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Therapeutic Drug Monitoring (TDM): Practical Questions & Answers

Therapeutic Drug Monitoring ( TDM ):Practical Questions and Answers

Charles A. Peloquin, Pharm. D.Professor, and Director Infectious Disease Pharmacokinetics LaboratoryCollege of Pharmacy and The Emerging Pathogens InstituteUniversity of Florida

Drugs FDA Approved for TB

Aminosalicylate sodium (PAS)

Bedaquiline

Capreomycin, Streptomycin

Cycloserine

Ethionamide

Ethambutol

Isoniazid

Pyrazinamide

Rifampin, Rifapentine

Drugs not FDA approved for TB

Other Aminoglycosides:

Amikacin

Kanamycin

Fluoroquinolones:

Moxifloxacin

Levofloxacin


Drugs not FDA approved for TB

Macrolides - generally poor TB drugs:

Azithromycin

Clarithromycin

( indicated for, and primarily useful for, MAC )

Amoxicillin - clavulanate ( role not established )

Clofazimine ( role being re - evaluated )

Rifabutin ( used for TB and MAC )

Linezolid , newer agents Sutezolid and AZD-5847

Outside US: prothionamide, thiacetazone, viomycin

A drug must enter the organism,

bind to a specific target,

and produce an inhibitory or lethal effect.

Unless the drug is delivered to the site of

infection ( PK ), nothing happens ( PD ).

How Do Antibiotics Work ?

PK and PD


Pharmacodynamics ( PD )

role: primary drug, along with INH

action: DNA - dependent RNA polymerase

dosage: oral, I.V.

dose: 600 mg QD // 10-20 mg / Kg for kidsmuch higher doses being studied

cleared: liver >> kidneys

toxicity: hepatotoxicity, flu - like syndrome

Rifampin ( RIF )

Rifamycin Comparison

CYP 3A4 * Uniqueinduction features

Rifampin 1.00 flu - like syndrome

Rifapentine 0.85 to 1.00+ 99% protein bound

Rifabutin 0.40 uveitis, neutropenia

• Liver enzyme induction speeds up clearance of other drugs



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

Rifampin 0.25 12 48 3

Rifapentine 0.06 12 200 15

Rifabutin 0.06 0.6 10 36

• 7H12 broth minimal inhibitory concentration

• ^ total Rx ( free and bound )


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

Rifampin 0.25 1.8 7.2 3

Rifapentine 0.06 0.12 2.0 15

Rifabutin 0.06 0.09 1.5 36

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

The study of the movement of drugs

through the body.

Most commonly based on the study of

serum concentrations in relation to dose,

with interpretation and dose adjustment.

Pharmacokinetics ( PK )


PK: Plasma Elimination Half - Life

t 1/2 is defined as the time for concentrations

( in plasma ) to decline by 50 %.

After 7 t 1/2’s, nearly all of the drug is gone,

regardless of the starting concentration.

t 1/2 is independent of dose and concentration.

PK: Clearance

t 1/2 is inversely proportional to

the clearance of a drug ( Cl ).

Clearance can be thought of as the size

of the drain in the bathtub.

A big drain will empty the tub faster.


PK: Clearance

Clearance organs:

Kidneys : especially water soluble drugs

– creatinine clearance might predict

Liver : metabolize drugs to make water sol.

– AST, ALT usually do not predict

[ minor: lungs, skin, saliva… ]

PK: Volume of Distribution

t 1/2 is directly proportional to

the volume of distribution ( V ).

V can be viewed as the size of the bathtub.

Big tubs take a longer time to drain.

t 1/2 is viewed as a proportionality constant,

dependent upon Cl and V.

PK: Volume of Distribution

Large volumes of distribution typically

reflect drug penetration into tissues which

return the drug to the plasma space

only slowly.

Drug molecules inside of tissues are

unavailable to the organs of clearance.


PK: Data Handling

The most common parameters clinically are

are Cmax ( peak ), Cmin ( trough ), Tmax, & t1/2

Simple kinetics can be done with a calculator,

or with a spreadsheet.

The most common calculations involve

linear regression ( fitting a straight line to data ).

Example: Amikacin Kinetics

the study of the relationships betweendrug concentrations and responses

Methods

• in vitro models• animal models• human clinical trials with dose escalation



Evans, 1986

Minimal inhibitory concentration ( MIC )

The concentration of the drug required

to inhibit the growth of an organism

in the laboratory.

From this: “ susceptible ” or “ resistant ”

[ This test cannot be done within the patient. ]

Antibiotic Terms

ID: Usual PK - PD Response Parameters

• Cmax / MIC

• Time > MIC

• AUC > MIC


MIC

Cmax

AUC > MIC

10

8

6

4

2

0

Cmax = 9 mcg / ml

MIC = 3 mcg / ml

Cmax / MIC = 3

T > MIC = 8 h

AUC ( mcg * h / ml )

PD: Response Parameters

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 4 8 12 16 20 24

CO

NC

TIME

ISONIAZID

slow

fast

MIC

0.0

0.5

1.0

1.5

2.0

2.5

0 4 8 12 16 20 24

CO

NC

TIME

ETHIONAMIDE

eta

MIC



Killing of TB by most TB drugs can be

described very well using AUC / MIC,

and more AUC is better.

This has been known for many years,

and has been widely published.

PD: Response Parameters

“Concentration - dependent” antimicrobials

best given as large ( daily ) doses

• aminoglycosides, quinolones, RIFAMYCINS

( based on in vitro, animal and human data )

• target a Cmax / M I C of at least 10 - 12

Rifampin has profoundconcentration – dependent killing

Week 5 mg/kg 10 mg/kg 20 mg/kg 40 mg/kg

Lung CFUweek 1

100,000,000 100,000,000 100,000,000 100,000,000

Lung CFUweek 10

10,000 100 10 0

% reduction 99.99000% 99.99990% 99.99999% 100.00000%

Verbist L. Acta Tuberculosa et Phneumolgia Belgica1969 ; number 3 - 4: 397 - 412.;


PD: Sterilizing Activity of Rifampin

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

Mean value after 600 mg oral dose

Evans, 1986

Rifampin 600 mg in Humans

Cumulative percentage culture negative:

month 1 2 3

HRZS QD 38 77 97

HRZE QD 35 77 99

H 300 mg, S 750 mg, Z 35 mg / Kg, E 25 mg / Kg

isoniazid streptomcyin pyrazinamide ethambutol

Br J Dis Chest 1981 ; 75 : 141 - 153.


Rifampin 1200 mg in Humans

Cumulative percentage culture negative

month 1 2 3

HRS QD 72 94 98

HRS QOD 70 93 100

H 900 mg, S 1000 mg QD both regimens

isoniazid streptomycin

Kreis B et al. Bull Int Union Tuber 1976 ; 51 : 71 - 75.

Rifampin 600 mg vs. 1200 mg

Cumulative percentage culture negative

month 1 2 3

HRZS QD 38 77 97

R 600 mg, with Z

HRS QD 72 94 98

R 1200 mg, NO Z

INH 900 mg

Rifampin 1200 mg

Flu - like syndrome was NOT reported

by Kreis et al ( 3 months of treatment )

Even with highly - intermittent RIF,

syndrome usually appears after 3 to 6 months.

Kreis B et al. Bull Int Union Tuber 1976 ; 51 : 71 - 75.

Peloquin C. Int J Tuberc Lung Dis 2003; 7: 3 - 5.


Evans, 1986

PD: Response Data

Association between Acquired Rifamycin Resistance and the Pharmacokinetics of Rifabutin and Isoniazid among Patients with HIV and TB [ Study 23A ].

Weiner M, Benator D, Burman W, Peloquin CA, Khan A, Vernon A, Jones B S, Silva-Trigo C, Zhao Z, Hodge T and the Tuberculosis Trials Consortium

Clinical Infectious Diseases 2005; 40: 1481 - 1491.

Lower rifabutin AUC associated with failure, relapse, and ARR

• P for RBT AUC ARR vs. cure, Mann-Whitney• Odds ratio for CD4 count 1.01• Odds ratio for RBN AUC 23

0.045.1

(4.0 - 7.4)

4.8

(4.2 – 6.2)

82CURE

3.1

(2.0 - 3.8)

4.6

(3.5 - 5.7)

6ARR

P-Value*

AUC0-24

Med (IQC)

Dose mg/kg

Med (IQC)

No.Group


Rifampin has profoundconcentration – dependent killing

Week 5 mg/kg 10 mg/kg 20 mg/kg 40 mg/kg

Lung CFUweek 1

100,000,000 100,000,000 100,000,000 100,000,000

Lung CFUweek 10

10,000 100 10 0

% reduction 99.99000% 99.99990% 99.99999% 100.00000%

Verbist L. Acta Tuberculosa et Phneumolgia Belgica1969 ; number 3 - 4: 397 - 412.;

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.


High RPNT exposures (AUC) were associated

with 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.


Daily Rifapentine for Treatmentof Pulmonary Tuberculosis


Where Does TB Drug PK Data Come From ?

Data were compiled from all available sources

( both healthy volunteers and TB patients ) by :

Mack Holdiness Clin Pharmacokinet. 1984; 9 (6) : 511 - 44

Charles Peloquin ( 1991 and later )

Global Alliance for TB Drug DevelopmentHandbook of Anti - Tuberculosis Agents 2008

among others …

Where Does TB Drug PK Data Come From ?

CHAPTER 2ANTITUBERCULOSIS DRUGS: PHARMACOKINETICSCharles A. Peloquin, Pharm.D.

In Heifets L , ed. Drug Susceptibility in theChemotherapy of Mycobacterial Infections. CRC Press, Boca Raton, 1991, p 59 - 88.

191 references

The drug must access the organism and bind to a target to produce an inhibitory or lethal effect.

Access requires absorption and delivery by the blood to the site of infection.

By Analogy: Gravity – not just a good idea - it’s the law

Antibiotic Essentials


Malabsorption, or lack of blood flow to the site of infection, lead to treatment failures and to the selection of resistance.

The question : Standardized treatment for everyone,and if they don’t respond, continue the same tx,

Or

See why this is happening, adapt, and overcome.

Antibiotic Essentials

Slow responses to TB treatment are common, as shown on the next slide.

While many of these slow responses are dueto treatment interruptions ( adverse drug reactions, patients leaving treatment programs, etc. ), in our experience, a substantial portionof these are due to poor drug absorption.

Role for Therapeutic drug monitoring

aims to promote optimum drug treatment

by maintaining serum drug concentrations

within a "normal range," or preferably

a "therapeutic range”

How can we apply this ?

Therapeutic Drug Monitoring ( TDM )


Completion of TB Therapy,United States, 1993 – 2010*

* Updated as of June 10, 2013. Data available through 2010 only.

Note: Includes persons alive at diagnosis, with initial drug regimen of one or more drugs prescribed, who did not die during therapy. Excludes persons with initial isolate rifampin resistant, or patient with meningeal disease, or pediatric patient (aged <15) with miliary disease or positive blood culture.

Pe

rce

nta

ge

0

20

40

60

80

100

Completed in 1 year or less Completed


• Updated as of June 10, 2013.

• Data available through 2010 only.

Note: Includes persons alive at diagnosis, with initial drug regimen of one or more drugs prescribed, who did not die during therapy.

Excludes: rifampin resistant TB, meningeal disease, or pediatric patients (aged <15) with miliary disease or positive blood culture.

TB Treatment Is Guideline - Driven

The standard claim is that TB can be treated

with a 6 – month regimen that has roughly

98 % success, followed by about 3 % relapses,

for about a 95 % overall cure.



• So, what percentage of US TB patients

complete the 6-month regimen in 6 months?

Length of Treatment in the US

Remember, this is supposed to be a 6 – month

“short – course” therapy.

If it takes 12 to 18 months,

it is no longer “short – course” therapy…

and you pay for every month.

So what ?

12 / 6 = 2


“ In theory, there is no difference between theory

and practice. In practice, there is.”

Yogi Berra

So what ?

The average weight of the patients, predominantly male, in the BMRC Hong Kong and East Africa trials was 48 kg.

600 mg / 48 kg = 12.5 mg / kg

600 mg / 90 kg = 6.7 mg / kg

For many patients, we give a lot less drug thanwas studied originally …

And another thing …

And this is what it looks like …

48 kg 96 kg

600 mg in 600 mg inOriginal patients

Current patients

Full Not Full


Kind of like putting 10 gallons of gas in each of these vehicles …

Full Not Full



Mean value after 600 mg oral dose



most useful when there is a direct

relationship between serum concentrations

and therapeutic response,

and when serum concentrations serve as a

surrogate for drug concentrations

at the site of action

TDM


most important when there is a narrow range

of concentrations that are effective and safe,

and when toxicity or lack of effectiveness

puts the patient at great risk

TDM

in conjunction with other clinical data,

allows for an assessment of

the patient's status,

and for timely therapeutic interventions

TDM

Spruill WJ, Wade WE, DiPiro JT, Blouin RA, Pruemer JM,

Concepts in Clinical Pharmacokinetics, 6th Ed.

American Society of Health - System Pharmacists 2014.

TDM


Jelliffe R.

Goal - oriented, model - based drug

regimens: setting individualized goals for

each patient.

Ther Drug Monit 2000; 22: 325 – 329.

TDM

Roger Jelliffe’s Key Points:

“ Therapeutic ” concentrations vary by patient

Once a drug is chosen, a goal should be set for the desired serum concentrations.

This goal should be achieved with thegreatest precision possible.

TDM

Roger Jelliffe’s Key Points:

In other words, if you are relying on drugs

to cure the patient, you may as well

give the right amount to EACH patient.

TDM


Evans, 1986

TDM with Oral TB Drugs

Two hour post dose blood draws generally

capture the “peak” concentration.

Six hour post dose blood draws generally

separate delayed absorption from malabsorption.

Peloquin CA. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs 2002; 62: 2169 - 2183.

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0

Conc

entra

tion

( m

cg /

ml )

Time ( hour )

NIH A

NIH B

AACTG

Vols

Rifampin Plasma Concentrations


The decision to use TDM is the same as

the decision to check a CBC with diff. ,

or the decision to get a CT or MRI.

None of these guarantees the outcome of Tx.

However, all of these inform the clinician

prior to making clinical decisions.

TDM

Role for TDM

TDM allows you to individualize therapy.

TDM allows you to optimize the

pharmacodynamically - linked variable

[ typically Cmax or AUC ].

Role for TDM

TDM may allow you to shorten treatment,

or to avoid concentration - related toxicities.

TDM allows you to unravel complicatedmulti - drug interactions


In the end, knowing is better than guessing.

So what is the big idea, anyway ?

Any patient in whom you wish to control

drug exposure.

In what populations should TDM be used?

In our lab, a single test is $80.

A pair of tests ( i.e., 2 and 6 hour samples ) per drug are $70 each ( $20 discount ).

Shipping costs vary.

How much does TDM cost ?


Same as a chemistry panel : plain red top tube.

Time the observed dose.

Time the blood draw (s).

Record the information on the form.

Process the sample promptly.

What are specimen collection Requirements ?

Several labs offer some testing.

Two labs offer most testing.

One lab includes PK consultations with each sample for each patient at noextra charge.

Where is testing done ?

Process the sample within 1 hour if possible.

If not, collect in a green top tube, invert x 3,and place on ice chips until processed.

Given INH stability is questionable…


No.

Each drug is absorbed independently.

You can have good absorption of one,but not of the other.

Can rifampin be used as a surrogate for INH absorption ?

No.

Each drug is absorbed independently.

Ex. Posaconazole is poorly absorbed and requires high fat food for absorption –just the opposite of RIPE.

Should we use another surrogate marker of absorption ?

As a general population, they appear to have

lower serum concentrations of TB drugs.

See next slide…

What about DM patients…


BMC Infect Dis. 2017; 17: 125

Early interventions for diabetes related tuberculosis associate with hastened sputum microbiological clearance in Virginia, USA.

Alkabab Y, Keller S, Dodge D, Houpt E, Staley D, Heysell S.

Thanks

• Thanks to Eric Nuermberger, MD and William Burman, MD for providing several slides

• The IDP Lab Team: TJ Zagurski, Kyung Mee Kim, Roger Sedlacek,Emily Graham, Yasuhiro Horita

http://idpl.pharmacy.ufl.edu

http://idpl.cop.ufl.edu/

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