Pharmacokinetics (PK) and Pharmacodynamics (PD) in the Treatment of Tuberculosis

Shaun E. Gleason, PharmD, MGSAssociate Professor, Department of Clinical Pharmacy

Director, Distance Degrees and Programs

University of Colorado Skaggs School of Pharmacy

and Pharmaceutical Sciences

Disclosure: Past employee & current stockholder of Johnson & Johnson Family of Companies

April 2018

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Same as it ever was….

Yeah, the twister comesHere comes the twisterSame as it ever was….

- Once in a Lifetime, Talking Heads1

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Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharm Ther 2015; 2015;98(4):387-393.

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Learning ObjectivesAt the end of this presentation, the learner will be able to:• Describe the basic concepts of PK/PD, specifically:

– the fundamentals of PK– the difference between PK and PD

• Describe the use of PK / PD principles in TB therapy, in particular, related to these in the use of: – INH– Rifamycins– Aminoglycosides

• Discuss the use of Clinical PK / Therapeutic Drug Monitoring in TB in relation to:– Optimizing efficacy– Minimizing toxicity– Patients needing it most

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Intro to PK and PD• Pharmacokinetics (PK):

– ADME: Study of the time course ofAbsorption, Distribution, Metabolism & Excretion.

• Clinical Pharmacokinetics– The application of PK principles to the safe and

effective therapeutic management of drugs in an individual patient

– aka Therapeutic Drug Monitoring (TDM)

• Pharmacodynamics (PD)– Relationship between drug concentration at the site of

action and the resulting effect

DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17.

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Pharmaco-KINETICS

Pharmaco-DYNAMICS

Prescribed

Dosing

Regimen

Drug at Site

of Action

Drug

Effects

• Dosing & med errors• Absorption• Tissue & body fluid mass

and volume• Drug interactions• Elimination• Drug metabolism• Adherence

• Genetic factors• Drug interactions• Tolerance• Drug receptor

status• Effect of drug

COMBOS

DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17..

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Pharmacokinetics 101

• Assume plasma/serum concs = concs at site• Bioavailability / Absorption

– Drug properties– Pt factors– Drug / food interactions

• Vol of Dist (Vd): dosing proportional to Vd– Drug properties – Pt factorsDiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-27.

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Pharmacokinetics 101• Clearance (volume / time):

measure of removal of drug from plasma

Organs ofElim’n

(Kidneys, Liver)

Cin Cout

Elimination

Blood flow

Blood flow

DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p19-27.

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• Half-life (T1/2):– Time for concs to decrease by 50%– T1/2 is independent of dose and concentration– Regardless of conc, drug gone after 5-7 T1/2’s

– A proportionality constant, dependent on Cl & Vd

T1/2 = 0.693 x VdCl

• Clearance / Elimination: related to volume and T1/2of drug

T1/2 = 0.693/ Ke Ke = Cl / Vd Cl = Ke x VdKe = ln C1/C2 / T

Pharmacokinetics 101

DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010; p29-44..

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PK Case – AB – PK ParameterAB is a 42 yo WM being treated for TB with SM 1000mg (~13 mg/kg) IV QM-F. Other meds: RIF/EMB/PZA • AB has a h/o CHF, ESLD, and DM. • Wt = 75 kg, Ht = 65 in. • Labs: BUN = 15, SCr = 1.1• SM MIC = 8 mcg/ml• Serum SM concs reveal:

– Calculated Cmax = 22 mcg/ml (nl=35-45 mcg/ml)

– Serum T1/2 = 5.2 hrs (nl SM T1/2 = 2-3 hrs)9

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Pt Case AB QuestionWhat is the most likely cause of AB’s

serum SM concentrations and PK parameters being not quite normal?a. Renal dysfunctionb. Large volume of distributionc. Reduced absorption of the streptomycind. Drug interaction affecting metabolism of SM

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Use of PK / PD Principles

in TB TherapyProp

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PK/ PD Response Parameters• Time > MIC

– More frequent dosing to maintain time above the MIC– INH, Ethionamide

• AUC > MIC• Cmax / MIC

– Concentration-dependent– Best given as large (usually daily) doses– Aim for ratio of at least 10-12 – AMG’s, FQ’s, Rifamycins

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MIC

Cmax

AUC > MIC

10

8

6

4

2

0

Cmax = 9 mcg/ml

MIC = 3 mcg/ml

Cmax/MIC = 3

T > MIC = 8h

AUC (mcg * h/ml)

PD: Response ParametersC

onc

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MIC

Cmax2.5

2.0

1.5

1.0

0.5

0

Ethionamide

T > MIC = ~ 4h

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INH Concs. by Acetylator status

Time / Hours

Conc.(mg/l)

SLOW = t½ 3.35 hr, AUC 54.9 mcg*hr/mL

FAST = t½ 1 hr, AUC 25.0 mcg*hr/mLInt.= t½ 1.56 hr, AUC 35.7 mcg*hr/mL

MIC

Parkin DP, Vandenplas S, Botha FJH, et al. Trimodality of Isoniazid: phenotype and genotype in patients with tuberculosis. Am J Respir Crit Care Med. 1997;155 (5):1717-22.

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Pharmaco-KINETICS

Pharmaco-DYNAMICS

Prescribed

Dosing

Regimen

Drug at Site

of Action

Drug

Effects

• Dosing & med errors• Absorption• Tissue & body fluid mass

and volume• Drug interactions• Elimination• Drug metabolism• Adherence

• Genetic factors• Drug interactions• Tolerance• Pt factors• Drug receptor

status• Effect of drug

COMBOSDiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17.

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PD: Impact of PK Mismatch• PK Mismatch

– Short T1/2 drug + long T ½ drug Resistance or Failure

• Reports in TB– Strong relationship between low INH and therapeutic

failure/relapse in QW INH/RPT1

– No effect of mismatch2: INH and rifampin

– Important in HIV co-infection 3, 4

1. Weiner M, Burman W, Vernon A, et al. Am J Respir Crit Care Med. 2003; 167: 1341 - 13472. Srivastava S et al. Antimicrob. Agents Chemother. 2011; 55: 5085-5089..3. Peloquin CA. Antimicrob. Agents Chemother. 2012; 56(3): 1666.4. Egelund EF and Peloquin CA. Clin Infect Dis. 2012; 55: 178-179.

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PK Mismatch PD Response: Low INH with Rifampin & Rifapentine

Weiner M et al. Am J Respir Crit Care Med. 2003; 167: 1341 - 1347..

PK Param BIW I/RifFAILURE /

Relapse

(n=16)Cure

(n=33)

PValue

QW I/RptFAILURE/

relapse

(n=22)Cure

(n=49)

P Value

INH

MedAUC

43.3 48.4 0.65 36.0 55.9 0.0005

Med Cmax 11.9 10.2 0.9 11.1 11.9 0.08

Med T1/2 2.1 2.3 0.42 1.4 2.4 0.02

Rifamycin

Med AUC 46.1 50.5 0.23 211 196 0.47

Med Cmax 8.3 7.7 0.96 12.3 12.2 0.31

Med T1/2 2.2 3.4 0.11 14.6 16.8 0.04

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Reduced Concentrations in HIV+

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HIV+ HIV+

Rifampin Ethambutol

Hlthy vol Hlthy vol

Perlman DC et al for the ACTG 309 Team. The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with TB. Clin Infect Dis 2005; 41:1638-47.

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EFFECT: RFB & INH AUC in HIV+ ARR Failures / Relapse

N=5; Acquired rifamycin resistance (ARR) N=90; no ARR failure or relapse

Weiner M et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis.Clin Infect Dis 2005; 40:1481-91.

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ID (TB): Usual PK/PD Response Parameters

• Time > MIC– More frequent dosing to maintain time above the MIC– INH, Ethionamide

• AUC > MIC • Cmax / MIC

– Concentration-dependent– Best given as large (daily, intermittent) doses– Aim for Cmax to MIC ratio of at least 10-12 (AMG’s)

– AMG’s, FQ’s, Rifamycins

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MIC

Cmax

AUC > MIC

10

8

6

4

2

0

Cmax = 9 mcg/ml

MIC = 3 mcg/ml

Cmax/MIC = 3

T > MIC = 8h

AUC (mcg * h/ml)

PD: Response Parameters

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Cmax

70

60

50

40

30

20

10

0

mcg/ml

Streptomycin

Cmax = 64 mcg/mlMIC = 8 mcg/ml

Cmax/ MIC = 8

MICProp

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Rifampin 600 mg in Humans

Cumulative % Culture Negative Month 1 2 3H300R600Z2S2 QD 38 77 97H300R600Z2E2 QD 35 77 99

Other doses: S750mg, Z 35mgkg, E 25mg/kg, R 450 mg if <50kg

British Thoracic Association. A controlled trial of six months of chemotherapy in pulmonary tuberculosis. Br J Dis Chest 1981;75:141-153.

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Rifampin 1200mg in Humans

Cumulative % Culture NegativeMonth 1 2 3 H900R1200S2 QD 72 94 98H900R1200S2 QOD* 70 93 100

Other doses: S 1000 mg QD* both regimens

Kreis B, Pretet S. Two three-month treatment regimens for pulmonary tuberculosis. Bull Int Union Tuber 1976; 51:71-75.

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Rifampin 600mg vs 1200mgCumulative % Culture NegativeMonth 1 2 3 H300R600 Z2 S2 QD 38 77 97H900R1200 S2 QD 72 94 98

Other doses: S 750mg in first, 1000 mg QD in second

Note: RIF dose response also seen with INH 300mg + RIF 450mg, 600mg, or 750mg QD (Long et al)

Br J Dis Chest 1981; 75: 141-153. Kreis B et al. Bull Int Union Tuber 1976; 51: 71-75.

Long MW, Snider DE, Farer LS. Am Rev Resp Dis. 1979; 119: 879-894.

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Rifampin 1200mg• Flu-like syndrome: NOT reported by Kreis et al

• More related to intermittent therapy

• May be best to optimize current regimens

Kreis B et al. Bull Int Union Tuber 1976; 51:71-75.Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of

tuberculosis medications. Clin Pharm Ther. 2015; 2015;98(4):387-393.Peloquin C. What is the ‘right’ dose of rifampin? Int J Tuberc Lung Dis 2003; 7: 3-5.

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Pt Case: AB Dose Optimization• Recall that AB had an SM Cmax of 22 mcg/ml

and an SM MIC of 8 mcg/ml. AB also had an extended serum T1/2 of 5.2 hrs.

• We are concerned about the effectiveness of this SM dose because of which dosing principle?a) The Time > MIC is not optimalb) The Cmax / MIC is not optimalc) The AUC > MIC is not optimal

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Use of Therapeutic Drug Monitoring (TDM)

in TBPropert

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Therapeutic Drug Monitoring (TDM)*

GOAL: Optimization of therapy for individual pt: • Maximize efficacy

and/or• Minimize toxicity

Use with other clinical data

Most valuable when• Wide intersubject variation• Therapeutic concs ≈ toxic concs• Serum concs surrogate for concs at site of

action

*aka “Clinical Pharmacokinetics”

DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda, MD : American Society of Health-System Pharmacists; 2010. p1-17..

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TDM: What it’s really about• NOT necessarily “normal” ranges

• Rather, individualized goals for each pt. • Goals should consider:

– Efficacy needs– Toxicity acceptance

• Once drug is chosen:– Determine desired conc. – Try to achieve!

• “Therapeutic” concentrations vary by patientJelliffe R. Goal-oriented, model-based regimens: setting individualized goals for each patient. Ther Drug Mon 2000; 22(3): 325-329.

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Pro

bab

ilit

y (

% )

Drug Concentration ( mcg / ml )

15 25 35 45

Toxicity

50

100Response

Adapted from: Evans W in General Principles of Pharmacokinetic Michael E Burton, Leslie M Shaw, Jerome J Schentag, William E Evans. Applied Pharmacokinetics and Pharmacodynamics:

Principles of Therapeutic Drug Monitoring. 4th Edition 2006

Tx Range

*

Potential ex: Cycloserine

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TDM with TB Drugs

1. Pasipanodya JG et al. Clin Infect. Dis. 2012; 55: 169-77. 2. Peloquin CA. Use of Therapeutic Drug Monitoring in Tuberculosis Patients. Chest 2004; 126:1722-24.

3. Peloquin CA. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs 2002; 62: 2169 – 2183.4. Srivastava S et al; Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment?

Eur Resp J. 2013; 42: 1449-53.

May be more important than adherence(??)1

• Meta-analysis: PK variability to single drug associated with failure & acquired resistance

• Need at least 60% non-adherence to impact outcomes

Useful for2-4

• Slow to respond to treatment• Drug-resistant TB• Risk of drug-drug interactions• Concurrent disease (HIV, DM, Hep/renal dysfunction)Prop

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PD: Drug toleranceAminoglycoside Toxicity

• AK, SM, KM Regimens in TB and MAC:– 12-15 mg/kg IV 5x/wk Cmax = 35-45 mcg/ml– 22-25 mg/kg IV TIW Cmax = 65-80 mcg/ml

• Dose or serum concentrations did not predict:– Hearing loss– Vestibular toxicity– Nephrotoxicity

• Conclusions– Older pts minimize duration– Larger pts ok to go >1000mg

Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clinical Infectious Diseases. 2004; 38:1538-1544.

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TDM: “How to” guideDrug 1-2 hr post-

dose

6 hr post-

dose

10 hr post-dose

INH X XRifampin X XEthambutol X XPyrazinamide X XAK, SM, CM, KM*(*or 30 min /p infusion)

X X X (ideally)

Levo & Moxi X XCycloserine X XPAS X XEthionamide X X

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• Two or more time-points ideal (better PK info)– If can only do one, check the Cmax (“peak”; first one)

• Consult an expert• Don’t be afraid of the info! Dose “max” is not

necessarily the max in your patient

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Back to AB:Recall:• AB is a 42 yo WM being treated for TB with:

– SM 1000mg (~13 mg/kg) IV QM-F,– RIF 600 mg po QD,– EMB 800 mg po QD,– PZA 1000 mg po QD. AB has a h/o CHF and DM.

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AB - Regimen Questions:

Which other med(s) might we be most concerned about not being optimized in AB (and why)?

a) Rifampinb) Rifampin and PZAc) Rifampin and Ethambutol

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AB - Regimen Questions (cont’d):

Rifampin serum concs. reveal (nl = 8-24 mcg/ml):

– 2 hr: 6 mcg/ml– 6 hr: 3 mcg/ml

Without doing PK calculations, what might be a better new RIF dose (and why)?

a) RIF 600 mg IV QDb) RIF 600 mg PO BIDc) RIF 900 mg PO QD

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Conclusions• Overview of PK/PD

– PK – time course ADME; PD - effect at site– Therapeutic Drug Monitoring (TDM)

• PK / PD in TB– INH – time-dependent– RIF, AMGs – concentration dependent– PK mismatch important, especially with INH and long

half-life rifamycins (RFB and RPT)

• Use of TDM in TB– Important in TB tx– Offers individualized tx

• Efficacy / Toxicity• Drug Interactions / Concurrent clinical problems

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With an understanding of PK/PD and TDM, let’s aim to make TB treatment

NOT

“the same as it ever was.”

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Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharm Ther. 2015; 2015;98(4):387-393.

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Questions?

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References• British Thoracic Association. A controlled trial of six months of chemotherapy in pulmonary

tuberculosis. Br J Dis Chest 1981;75:141-153.• DiPiro JT, Spruill WJ, Wade WE et al. Concepts in Clinical Pharmacokinetics, 5th ed. Bethesda,

MD: American Society of Health-System Pharmacists; 2010. p1-44• Egelund EF and Peloquin CA. Pharmacokinetic variability and tuberculosis treatment

outcomes, including acquired drug resistance. Clin Infect Dis. 2012; 55: 178-179.• Egelund EF, Alsultan A and Peloquin CA. Optimizing the clinical pharmacology of tuberculosis

medications. Clin Pharm Ther. 2015; 2015;98(4):387-393.• Jelliffe R. Goal-oriented, model-based regimens: setting individualized goals for each patient.

Ther Drug Mon 2000; 22(3): 325-329• Kreis B, Pretet S. Two three-month treatment regimens for pulmonary tuberculosis. Bull Int

Union Tuber 1976; 51:71-75.• Long MW, Snider DE, Farer LS. US publich health service cooperative trial of three rifampin-

isoniazid regimens in treatment of pulmonary tuberculosis. Am Rev Resp Dis. 1979; 119: 879-89.

• Li J et al. Use of Therapeutic Drug Monitoring in Tuberculosis Patients. Chest 2004; 126:1770-76.

• McCormack JP, Jewesson PJ. A critical re-evaluation of the “therapeutic range” of

aminoglycosides. Clinical Infectious Diseases. 1992; 14: 320 –339.• Parkin DP, Vandenplas S, Botha FJH, et al. Trimodality of Isoniazid: phenotype and genotype

in patients with tuberculosis.. Am J Respir Crit Care Med. 1997;155 (5):1717-22.

• Pasipanodya JG et al. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy. Clin Infec. Dis. 2012; 55: 169-77.

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References - continued• Peloquin CA. Pharmacokinetic mismatch of tuberculosis drugs. Antimicrob. Agents

Chemother. 2012; 56(3): 1666.• Peloquin C. What is the ‘right’ dose of rifampin? Int J Tuberc Lung Dis 2003; 7: 3-5.• Peloquin CA. Use of Therapeutic Drug Monitoring in Tuberculosis Patients Chest 2004;

126:1722-24• Peloquin CA. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs 2002; 62:

2169 – 2183.• Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly

dosing for treatment of mycobacterial diseases. Clinical Infectious Diseases. 2004; 38:1538-1544.

• Perlman DC et al for the ACTG 309 Team. The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with TB. Clin Infect Dis 2005; 41:1638-47.

• Srivastava S et al. Pharmacokinetic mismatch does not lead to emergence of isoniazid- or rifampin-resistant Mycobacterium tuberculosis resistance but to better antimicrobbial effect: a new paradigm for antituberculosis drug scheduling. Antimicrob. Agents Chemother. 2011; 55: 5085-5089.

• Weiner M, Burman W, Vernon A, Benator D, Peloquin CA, Khan A, Weis S, King B, Shah N, Hodge T and the Tuberculosis Trials Consortium. Am J Respir Crit Care Med. 2003; 167: 1341 - 1347.

• Weiner M et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis.Clin Infect Dis 2005; 40:1481-91

• Weiner M, Burman W, Vernon A, et al. Low Isoniazid Concentration Associated with Outcome of Tuberculosis Treatment with Once-Weekly Isoniazid and Rifapentine. Am J Respir Crit Care Med. 2003; 167: 1341 - 1347.

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