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ICU PHARMACOTHERAPY IN SPECIAL POPULATIONS:Part 1- General principles and drug dosing in morbid obesity

Jeffrey F. Barletta, Pharm.D., FCCMAssociate Professor & Vice ChairDepartment of Pharmacy PracticeMidwestern University, College of PharmacyGlendale, Arizona

Disclosures• Hospira, Inc.- Consultant• Cubist Pharmaceuticals- Consultant

Objectives• Part 1:

• Craft a dosing regimen for medication therapy in ICU patients using principles of dose individualization

• Develop a plan for crafting a medication regimen for a morbidly obese ICU patient.

• Part 2:• Describe the factors that influence drug dosing in patients on:

• Extracorporeal membranous oxygenation (ECMO)

• Renal replacement therapies (RRT)

• Molecular adsorbent recirculation systems (MARS)

How are ICU Patients Different?

Hyperdynamic

Altered fluid balance

End organ dysfunction

Artificial Organ support

Increased co-morbidities More medications

Augmented renal clearance

Increased chance for

failure

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Pharmacokinetic Alterations in Critical Illness

DistributionProtein binding

Body compositionVolume status

Absorption

Gut wall edemaGut stasisGI blood flowDrugsEnteral Nutrition

EliminationOrgan function

Blood flowInteracting drugs

Administered Dose

Effect Site Concentration

Pharmacologic Effect

Vdc Vdp

Dose Individualization

Principles of Dose Individualization • Pharmacokinetic evaluation

• Pharmacodynamic evaluation• Organism MIC• Time dependent vs. concentration dependent

• Loading doses

• Use of prolonged or continuous infusions

• Therapeutic drug monitoring

Therapeutic Drug Monitoring:Beta-lactams

Goal = Trough concentration 4 – 5 x MIC but not > 10 x MIC

Antibiotic

Pip/Tazo

Meropenem

Cefazolin

Ceftriaxone

Dose Maintained

23%

16%

0%

67%

n

116

51

6

33

Dose Increased

49%

57%

100%

21%

Dose Decreased

28%

27%

0%

12%

Roberts, et al. Int J Antimicrob Agents 2010;36:332-9.

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Are Recommended Doses High Enough?

0% 20% 40% 60% 80% 100%

TOTAL

Meropenem

Piperacillin

Doripenem

Ceftriaxone

Cefepime

Cefazolin

100% T > MIC

50% T > MIC

Roberts, et al. Clin Infect Dis 2014;58:1072-83.

(3 gm/day)

(6 gm/day)

(2 gm/day)

(1.75 gm/day)

(12 gm/day)

(3 gm/day)

*doses shown represent median dose/day

Augmented Renal Clearance

0%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7Study Day

***65% of patients manifested ARC on at least one occasion***

Udy, et al. Crit Care Med 2014;42:520-27.

Augmented Renal Clearance

CrC

l

Study Day

Trauma

Surgical Emerg

Elective

Emergency

Udy, et al. Crit Care Med 2014;42:520-27.

DRUG DOSING IN MORBID OBESITY

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Prevalence of Obesity in the U.S.2011 – 2012

0

10

20

30

40

50

60

70

BMI ≥ 25 BMI ≥ 30 BMI ≥ 35 BMI ≥ 40

69

35.1

14.56.4

Ogden, et al. JAMA 2014;311:806-14.

Adults ≥ 20 years old

Size Descriptors• Total body weight• Ideal body weight

• Surrogate for LBW• Devine method [50 (if ♂) or 45.5 (if ♀) + 2.3 kg/inch > 5 ft]

• Lean body weight• ♂: (9270 x TBW) / (6680 + 216 x BMI)• ♀: (9270 x TBW) / (8780 + 244 x BMI)

• Adjusted body weight• Originated from aminoglycoside dosing• Correction factor usually 0.4 but much variability exists

• Body mass index• Descriptor used to characterize obesity

• Body surface area• Limited evidence to support it’s use• Oncology medications Devine. Drug Intell Clin Pharm 1974;8:650-5.

Janmahasatian, et al. Clin Pharmacokinet 2005; 44:1051-65.Bauer, et al. Eur J Clin Pharmacol 1983;24:643-7.

Limitations of Size DescriptorsAll weights are not created equal

Generalized Treatment Approach• Published dosing recommendations are usually appropriate for

patients with mild to moderate forms of obesity (BMI < 35 kg/m2).

• The 2 independent PK parameters used to describe drug distribution are volume of distribution (Vd) & clearance (Cl).

• Drugs with a small Vd do not widely distribute into adipose tissue.

• Large Vd does not necessarily mean high lipophilicity.

• Clearance tends to increase with increasing size but to what extent is variable.

• Don’t forget about ADE’s.

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Estimating Clearance

Method

Measured CrCl

Cockcroft-Gault (TBW)

Cockcroft-Gault (IBW)

Cockcroft-Gault (AdjBW 0.3)

Cockcroft-Gault (AdjBW 0.4)

Cockcroft-Gault (LBW)

Salazar-Corcoran

Mean ± SD

110 ± 44

217 ± 113

85 ± 29

129 ± 55

142 ± 63

102 ± 43

155 ± 65

Bias

-

-107 (-133, -82)

+24 (15, 34)

-20 (-32, -8)

-32 (-46, -19)

+8 (-2.6, 19)

-46 (-60, -32)

Interpretation

Reference

Overestimate

Underestimate

Overestimate

Overestimate

Underestimate

Overestimate

Demirovic, et al. Am J Health-Syst Pharm 2009;66:642-8.

Treatment Algorithm

Evaluate clinical trials

Evaluate pharmacokinetic trials

Assess for dose proportionality

Search for studies with similar agents

Consider an alternative agent

Drug Dosing in Morbid Obesity:ANTICOAGULANTS

Patient Case• 64 year old female who is admitted to the ICU following

surgery to repair her hip which she fractured secondary to a ground-level fall. Her weight is 160 kg (BMI = 47 kg/m2) and her SCr = 0.9 mg/dL.

• What therapy should we give for VTE prophylaxis?

A. Enoxaparin 40 mg sub-q daily

B. Enoxaparin 40 mg sub-q twice daily

C. Enoxaparin 80 mg sub-q daily

D. Enoxaparin 80 mg sub-q twice daily

E. Heparin 5,000 units sub-q thrice daily

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BMI-Adjusted Enoxaparin Dosing Strategy: Anti Xa-Levels

Borkgren-Okonek, et al. Surg Obes Relat Dis 2008;4:625-31.

0

10

20

30

40

50

60

70

80

BMI ≤ 50 BMI > 5040 mg Q 12 hr 60 mg Q 12 hr

N=124Wt = 126 kg; BMI = 45

N=99Wt = 161 kg; BMI = 57

Anti-Xa levels:

Subtherapeutic(< 0.18)

Therapeutic (0.18 – 0.44)

Supratherapeutic(> 0.44)

Enoxaparin in Surgical ICU Patients: Anti-Xa Levels

Enoxaparin 0.5 mg/kg Q 12 hoursWeight = 137 kg (range, 97 – 267)BMI = 46.4 kg/m2 (range, 36 – 77)

91% Mean = 0.34 IU/ml

DVT = 1/23Major bleeding = 0Minor bleeding = 1/23

Ludwig, et al. Ann Pharmacother 2011;45:1356-62.

Enoxaparin Dose in Bariatric Surgery: Incidence of VTE

0%

2%

4%

6%

8%

10%

30 mg BID 40 mg BID

Post-op VTE

5.4%(5/92) 0.5%

(2/389)

(BMI = 51.7) (BMI = 50.4)

* p<0.01

Scholten, et al. Obes Surg 2002;12:19-24.

What can we conclude…

• Most data are with enoxaparin

• Doses higher than 40 mg daily are required

• Exactly how much higher is not clear

• Bariatric surgery versus critically ill patients

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Patient Case- Clinical Course• It is POD#3 and the patient complains of pain and swelling in her left leg. Ultrasound confirms a DVT.• Hgb & Hct = 9 g/dL & 27%• SCr = 1.0 mg/dL• Weight = 160 kg

• How should we treat the DVT?

A. Unfractionated heparin

B. Low molecular weight heparin

C. IVC filter

Heparin

• Volume of distribution is similar to blood volume.

• Published nomograms are based on TBW.• 80 unit/kg bolus• 18 units/kg/hr infusion

• Few studies have included large numbers with morbid obesity.

Heparin Response & Obesity

P=.005

Barletta JF, et al. Surg Obes Relat Dis 2008;4:748-53

Morbidly Obese Non-Morbidly Obese(BMI = 53; Wt = 151 kg) (BMI = 31; Wt = 97 kg)

Supra-therapeutic aPTT Values & BMI

BMI Group

Pat

ient

s w

ith S

upra

-the

rape

utic

aP

TT

P=.018

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Unfractionated Heparin in a 388 kg Patient

Myzienski, et al. Pharmacotherapy 2010;30:105e-12e.

Final infusion rate = 3650 units/hour 9.4 units/kg/hr (TBW)

18.7 units/kg/hr (AdjBW)

aPTT Heparin dose

Patient Case- Clinical Course

The hospital is experiencing a critical shortage of unfractionated heparin. What is your strategy for dosing LWMH in this patient?

A. Actual body weight with a dose capping strategy

B. Actual body weight but no dose capping strategy

C. Adjusted body weight

D. Ideal body weight

Clinical Studies in Obese Patients

PharmacodynamicYee, 2000Wilson, 2001Barrett, 2001Sanderink, 2002Hainer, 2002Smith, 2003Bazinet, 2005

Clinical Outcomes/VTEMerli, 2001Al-Yaseen, 2005RIETE, 2005

Clinical Outcomes/ACSFRISC, 1996Klein, 1997Spinler, 2003

10378124352181

283193294

356NA921

NObese Pts

DalteparinDalteparinEnoxaparinEnoxaparinTinzaparinDalteparinEnoxaparin

EnoxaparinDalteparin

NA

DalteparinDalteparinEnoxaparin

Drug

10690

100130118

-

81114112

--

94

Avg. Wt (kg)

-56-190

78-144101-16594-176

-

44-15591-182101-160

47-12542-12560-159

Wt. Range (kg)

Nutescu, et al. Ann Pharmacother 2009;43:1064-83.

Clinical Outcomes: Enoxaparin & Obesity

Spinler, et al. Am Heart J 2003;146:33-41.

Age (yrs)

Weight (kg)

BMI (kg/m2)

Any Hemorrhage

Major Hemorrhage

61 ± 11

94 ± 14

33.8 ± 4

8.5%

0.8%

65 ± 12

73 ± 11

25.4 ± 2.8

6.8%*

1.3%

Obese(n=921)

Non-Obese(n=2595)

Subgroup Analysis from the ESSENCE and TIMI 11B Studies

*p=.004

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Clinical Outcomes: Enoxaparin & Obesity

0

2

4

6

8

10

12

≤ 100 101-120 121-150 > 150

6.6

4.6

5.6

11.4

Maj

or B

leed

ing

Rat

e (%

)

The CRUSADE Initiative

Spinler, et al. Pharmacotherapy 2009;29:631-38.

Enoxaparin Dosing & Bleeding rates

TBW (kg)

≤ 100

101 – 120

121 – 150

> 150

9.6%

7.3%

6.1%

6.5%

6.6%

4.6%

5.6%

11.4%

0.78 (0.69 – 0.89)

0.68 (0.48 – 0.95)

0.99 (0.57 – 1.7)

2.42 (0.7 – 8.37)

ReducedDose

RecommendedDose

Adjusted OR(95% CI)

Bleeding Rates

Reduced dose: < 0.95 mg/kgRecommended dose: 0.95 – 1.05 mg/kg

Spinler, et al. Pharmacotherapy 2009;29:631-38.

Drug Dosing in Morbid Obesity:ANTIMICROBIALS

Ph’kinetic / Ph’dynamic Principles

Cmax

MICT>MIC PAE

Time

Con

cent

ratio

n

Cmax:MIC

AUIC

Cmin

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Ph’kinetic / Ph’dynamic Alterations with Obesity

Cmax

MICShorterT>MIC

PAE

Time

Con

cent

ratio

n

Decreased Cmax:MIC

Decreased AUIC

Cmin

Pharmacokinetic / Pharmacodynamic Considerations

Clinical success

Drug Dose

Drug Concentration at Effect Site

PD goalsAchieved

T > MICAUIC

Cmax:MIC

Pharmacologic Effect

?

Drug Dose

Drug Concentration at Effect Site

PharmacokineticVariability

PD Goals

???

Surgical Prophylaxis: Cefazolin

0 2 4 6 8

BMI>50 : Cefazolin 3 gm

BMI>50 : Cefazolin 2 gm

BMI>40 : Cefazolin 2 gm

Hours

T>MIC

Protective duration

(*MIC = 8)

(*T>MIC = 70%)

Ho, et al. Surgical Infect 2012;13:33-7.

(Mean BMI = 44 ± 3)

(Mean BMI = 56 ± 9)

(Mean BMI = 55 ± 3)

Tissue Concentrations: Cefazolin 2 gm x1

Non-obese, after 180 minObese, after 120 min

Non-obese, after 240 min

Obese, after 180 min

Obese, after 240 min

Non-obese, after 120 min

Pro

babi

lity

of ta

rget

atta

inm

ent

Brill, et al. J Antimicrob Chemother 2014;69:715-23.

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Piperacillin/tazobactam in a Trauma/Surgical ICU

Sturm, et al. Pharmacotherapy 2014;34:28-35

Dose

3.375 g every 8 hours

3.375 g every 6 hours

3.375 g every 6 hours

4.5 g every 8 hours

4.5 g every 6 hours

4.5 g every 6 hours

Infusion

4

0.5

4

4

0.5

4

MIC

1632

1632

1632

1632

1632

1632

PD Goal Achieved

100%29%

100%78%

100%62%

100%93%

100%100%

100%100%

9 ICU patients

TBW = 164 kg

BMI = 57

Cefepime in Bariatric Surgery

0

20

40

60

80

100

120

0.0625 0.125 0.25 0.5 1 2 4 8 16

10 patients; wt = 139 kg; BMI = 48

Rich, et al. Obes Surg 2012;22:465-71.

% T

ime

> M

IC

MIC (mg/L)

2 gm Q8 hrs2 gm Q12 hrs

Meropenem in ICU Patients

Cheatham, et al. J Clin Pharmacol 2013;54:324-30.

9 ICU patients

Weight = 152 kg

BMI = 55

Levofloxacin Pharmacodynamics

MIC

Time

Con

cent

ratio

n AUIC

PD Goals:Gram +: AUIC > 35Gram - : AUIC > 125

Levofloxacin 750 mg Q24; AUC ≈ 108

MIC ≈ 0.86

Ortho-McNeil. Levofloxacin (Levaquin) package insert. 2008.

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Levofloxacin- PK / PD in Obesity

Vd = 83 L; T½ = 7 hrsAUC = 90

MIC threshold = 0.72

Vd = 80 L; T½ = 7.9 hrsAUC = 108

MIC threshold = 0.86

Cook, et al. Antimicrob Agents Chemother 2011;55:3240-3.Ortho-McNeil. Levofloxacin (Levaquin) package insert. 2008.

15 Obese Patients(Wt = 162 kg; BMI = 55) Non-Obese Patients

Aminoglycosides• Antibiotic class with the most data in obesity.

• Both Vd and Cl are increased but much variability.

• Adjusted body weight is recommended.

• Comfort level with large doses may hinder ability to reach goal concentrations in a timely fashion.

Vancomycin• PK alterations with obesity:

• Increased Vd (13% - 49%) • Increased Cl (131-156%)

• PK parameters better correlated with TBW.

• “For obese patients, initial dosing can be based on TBW and then adjusted based on serum concentrations” (Grade A, LOE = II)

Blouin R, et al. Antimicrob Agents Chemother 1982;21:575-80.Pai MP, Bearden DT. Pharmacotherapy 2007;27:1081-91.Rybak, et al. Am J Health-Syst Pharm 2009;66:82-98.

Bauer, et al. Eur J Clin Pharmacol 1998;54:621-5.

Vancomycin: Pharmacokinetic Alterations

0 50 100 150 200 250 300TBW

Cle

aran

ce

350

300

250

200

150

100

50

0

0 50 100 150 200 250 300TBW

100

80

60

40

20

0Vol

ume

of D

istr

ibut

ion

Volume of Distribution Clearance

R=0.490, p<.05 R=0.948, p<.001

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5,000 simulated patients

Is Trough the Right Parameter?Distribution of Vancomycin Trough Values with AUC ≥ 400

Median: 13.3 (1.9 – 72.6)

Neely, et al. Antimicrob Agents Chemother 2014;58:309-16.

Vancomycin & Outcome: Trough vs. AUC?

MIC ≥ 1.5

Vanco trough 15 – 20 mg/L

AUC : MIC < 430 (Etest)

AUC : MIC < 399 (BMD)

Success

30%

18%

25%

23%

Failure

45%

30%

50%

45%

P-value

.236

.338

.039

.065

Multivariate Analysis:

AUC : MIC < 430 (Etest):OR (95% CI) = 4.39 (1.26 – 15.35), p=.02

AUC : MIC < 399 (BMD):OR (95% CI) = 3.73 (1.1 – 12.61), p=.034

Jung, et al. Int J Antimicrob Agents 2014;43:179-83.

Linezolid

Wt

BMI

AUC

Cmax

Vd (L)

Cl (L/hr)

Moderate Obesity

99 ± 14

36.2 ± 1.7

130 ± 60

20.9 ± 5

44.1 ± 10

7.83 ± 1.77

Morbid Obesity

120 ± 16

45.3 ± 3.2

109 ± 26

18.8 ± 2.6

62 ± 40

7.39 ± 2

P-value

-

-

.320

.237

.089

.619

Bhalodi, et al. Antimicrob Agents Chemother 2013;57:1144-49.

20 Adult Volunteers; Dose = 600 mg Q 12hrs

Linezolid

Wt

BMI

AUC

Cmax

Vd (L)

Cl (L/hr)

Moderate Obesity

99 ± 14

36.2 ± 1.7

130 ± 60

20.9 ± 5

44.1 ± 10

7.83 ± 1.77

Morbid Obesity

120 ± 16

45.3 ± 3.2

109 ± 26

18.8 ± 2.6

62 ± 40

7.39 ± 2

P-value

-

-

.320

.237

.089

.619

Bhalodi, et al. Antimicrob Agents Chemother 2013;57:1144-49.Muzevich, et al. Ann Pharmaocther 2013;47:e25

20 Adult Volunteers; Dose = 600 mg Q 12hrs

Case Report

265 kg

82 kg/m2

-

4.13

FAILURE

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Conclusion• Drug dosing in ICU patients should be individualized.

• High quality evidence in the critically ill obese patient is lacking.

• Assess for principles of dose proportionality.

• Consider ADE’s.

• Attainment of pharmacodynamic goals must be considered.