longer than rifampinHalf-life 5 times longer than rifampin Concentrates 24-60 fold within macrophagesConcentrates 24-60 fold within macrophages Potent P450 enzyme inducerPotent P450 enzyme inducer
Bemer-Melchior, Bemer-Melchior, J Antimicrob ChemotherJ Antimicrob Chemother 46: 571 46: 571
Rifapentine plus Moxifloxacin
The problem:The problem: Rifapentine could induce moxifloxacin Rifapentine could induce moxifloxacin
metabolism, decrease moxi metabolism, decrease moxi concentrations, and reduce moxi’s anti-concentrations, and reduce moxi’s anti-TB activity.TB activity.
How rifamycins induce drug metabolizing enzymes
- Dooley et al., J Infect Dis 2008;198:948
1 4 5 6 7 19 20 21 229 1412 16
Rifapentine 900 mg thrice-weekly
Moxi24hPK
RPT48hPK
Moxi/RPT72hPK
Moxifloxacin400 mg daily
Study Design: PK interactions between rifapentine and moxifloxacin
Effect of RPT on Moxi Concentrations
Dooley et al, Antimicrob Agents Chemother 2008;52:4037-42
Moxi alone
Moxi + RPT
RPT Concentration: single vs. multiple doses
RPT single dose
RPT multiple doses
Dooley et al, Antimicrob Agents Chemother 2008;52:4037-42
Treatment of the TB/HIV co-infected patient
The problem:The problem: PK interactions between ARV’s and anti-TB drugs PK interactions between ARV’s and anti-TB drugs
may or may not be clinically significant.may or may not be clinically significant. Definitive clinical studies are difficult to doDefinitive clinical studies are difficult to do
Future pharmacology priorities for new TB drugs and regimens?
Future TBC PK/PD Priority Studies?
Clinically important questions unlikely to be Clinically important questions unlikely to be studied by industry (cost, time, or priority studied by industry (cost, time, or priority constraints)constraints)
Scientifically important questions of little interest Scientifically important questions of little interest to industryto industry
Studies involving drugs off patent or unprofitableStudies involving drugs off patent or unprofitable Studies in special patient populations, or long-term Studies in special patient populations, or long-term
studies in patientsstudies in patients
Study opportunities with TMC-207:
An investigational inhibitor of mycobacterial ATP synthase
TMC-207 A diarylquinoline with activity against drug-sensitive A diarylquinoline with activity against drug-sensitive
and drug-resistant TB, including XDR-TB.and drug-resistant TB, including XDR-TB. Inhibits the proton pump function of mycobacterial Inhibits the proton pump function of mycobacterial
ATP synthase -- a novel mechanism of action.ATP synthase -- a novel mechanism of action. Intracellular [ATP] is significantly lower in hypoxic Intracellular [ATP] is significantly lower in hypoxic
nonreplicating nonreplicating M. tuberculosisM. tuberculosis, which are more , which are more susceptible to ATP depletion.susceptible to ATP depletion.
TMC-207 may be uniquely bactericidal and TMC-207 may be uniquely bactericidal and sterilizing for nonreplicating MTB, allowing sterilizing for nonreplicating MTB, allowing dramatic shortening of the course of treatment.dramatic shortening of the course of treatment.
Van Heeswijk et al., ICAAC 2007; abstract A-780
TMC207 Human Pharmacokinetics
TMC-207 activity against MDR-TB 47 patients with MDR-TB were randomized to 47 patients with MDR-TB were randomized to
receive a 5-drug MDR regimen receive a 5-drug MDR regimen (KAN+OFX+ETA+TER+PZA) plus either placebo (KAN+OFX+ETA+TER+PZA) plus either placebo (n=24) or TMC207 (n=23) for 8 weeks and then (n=24) or TMC207 (n=23) for 8 weeks and then continued with the MDR regimen.continued with the MDR regimen.
Efficacy assessment at 8 weeks:Efficacy assessment at 8 weeks: By serial sputum colony countingBy serial sputum colony counting: 0/9 TMC207-treated : 0/9 TMC207-treated
patients culture-positive versus 9/13 patients in the control patients culture-positive versus 9/13 patients in the control groupgroup
By MGIT tubesBy MGIT tubes: 47.5% of TMC207 treated patients : 47.5% of TMC207 treated patients became culture negative versus 8.7% treated with placebo became culture negative versus 8.7% treated with placebo (p=0.003) (p=0.003)
- Diacon et al., 48- Diacon et al., 48thth ICAAC, 2008, Washington, DC , ICAAC, 2008, Washington, DC , LB AbstractLB Abstract
Culture conversion in liquid media
p = 0.003
8.7% culture negative
47.5% culture
negative
Diacon et al., ICAAC 2008; LB abstract
ACTG Protocol 5267:Safety, Tolerability, and Pharmacokinetic
Interaction Study of Single Dose TMC207 and Efavirenz in Healthy Volunteers
Kelly Dooley, Susan Swindells, David Haas, Kelly Dooley, Susan Swindells, David Haas, Jeong-Gun Park, Reena Masih, Ilene Wiggins, Jeong-Gun Park, Reena Masih, Ilene Wiggins,
Francesca Aweeka, Amita Gupta, Kristy Grimm, Francesca Aweeka, Amita Gupta, Kristy Grimm, Rolf P.G. van Heeswijk, Sonia Qasba, and Rolf P.G. van Heeswijk, Sonia Qasba, and
Charles Flexner, for the 5267 Protocol Team Charles Flexner, for the 5267 Protocol Team
ACTG 5267 Study Design
1 7 14 49
EFV600 mg PO daily
21 3528 42
TMC207 400 mg
TMC207 & M2336h PK (TMC alone) EFV 24h PK
(steady state)TMC207 & M2336h PK (TMC+EFV)
15 29
What we are learning from studies of TMC-207
Industry is willing to collaborate with government Industry is willing to collaborate with government and academia on important pre-approval and academia on important pre-approval pharmacology studies.pharmacology studies.
Industry is willing to provide reagents to develop Industry is willing to provide reagents to develop investigational drug assays (pre-approval).investigational drug assays (pre-approval).
Industry is still struggling to define a business model Industry is still struggling to define a business model for development and marketing of new drugs for for development and marketing of new drugs for tuberculosis.tuberculosis.
Pre- and post-exposure prophylaxis for clinical tuberculosis: a new paradigm?
A single antibiotic with appropriate pharmacologic A single antibiotic with appropriate pharmacologic properties should be able to eradicate latent TB with a properties should be able to eradicate latent TB with a single dose.single dose. Kill metabolically active and inactive organismsKill metabolically active and inactive organisms Kill intracellular and extracellular organismsKill intracellular and extracellular organisms High antimicrobial potency and low resistanceHigh antimicrobial potency and low resistance Very long half-life in the effect compartmentVery long half-life in the effect compartment Wide therapeutic indexWide therapeutic index
Such an agent could make possible regional eradication Such an agent could make possible regional eradication of TB, similar to strategies deployed to eradicate of TB, similar to strategies deployed to eradicate onchocerciasis.onchocerciasis.
Acknowledgements
RPT-Moxifloxacin StudiesRPT-Moxifloxacin StudiesJHUJHUKelly Dooley Kelly Dooley Richard ChaissonRichard ChaissonSusan DormanSusan DormanEric NuermbergerEric NuermbergerJudith HackmanJudith Hackman
NJH, DenverNJH, DenverChuck PeloquinChuck Peloquin