Continuing Educ ation Credit

1

All Rights Reserved, Duke Medicine 2007

Welcome to Spring Symposium 2013!

• June 10, 2013 from 5:30 p.m. until 9:30p.m.

• Duke University Hospital Room 2002

• Eight great topics by nine great speakers

• Dinner and Fellowship with Colleagues


And continuing education credit!

Continuing Education Credit

This symposium, ACPE # 0046-9999-13-117-L01-P will provide 3.0 contact hour of continuing

pharmacy education credit. No partial credit will be given. To Receive CE credit, attendance

must be acknowledged at the registration desk upon arrival at and departure of the program.

Statements of credit can be viewed and printed from CPE Monitor. Participants will receive an

email once credit processing has been completed and credit has been uploaded to the CPE

Monitor site. This process can take up to 4 weeks to appear on the CPE Monitor site.

The University of North Carolina Eshelman School of Pharmacy is accredited by the

Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

2


Meredith T. Moorman, PharmD, BCOP

Hematology/Oncology Clinical Pharmacist

Duke University Hospital Spring Symposium

June 10, 2013

New Therapies for Chronic

Myelogenous Leukemia (CML)


Disclosures

• The author of this presentation has nothing to

disclose concerning possible financial or personal

relationships with commercial entities that may have

a direct or indirect interest in the subject matter of this

presentation


Objectives

At the conclusion of this knowledge-based presentation,

the participant should be able to:

1. Name three new agents approved for the treatment

of CML

2. Identify how these agents differ from previously

approved therapies for CML

3. Compare and contrast side effect profiles of

bosutinib, ponatinib, and omacetaxine

3


CML Incidence and Mortality

Sellers WR. Cell 2011;147(1):26-31.


The Philadelphia Chromosome

http://www.mayoclinic.com/health/medical/IM03579


Phases of CML Phase of

Disease

Criteria

Chronic

(CP)

•BCR-ABL positive

•Not classified as accelerated or blast phase

Accelerated

(AP)

•Presence of any of the following:

•Persistent or rising leukocytosis >10 x109/L and/or persistent or increasing

splenomegaly unresponsive to therapy

•Persistent thrombocytosis (>1000 x109/L) uncontrolled by therapy

•Persistent thrombocytopenia (<100 x109/L) unrelated to therapy

•Clonal cytogenetic evolution from diagnostic karyotype

•≥20% basophils in peripheral blood

•10-19% myeloblasts in the blood or bone marrow

Blast (BP) •≥20% blasts in peripheral blood or of bone marrow nucleated cells

•Extramedullary blast proliferation

(Blast lineage is myeloid in 70% of cases, lymphoid in 20%, and may be mixed

phenotype)

Swerdlow SH et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th edition). IARC Press: Lyon 2008.

4


Response criteria in CML

Hematologic Response Cytogenetic Response Molecular Response

Complete

(CHR) •Platelets < 450 x

109L

•WBC < 10 x 109L

•No immature

granulocytes and

<5% basophils on

differential

•Spleen not

palpable

Complete

(CCyR) Ph+ 0%

Complete

(CMR)

Transcripts

nonquantifiable

and undetectable

Partial

(PCyR) Ph+ 1-35%

Minor Ph+ 36-65%

Minimal Ph+66-99% Major

(MMR) ≤ 0.1%

None Ph+ >95%

Adapted from http://www.epgonline.org/images/cml/2141-b.gif


Warning signs about response

• At any time:

– Loss of CHR, CCyR, MMR (confirmed on 2

occasions)

– Rise in transcript levels

– Development of other (or new) chromosomal

abnormalities

3 months 6 months 12 months 18 months

Treatment

Failure No HR <CHR

<PCyR <CCyR No CyR

Suboptimal

Response <CHR <PCyR <CCyR <MMR

Adapted from http://www.epgonline.org/images/cml/2141-c.gif


Timeline of Recent Drug Approvals in CML

May 2001 - Gleevec® (imatinib)

June 2006 - Sprycel® (dasatinib)

October 2007 - Tasigna® (nilotinib)

September 2012 – Bosulif® (bosutinib)

October 2012 – Synribo® (omacetaxine)

December 2012 – Iclusig® (ponatinib)

5


Bosutinib

• Approved for use in adults with all phases of Ph+

CML with resistance or intolerance to prior tyrosine

kinase inhibitors (TKIs)

• Active against BCR-ABL TKI, as well as Src, Lyn,

Hck kinases

• Inhibits 16/18 imatinib-resistant Bcr-Abl forms (not

active against T315I and V299L)

• Investigated in both CP CML patients with resistance

or intolerance and compared to imatinib in newly

diagnosed CP CML (BELA trial)

Cortes J et al. Blood 2011;118(17): 4567-4576.

Cortes J et al. J Clin Onc 2012;30(28):3486-3492.

Khoury H et al. Blood 2012;119(15):3403-3412.


http://images-mediawiki-sites.thefullwiki.org/07/2/3/0/91613632266212093.png

Mechanism of Action of Bosutinib


Bosutinib in TKI resistant CML

Response Criteria Imatinib-

Resistant

(n=287)

Multiple TKI Resistant

(n=118)

Hematologic response 86% 73%

Cytogenetic response

Major

Complete

31

41

32

24

Molecular response

Major

Complete

64

53

15

11

• Median time to MCyR = 12.3 weeks

• Major AEs: diarrhea (84%), N/V (44/35%)

Cortes J et al. Blood 2011;118(17): 4567-4576.

Khoury H et al. Blood 2012;119(15):3403-3412.

6


Bosutinib vs. Imatinib in Newly

Diagnosed CML (BELA trial)

Response Criteria Bosutinib

(n=250)

Imatinib

(n=252)

P value

Hematologic response 71% 85% >0.999

Cytogenetic response

Major

Complete (at 12 mos)*

73

70

78

68

0.601

Molecular response

Major

Complete

41

12

27

3

<0.001

<0.001

• Bosutinib 500 mg po daily vs. imatinib 400 mg po daily

• Median time to response: 12.9 vs. 24.6 weeks (p<0.001)

• Fewer bosutinib treated patients with progression to AP/BP

(4 patients vs. 10 patients) Cortes J et al. J Clin Onc 2012;30(28):3486-3492.


Adverse reactions with bosutinib

• Gastrointestinal

– Diarrhea (82%), nausea (46%), vomiting (39%),

abdominal pain (37%)

• Hematologic

– Thrombocytopenia (41%), anemia (27%),

neutropenia (17%)

• Other

– Edema (14%), AST/ALT increases (~15%), rash

(35%)


Bosutinib – dosing and dose modifications

• Dosing: 500 mg po daily

– Escalate to 600 mg po daily in patients not

achieving CHR at 8 weeks or CCyR at 12 weeks

and do not have > grade 3 toxicity

• Dose modifications

– Elevated liver function tests (>5x ULN)

– Diarrhea (>7 stools/day over baseline)

– Neutropenia (ANC < 1000)

– Thrombocytopenia (platelets < 50K)

• Drug interactions

– Caution with CYP3A4 inducers/inhibitors

7


Ponatinib

• Approved for use in adults with all phases of Ph+

CML or Ph+ ALL with resistance or intolerance to

prior TKIs

• Active against BCR-ABL, VEGFR, PDGFR, FGFR,

Src, KIT, RET, FLT3

• Demonstrated significant activity in patients harboring

T315I mutation


PACE (Ponatinib Ph+ ALL and CML

Evaluation) Trial

• Open label trial in Ph+ ALL and Ph+ CML patients

resistant or intolerant (R/I) to nilotinib or dasatinib,

with or without T315I mutation

• Patients divided into cohorts based on disease stage

and mutation status

• Primary endpoints:

– Ph+ ALL: major HR at any time within 6 months

– Ph+ CML: MCyR at any time within 12 months

• Heavily pretreated population – 53% of patients

exposed to all 3 approved TKI

Cortes JE (2012). Abstract 163 from 2012 ASH Annual Meeting Abstracts.*


• Median follow-up was 11 months

• Responses considered durable: probability of maintaining

primary endpoint at 1 year was 91% (CP-CML), 42% (AP-CML),

35% (BP-CML/ALL)

• Higher response rates seen in patients with less exposure to

TKI and shorter disease duration

• Most common AEs: thrombocytopenia (36%), rash (33%), dry

skin (31%)

• Pancreatitis most common serious AE (5%)

PACE trial results

CP-CML

n/N (%)

AP-CML

n/N (%)

BP-CML/Ph+ ALL

n/N (%)

R/I 101/203 (50) 38/65 (58) 17/48 (35)

T315I 45/64 (70) 9/18 (50) 15/46 (33)

Total 146/267(55) 47/83 (57) 32/94 (34)

8


Ponatinib – dosing and dose

modifications

• Dosing: 45 mg po daily

– Can be taken with or without food

• Dose modifications:

– Neutropenia (ANC<1000)

– Thrombocytopenia (platelets<50K)

– Elevated LFTs (>3x ULN or AST/ALT≥3x ULN +

bilirubin > 2x ULN and alk phos <2x ULN)

– Elevated lipase or pancreatitis

• Caution with CYP3A4 inhibitors/inducers

– Reduce dose to 30 mg po daily with strong

inhibitors


Adverse reactions with ponatinib

• Black box warning

– Arterial thrombosis (serious, 8% patients)

– Hepatotoxicity (LFT elevations in 56% patients)

• Clinically significant

– Hypertension (53-71%)

– Pleural effusion (3-19%)

– Peripheral edema (13-22%)

– Rash (34-54%)

– Arthralgia/myalgia (6-31%)

– Glucose increased (58%)


Omacetaxine

• Approved for use in adult patients with CP or AP

CML with resistance and/or intolerance to two or

more TKI

• Reversible protein translation inhibitor, not affected

by mutations in BCR-ABL

• Like ponatinib, it has demonstrated activity in patients

with T315I

• Studied in patients with any phase of CML, T315I

mutation positive, and who had failed 1 or more TKI

therapies

9


Omacetaxine study results

• Study included 62 patients with T315I mutation

• 74% had failed at least two TKIs

• Primary endpoint was number of patients achieving

either CHR (77%) or MCyR (23%)

• Median # cycles to achieve CHR = 1, MCyR = 2.5

• Duration of response = 9.1 months (CHR), 6.6

months (MCyR)

• AEs: thrombocytopenia (76%), neutropenia (44%),

anemia (39%), diarrhea (40%), nausea (34%), fever

(29%)


Omacetaxine – dosing and dose

modifications

• Dosing:

– Induction: 1.25 mg/m2 SubQ BID for 14 days in 28

day cycle

– Maintenance: 1.25 mg/m2 SubQ BID for 7 days in

28 day cycle

• Dose modifications

– If ANC < 500 or platelets < 50K during cycle, hold

therapy until ANC>1000 or platelets > 50K

– Reduce number of dosing days in next cycle by 2

(to 12 or 5)

– Manage other toxicities symptomatically


Cost of CML medications

• Estimated annual cost of newly approved agents:

– Bosutinib - $118,000

– Omacetaxine - $28,000 (induction), $14,000 (each

maintenance cycle)

– Ponatinib - $138,000

• Recent article highlights variable cost of agents in

different geographic areas

• Transplant may be considered earlier in course of

therapy, or as only option, because of limited one

time cost ~$70,000-80,000

Experts in Chronic Myeloid Leukemia. Blood 2013;121(22):4439-4442.

10


Conclusions

• Several new agents are available for treatment of

adults with Ph+ CML, including those with T315I

mutation

• Omacetaxine demonstrates a new mechanism of

action compared with other therapies available for

CML


Assessment Question

1. Which new agent for CML demonstrates a novel

mechanism of action compared to previously FDA

approved therapies?

A. Bosutinib

B. Omacetaxine

C. Ponatinib

D. All of the above

E. None of the above


Assessment Question

1. Which new agent for CML demonstrates a novel

mechanism of action compared to previously FDA

approved therapies?

A. Bosutinib

B. Omacetaxine

C. Ponatinib

D. All of the above

E. None of the above

11


Treatment Updates for

Advanced Prostate Cancer

Russell A. Moore, Pharm.D., BCOP

Clinical Pharmacist

Genitourinary Medical Oncology

Duke University Hospital

June 10, 2013

31


Disclosures





presentation


1. Compare and contrast outcomes for new and emerging

treatment strategies for advanced prostate cancer

2. Assess toxicities and patient management

considerations associated with the use of novel agents

in the treatment of castration-resistant prostate cancer

(CRPC)

3. Explain the results and implications of clinical trials for

newly approved and emerging agents for CRPC, and

discuss the safety, efficacy, and mechanism of action of

each of these agents

Objectives

12


Cancer Facts and Figures 2013. Available at: www.cancer.org.

Prostate Cancer: 2013 Estimates


Prostate Cancer Management

• Early stage disease

– Treatment Options: • Active surveillance, radiation therapy (RT), radical prostatectomy, or

androgen deprivation therapy (ADT) (in select patients)

• Advanced disease

– Progression after initial definitive therapy • RT + ADT

• Radical prostatectomy

– At initial diagnosis • Metastatic to lymph node or other site (N1 or M1)

– Treatment Options: medical / surgical castration

• Castration-Resistant Prostate Cancer (CRPC)

– Disease progression despite medical / surgical castration

– Testosterone level < 50 ng/dL

Prostate Cancer. NCCN Guidelines Version 3.2012. Available at: www.nccn.org


Treatment Paradigm by Disease State: 2010 Hormone Sensitive

Newly diagnosed Localized disease

Active Surveillancea

Radiation

Radiation + ADTa,b

Prostatectomy

Non-metastatic, Biochemical relapse

Prostatectomy Observation

Salvage radiationa

Brachytherapy

Cryosurgery ADT

Metastatic Hormone-naïve

Orchiectomy ADT

Castration-Resistant

Non-Metastatic

No standard 2nd-line hormonal

agents

Asymptomatic Metastatic

(chemo-naïve)

2nd-line ADT Docetaxela,b

Symptomatic Metastatic

(chemo-naïve)

Docetaxelb

Mitoxantrone

Palliative Radiation

89Strontium 153Samariuma,b

Metastatic Post-docetaxel

Mitoxantrone Docetaxel

rechallenge Other chemo a Selected patients

b Category 1 evidence

Adapted from: Higano CS, et al. Urol Oncol 2011;29(6 Suppl):S1-S8.

13


Treatment Paradigm by Disease State: 2013

a Selected patients b Category 1 evidence

Adapted from: Higano CS, et al. Urol Oncol 2011;29(6 Suppl):S1-S8.

Castration-Resistant

Asymptomatic Metastatic

(chemo-naïve)

Sipuleucel-Tb

Abirateroneb

Enzalutamide (off-label) 2nd-line ADT

Docetaxela,b

Symptomatic Metastatic

(chemo-naïve)

Abiraterone Enzalutamide (off-label)

Docetaxelb

Mitoxantrone

Palliative Radiation 89Strontium

153Samariuma,b

Metastatic Post-docetaxel

Cabazitaxelb

Sipuleucel-T

Abirateroneb

Enzalutamideb

Radium-223 Mitoxantrone

Docetaxel rechallenge

Other chemo

Bone Health in Metastatic Disease: Denosumabb or Zoledronic acidb


Androgen and the

Androgen Receptor (AR):

Targeting the Androgen Pathway


Model of the Evolution of CRPC

CRPC

Androgen-dependent cell CRPC, Castration Resistant Prostate Cancer

ADPC, Androgen-Dependent Prostate Cancer

14


Androgen and AR-defined

Prostate Cancer Cell States

Nelson PS. J Clin Oncol 2012;30:644-646.


Mechanisms of CRPC:

Persistent AR Pathway Signaling

• Hyperactive AR

– Amplification of the AR gene or increased protein expression

– AR point mutations

• Increased AR expression and expression of androgen-regulated genes (such as PSA)

– Increase in PSA = indicative of AR transcriptional activity reactivation

• Persistent intratumoral ligand: testosterone or precursors

– Intratumoral conversion

Taplin ME, Balk SP. J Cell Biochem 2004;91:483-490.

Stanbrough M, et al. Cancer Res 2006;66:2815-2825.


Higher AR Levels in CRPC Tumors AR expression in

bone marrow mets

Stanbrough M, et al. Cancer

Res. 2006;66:2815-2825.

At autopsy – 73% of 15

samples exhibit AR

amplification Friedlander TW, et al. Cancer Res

2012;72:616-625.

Increased AR mRNA

in CRPC tested

Holzbeierlein J, et al. Am J

Pathol 2004;164:217-227.

15


Drug Targets

Involving the

Androgen-Receptor

Pathway

Schweizer MT, Antonarakis ES. Ther Adv Urol 2012;4:167-178.


AR Signaling: Matching Biology to Therapy

Androgen

Production

AR

Binding

Signaling Event Intervention

Conversion

to DHT

Androgen

Transport/

Circulation/

Uptake

SCC Inhibitors CYP 17

Inihibitors

Block Transport

5-Alpha Reductase inhibitors

Ketoconazole Abiraterone Tak-700 Tok-001

Drugs

Dutasteride

Enzalutamide ARN-509 Tok-001

Novel AR Inhibitors

Pre

-R

ecep

tor

Rec

epto

r

Intracrine Production

Polymorphisms

Amplified 5 Alpha Reductase

Amplified AR Splice Variant AR

Aberration

None


Steroid / Androgen Synthesis Pathway

45

Schweizer MT, Antonarakis ES. Ther Adv Urol 2012;4:167-178.

16


CALGB 9583 (Phase III Trial)

• Antiandrogen withdrawal (AAWD) alone vs. simultaneous

AAWD and Ketoconazole

Observations With Ketoconazole

Small EJ, et al. J Clin Oncol 2004;22:1025-1033.

Ryan CJ, et al. Clin Cancer Res 2007;13:2030-2037.

3. Androgens rise at time

of disease progression

1. Approximately 30% are

progression free at 2 years 2. Higher baseline androgens

= better survival


Abiraterone: A CYP17 Inhibitor

Low-dose steroid replacement reduces mineralocorticoid-related toxicity

Attad G, et al. J Clin Oncol 2008;26:4563-4571.

Ryan CJ, et al. J Clin Oncol 2010;28:1481-1488.


Abiraterone Acetate (Zytiga)

• FDA-approved: April 28, 2011

– Metastatic CRPC in combination with prednisone

• Pharmacology

– Inhibits 17 alpha-hydroxylase/C17,20-lyase (CYP17), enzyme required for androgen biosynthesis

• Dosing

– 1,000 mg (250 mg tablet x 4) PO daily + Prednisone 5 mg PO bid

– Empty stomach (no food 2 hours before and at least 1 hour after the dose) • Increased absorption with food

• Adverse effects:

– Hot flushes, diarrhea, fatigue, muscle weakness, joint swelling/discomfort, HTN, hypo-K, fluid retention

48

Abiraterone Acetate. Facts and Comparisons. www.factsandcomparisons.com. [Accessed: 10/31/12].

17



COU-AA-301 Study

• Phase III, multicenter, randomized, double-blind,

placebo-controlled trial

– Metastatic, castration-resistant prostate cancer

• Primary endpoint = overall survival

49

Abiraterone acetate 1000 mg PO

daily on empty stomach +

Prednisone 5 mg PO bid (n=797)

Metastatic

CRPC,

previously

treated with

docetaxel

(N=1195) Placebo + Prednisone 5 mg PO

bid (n=398)

R

A

N

D

O

M

I

Z

E

D

de Bono JS, et al. N Engl J Med 2011;364:1995-2005.


COU-AA-301 Study: Overall Survival

de Bono JS, et al. N Engl J Med 2011;364:1995-2005.



COU-AA-302 Study

• Phase 3, multinational, randomized, double-blind,


– Chemotherapy naive patients with mCRPC AA 1000 mg daily

Prednisone 5 mg BID

(n = 546)

Co-Primary:

• rPFS by central review

• OS

Secondary:

• Time to opiate use

(cancer-related pain)

• Time to initiation of

chemotherapy

• Time to ECOG-PS

deterioration

• TTPP

Efficacy endpoints

Placebo daily

Prednisone 5 mg BID

(n = 542)

R A N D O M I Z E D

1:1

• Progressive chemo-

naïve mCRPC

patients

• Asymptomatic or

mildly symptomatic

Patients (N=1088)

Ryan CJ, et al. N Engl J Med 2013;368:138-148.

18


COU-AA-302 Study: rPFS

Primary End Point

Ryan CJ, et al. N Engl J Med 2013;368:138-148.


COU-AA-302 Study: Overall Survival

Strong Trend

53

Note: Prespecified boundary for significance (P≤0.001) not reached at the

observed number of events Ryan CJ, et al. N Engl J Med 2013;368:138-148.


Abiraterone Monitoring and Safety

• May cause HTN, hypo-K, fluid retention, and increases in AST/ALT

– Monitor BP, serum potassium, LFTs, and symptoms of fluid retention at least monthly

• Use with caution in patients with a history of cardiovascular disease

• Co-administer with a corticosteroid to suppress adrenocorticotropic hormone (ACTH) drive

• Drug interactions:

– Avoid (or caution) with CYP3A4 strong inhibitors and inducers

– Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index

• Pricing

– 250 mg (120): $7,674.37

54

Abiraterone Acetate. Lexi-comp. www.lexi-comp.com. [Accessed: 5/15/13].

19


Potential New CYP17 Inhibitors

• Orteronel (TAK-700)

– Higher specificity for C17-20 lyase inhibition vs. 17α-hydroxylase inhibition • May not require concomitant prednisone

– Currently in several phase III trials • Several of these do not include prednisone

• Galeterone (TOK-001)

– Disrupts multiple androgen signaling pathways simultaneously • Downregulation of the AR and competitive inhibition of

androgen binding and AR translocation into the nucleus

– Currently in phase I and phase II trials

Schweizer MT, et al. Ther Adv Urol 2012;4:167-178.


www.clinicaltrials.gov. [Accessed: 5/15/13].


AR Signaling: Matching Biology to Therapy

Androgen

Production

AR

Binding

Signaling Event Intervention

Conversion

to DHT

Androgen

Transport/

Circulation/

Uptake

SCC Inhibitors CYP 17

Inihibitors

Block Transport

5-Alpha Reductase inhibitors

Ketoconazole - Abiraterone Tak-700 Tok-001

Drugs

Dutasteride

Enzalutamide ARN-509 Tok-001

Novel AR Inhibitors

Pre

-R

ecep

tor

Rec

epto

r

Intracrine Production

Polymorphisms

Amplified 5 Alpha Reductase

Amplified AR Splice Variant AR

Aberration

None

20


Enzalutamide (Xtandi)

• FDA-approved: August 31, 2012

– Metastatic CRPC after docetaxel

• Pharmacology

– Competitively inhibits androgen binding to receptor and inhibits androgen receptor nuclear translocation and interaction with DNA

• Dosing

– 160 mg (40 mg capsule x 4) PO daily

– With or without food

• Adverse events

– Hot flushes, muscular weakness, fatigue, cardiovascular risks, weight gain, hyperlipidemia, muscle wasting, seizure (0.9%)

Enzalutamide. Facts and Comparisons. www.factsandcomparisons.com. [Accessed: 10/31/12].


59

AR Inhibition: Proposed Mechanism of Action

Scher, ASCO GU 2012



AFFIRM Trial • Phase 3, randomized, international, double-blind, placebo-

controlled trial

– CRPC previously treated with one or two chemotherapy regimens, at least one of which contained docetaxel

– Primary endpoint = overall survival

Enzalutamide 160 mg PO daily (n=800) Metastatic

CRPC,

previously

treated with

docetaxel

(N=1199) Matching Placebo PO daily (n=399)

R

A

N

D

O

M

I

Z

E

D

Scher HI, et al. N Engl J Med 2012;367:1187-1197.

21


Enzalutamide: AFFIRM Trial

Overall Survival

Median OS:

Enzalutamide: 18.4 mo

Placebo: 13.6 mo

37% reduction in risk of

death vs. placebo

Study halted and

unblinded at interim

analysis



Enzalutamide: AFFIRM Trial

Secondary Endpoints

62




PREVAIL Trial • Phase 3, multinational, randomized, double-blind,


– Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer

– Asymptomatic or mildly symptomatic

• Primary endpoints:

– Overall survival and progression-free survival

• Secondary endpoints:

– Time to first skeletal-related event

– Time to initiation of cytotoxic chemotherapy

• Estimated primary completion date: September 2014

– Interim analysis planned in 2013

63

www.clinicaltrials.gov. [Accessed: 5/1/13].

22


Enzalutamide Monitoring and Safety

• Seizure history or other predisposing factors

– Use with caution

• Drug interactions

– Strong CYP3A4 and moderate CYP2C9 and

2C19 inducer

– CYP3A4 and CYP2C8 substrate

• Pricing

– 40 mg (120): $8,940.00

Enzalutamide. Lexi-comp. www.lexi-comp.com. [Accessed: 5/15/13].


Potential New AR Inhibitors

• ARN-509

– Competitive AR inhibitor

– Purely antagonistic

– Reduce efficiency of nuclear translocation of the AR and impair AR binding to androgen-response elements of DNA

– Less effective blood-brain barrier penetration vs. enzalutamide • Possibly less off-target inhibitory effects on gamma

aminobutyric acid (GABA) type A = less seizure risk

– Currently in phase I and II clinical trials • NCT01790126, NCT01792687

Schweizer MT, et al. Ther Adv Urol 2012;4:167-178.


Emerging Agents for Advanced

Prostate Cancer

Androgen-Independent Pathway

66

23


All Rights Reserved, Duke Medicine 2007 www.clinicaltrials.gov. [Accessed: 5/15/13].


Radium-223 Chloride (Xofigo) (formerly known as Alpharadin) • Intravenous radioisotope

– FDA-approved: 5/15/13

• Alpha-particle emitter (first-in-class)

– High energy and short radius of activity

– Double-strand DNA breaks

– Lower penetration to surrounding tissues compared with beta-emitting radiopharmaceuticals

• Beta-particle emitters (available radioisotopes)

– Strontium-89 (Metastron) and Samarium-153 (Quadramet)

– Longer radius of activity

– Single-strand DNA breaks

– Approved for pain palliation due to skeletal metastases

Higano CS, Crawford ED. Urol Oncol 2011;29(6 Suppl):S1-S8.

Shore N, et al. BJU Int 2012;109(Suppl 6):22-32.

24


Radium-223 Targets Bone Metastases

Bone surface

Range of alpha-particle

Radium-223 Perez et al. Principles and Practice of Radiation Oncology. 5th ed.

Lippincott Williams & Wilkins;2007:103.

Cheetham PJ, et al. Oncology (Williston Park) 2012;26:330-337,341.

• Calcium mimetic natural bone-

targeting agent

• Preferential uptake in areas of

new bone formation

• Incorporated into bony matrix

• Excreted into small intestine


Radium-223 (Xofigo)

ALSYMPCA: Phase 3 Randomized Trial

71

Parker C, et al. European Multidisciplinary Cancer Congress. 2011; Abstract no. 1LBA


Month 0 3 6 9 12 15 18 21 24 27

Radium- 223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

ALSYMPCA: Overall Survival

0

10

20

30

40

50

60

70

80

90

100

%

Radium-223, n = 541

Median OS: 14.014.9 months

Placebo, n = 268

Median OS: 11.211.3 months

HR 0.695; 95% CI, 0.581-0.832

P = 0.00007

Adverse events: slightly worse with placebo Parker C, et al. ASCO 2012. Abstract LBA4512.

25


ALSYMPCA: Updated Analysis

Adverse Events of Interest

Parker C, et al. ASCO 2012. Abstract LBA4512.


Summary

• Compelling survival with abiraterone and enzalutamide in patients with heavily pretreated CRPC has reinforced the value of inhibiting the androgen receptor axis

• Need to further define the optimal application and timing of prostate cancer therapies

• Monotherapy vs. combination therapy and clinical efficacy?

• Financial implications of new agents

• New targeted therapies will need to be developed in conjunction with biomarkers that predict response (i.e., Her-2 trastuzumab in breast cancer)

74


Self-Assessment Question

• Which of the following agent(s) is/are approved for

the treatment of metastatic castration resistant

prostate cancer (mCRPC) pre-chemotherapy?

A. Ketoconazole

B. Enzalutamide (Xtandi)

C. Abiraterone (Zytiga)

D. Radium-223 (Xofigo)

E. B and C

F. All of the above

26


Implementation of Transitions of Care at

the Duke Outpatient Clinic June 10, 2013

Ben Smith PharmD, BCACP

Holly Causey PharmD, BCACP, CPP, CDE


The authors of this presentation have the following to

disclose concerning financial or personal relationships

with commercial entities that may have a direct or

indirect interest in the subject matter of this

presentation:

Ben Smith: nothing to disclose

Holly Causey: nothing to disclose

Disclosures


Objectives

Upon completion of this knowledge based program, the

participant should be able to:

– Describe current practices to reduce

hospitalization, including post-hospital follow-

up visits

– Review current transitional care programs

– Explain roles for pharmacists in transitions of

care

– Discuss implementation of transitions of care

at the Duke Outpatient Clinic

27


National Models of Care Transitions

• Project Red

– RN discharge advocate coordinated discharge

plan with hospital team/educated patient

– RN created after-hospital care plan

– Pharmacist contacted patient 2-4 days after

discharge

– Decreased hospital utilization for intervention

group (0.314 vs. 0.451 visit per person per

month; p=0.009)

Ann Intern Med. 2009;150:178-187


ASHP-APhA Medication Management in

Care Transitions Best Practices

• Einstein Healthcare Network

• Froedtert Hospital

• Hennepin County Medical Center

• Johns Hopkins Medicine

• Mission Hospital

• Sharp HealthCare

• University of Pittsburgh Medical Center

• University of Utah Hospitals and Clinics

http://www.pharmacist.com/medication-management-care-transitions-best-practices



• Einstein Healthcare Network

– Pharmacist med rec and patient consult upon

discharge

– Address medication access barriers

– Scripted pharmacist post-discharge phone call

– 30-day readmission rate 10.6% vs. 21.4% in

controls


28



• Froedtert Hospital

– Pharmacist completes med rec at admission,

transfers, and discharge

– High risk patients receive pharmacist follow-up

call 2-3 days post discharge

– Option to schedule for pharmacy visit

– HF readmissions decreased from 30.37% to

20.13%




• Hennepin County Medical Center

– Re-engineered discharge plan by care

coordinator

– Pharmacist completes med rec at discharge

– Follow-up phone call

– Patients without follow-up at discharge: Visit

with pharmacist and nurse practitioner within 7

days of discharge

– 30-day readmission rate 8% vs. 23%




• John Hopkins Medicine

– Screening criteria to determine population of

focus

– Post-discharge phone call completed by

inpatient pharmacist within 72 hrs of discharge

– Home-based med rec by inpatient or outpatient

pharmacist for select patients


29



• Mission Hospital

– Medication Access/education for uninsured

– Pharmacy technician performs up to 3 follow-

up calls following discharge within 72 hours,

within first week of refill, after first PCP visit

– Pharmacist clinic visits scheduled if needed

– Engagement with community partners

– $210,000 estimated cost avoidance in year 1




• Sharp HealthCare

– Pharmacy technicians interview patients

admitted > 24 hours

– Pharmacist review focuses on HF or

hospitalist referred patients

– Discharge med education and access focus

– Pharmacy resident f/u phone call or home visit

within 5 days

– HF readmissions decreased from 20% to 13%




• University of Pittsburgh School of Pharmacy and

Medical Center

– Screening questionnaire identifies patients

– Pharmacist performs med rec/education

during admission

– Inpatient pharmacist performs f/u call within 72

hours of discharge

– Two HCAHPS med questions improved from

22% and 27% to 75%

– 30-day readmissions 10.5% vs. 23.7%


30



• University of Utah Hospitals and Clinics

– Service covers 90% of discharges

– Med rec at admission, during hospitalization,

and at discharge

– Discharge pharmacist places note in EMR

– Clinic pharmacists perform f/u calls

– Clinic pharmacist visit scheduled if high risk

– Decreased HF readmissions: 20.5-22.1% to 16%



Implementation at the Duke

Outpatient Clinic


Phase 1

• Target: Duke Outpatient Clinic patients with Medicaid

and Aging/Blind/Disabled

• Implementation: late October 2012

• Documentation: CMIS, Maestro Care

• Involvement:

– CCNC

– DOC clinical pharmacists

– PCP

31


Phase 1 Process

Daily list of Medicaid ABD

patients hospitalized

and seen in ED

Contacted patient via phone for

comprehensive medication

review

Communicated with CCNC

care manager

PCP visit within 7-14 days


Phase 2

• Target: all Duke Outpatient Clinic patients

• Incorporation of Medicare transitional billing codes

• Implementation: February 2013

• Documentation: CMIS if applicable, Maestro Care,

PCP sent reminder email

• Involvement: interdisciplinary


Phase 2 Process

Hospital D/C list sent daily to front

desk staff

Phone call w/in 48 hours of discharge

PharmD call patient for medication review and follow up of other issues

Provider sees patient within

7-14 days post

discharge

Telephone note routed to Holly/Ben in Maestro Care

Telephone note routed to provider in Maestro Care

32


Front Desk Follow-Up Call

• Follow-up visit scheduled or patient reminded of

appointment time/date

• Medication access addressed

• Transportation availability addressed

• Telephone note CC’d to Holly/Ben in Maestro Care


Front Desk Follow-Up Call

• Contacted patient to remind and/or schedule patient for Duke

Outpatient Clinic hospital follow-up visit with physician. Patient

or caregiver asked to bring all medications, blood glucose

log/meter, and blood pressure log (as applicable).

• Patient or caregiver voiced understanding of appointment

date/time and informed that clinical pharmacist may contact

patient to discuss medications prior to visit.

Follow Up Appointment

1. The patient does have an appointment for follow up at Duke

Outpatient Clinic.

2. The patient believes that she can attend this appointment and

has transportation.

3. The patient verbalized that she was able to pick-up

medications prescribed at hospital discharge.


PharmD Follow-Up Call Assessment

• New medications and knowledge of medications

• Knowledge of reason for hospitalization

• Knowledge of current self-care needs

• Documentation of educational needs

• Home health utilization

• Ability of patient to attend scheduled appointment

• Request medications and/or medication list brought to

follow-up visit

• At the conclusion of our call, the telephone note was CC’d

to patient’s PCP along with an email reminder

33


Coordination of Care

• Avoid PharmD calls to patients targeted by other

services

– Community Care of NC

– Heart Failure follow-up team

– Stroke follow-up team


Interdisciplinary Effort

• Patient Service Associates (PSA)

• Licensed Clinical Social Worker (LCSW)

• MD

• PharmD

• RN


Hospital Follow-Up Visit

• RN assessment included in visit

• PCP Hospital Follow-Up Template Addresses:

– Medications

– Consultations/diagnostic tests

– Patient empowerment/education

– Home status/level of function

– Communication with providers/pharmacy

34


Metrics – Discharge Phone Calls


Metrics –Follow Up Scheduling


Areas for Improvement

• Telephone documentation by PSA to include:

– Patient has an alternate PCP

– If appointment was scheduled

– If patient to reschedule later

• Scheduling patients in < 14 days of discharge if

appointment set > 14 days

– If patient refuses, this should be documented

in the initial telephone note

35


Future of DOC Transitions

• Progress towards creating a transitions of care model

for all Duke ambulatory clinics

• Evaluate potential reduction of 30-day readmissions

• Evaluate increased primary care revenue capture


Acknowledgements

• Community Care of North Carolina

• DOC Discharge Clinic Committee

• DOC staff

• Matthew Ransom PharmD, BCACP


Self Assessment Question 1

• Question

– What are two tasks that health system

pharmacists can complete to facilitate care

transitions?

36


Health Literacy SAY WHAT?!?

Evan Frasure, PharmD

Continuity of Care Coordinator

Department of Pharmacy



Disclosures





presentation


Objectives

• Define health literacy and its prevalence in the U.S.

population

• Describe the impact of health literacy on pharmacy

practice

• Identify strategies for counseling patients with low

health literacy, including the use of “universal

precautions’

37


“The single biggest problem in

communication is the illusion

that it has taken place”

-George Bernard Shaw


“It is not just, nor fair, to expect a

patient to make appropriate health

decisions and safely manage

his/her care without first

understanding the information

needed to do so.”

Reducing the Risk by Designing a Safer, Shame-Free

Health Care Environment. AMA, 2007


What is Health Literacy Anyway?

“The ability to obtain, process,

and understand health

information to make informed

decisions about health care.”

AHRQ Health Literacy Universal

Precautions Toolkit

38


How Common is it?

• 36% of the U.S. adult population has limited health

literacy

• Only 12% achieve the proficient level

• Varies by race, age, ethnicity, education, and

socioeconomics

• Low health literacy may be present regardless of the

above demographics


National Center for Education

Statistics


National Center for

Education Statistics

39


National Center for

Education Statistics


Low Health Literacy is associated with . . .

• Less knowledge about disease

• More healthcare utilization/cost

– Hospital admissions

– ED visits

• Decreased medication adherence

• Poorer health status in the elderly

• Increased mortality rate in the elderly

Berkman et al, Anal Intern Med.

2011;155:97-107


PHARMACY SPECIFIC

IMPLICATIONS

40


Take 1 pill by mouth once

daily.

Health literacy level

Adequate – 84%

Marginal – 78%

Low – 74%

Davis TC et al. JGIM 2008;24

(1):57-62.


Take 1 pill by mouth every 12 hours


Adequate – 61%

Marginal – 51%

Low – 30%


(1):57-62.


Take two tablets by mouth twice daily


Adequate – 71%

Marginal – 57%

Low – 33%


(1):57-62.

41


Davis et al 2006. Adapted from

Table 3.


WHAT CAN I DO ABOUT IT?


Health Literacy Universal

Precautions Toolkit AHRQ

Pub. No. 10-0046-EF

42


Universal precautions

• You cannot tell by looking

• Higher literacy skills does not equal understanding

• Health literacy is not a state but rather a trait

• Everyone benefits from clear communication


Tool #3 - Raise awareness


Tool #5 - Teach-Back method

• A way to confirm understanding

• NOT A TEST

• Helps create dialogue between the patient and

provider

• Once part of a routine, it does not take longer to

perform

43


How do I get started?

• Start slowly

• Plan your approach

• Clarify

– As often as necessary

– Patient’s own words

• Practice, practice, practice


EXAMPLES OF TEACH-BACK


“Do you understand everything I told you today

about your diabetes?”

“We covered a lot today about your diabetes,

and I want to make sure that I explained things

clearly. So let’s review what I have discussed.

What are 3 things you can do that will help you

control your diabetes?”

44


“To be sure you understand what I just said,

please tell me how you will take this new

medication.”

“I want to be sure I explained your new

medication correctly. Will you tell me how you

are going to use this medication?”


Summary

• Health literacy is a major concern in today’s

healthcare environment

• Health literacy can greatly impact the proper use of

medications

• Using universal precautions including the teach-back

method can have significant impact


Self-assessment question

What factor(s) determine a patient’s

health literacy?

a) Formal education

b) Ethnicity

c) Age

d) None of the above

e) All of the above

45


BREAK TIME!


Incidence of Vancomycin-Induced

Nephrotoxicity in Patients with and without

Concomitant Piperacillin-Tazobactam

Lindsey D. Burgess, PharmD

PGY1 Pharmacy Resident


Durham, NC Co-investigator:

Richard H. Drew, PharmD, MS, BCPS, FCCP


Disclosure Statement

These individuals have the following to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation:

– Resident: Lindsey D. Burgess, PharmD: Nothing to disclose

– Co-Investigator: Richard H. Drew, PharmD, MS, BCPS, FCCP: Nothing to disclose

46


Objective

• Describe the relative incidence of nephrotoxicity

between vancomycin monotherapy and in

combination with piperacillin-tazobactam, and state

possible confounding factors


Background

• Acute kidney injury (AKI) is a complication of many

illnesses and pharmaceutical agents

• Development of AKI in hospitalized patients increases

morbidity and mortality

• Drug-induced mechanisms

– Hypoperfusion

• Angiotensin converting enzyme inhibitors or nonsteroidal anti-

inflammatory drugs

– Renal tubular necrosis

• Aminoglycoside antibiotics

– Interstitial nephritis

• Penicillin antibiotics

Pannu, N et al. Crit Care Med. 2008;36:S216-23.


Vancomycin

• Glycopeptide antibiotic used for the treatment of drug-

resistant gram positive organisms

– Methicillin-resistant S.aureus (MRSA)

• Associated with nephrotoxicity

– Incidence 5-35%

– Usually reversible

– Risk factors: advanced age, concomitant nephrotoxins,

pre-existing renal dysfunction, high trough

concentrations

• Requires careful monitoring of renal function and dose

adjustment when necessary Elyasi, S et al. Eur J Clin Pharmacol. 2012 Sep;68(9):1243-55.

47


Piperacillin-Tazobactam (PT)

• Ureidopenicillin and beta-lactamase inhibitor

• Frequently used in combination with vancomycin

– Adds gram-negative and anaerobic activity

• Infrequently associated with nephrotoxicity

– Rare published reports

– Incidence <1% Zosyn package insert. Pfizer, May 2012.

http://labeling.pfizer.com/ShowLabeling.aspx?id=416


Combination Vancomycin and PT:

Nephrotoxicity

• Combination reported to exhibit increased nephrotoxicity

compared to vancomycin monotherapy

– Incidence with combination 49.3% compared to 8.9%

with vancomycin monotherapy

• OR=9.95, p<0.001

• Based on the high frequency of co-administration,

confirmation of these findings would have significant

implications on empiric antimicrobial therapy

Min E, Box K, Lane J et al. Crit Care Med. 2011; 39(Suppl.):200.


Purpose of Study

• Investigate the incidence of nephrotoxicity in

hospitalized adult patients receiving

intravenous (IV) vancomycin monotherapy

compared to combination therapy with

vancomycin and PT

• Explore the effect of confounding variables on

the development of vancomycin-induced

nephrotoxicity

48


Objectives

• Primary

– Compare the incidence of nephrotoxicity in hospitalized

adult patients receiving IV vancomycin with and without

the addition of IV PT

• Secondary

– Determine the impact of the following on incidence of

nephrotoxicity in patients receiving vancomycin therapy

• Concomitant nephrotoxic agents

• Age

• Vancomycin trough concentration >15 mcg/ml

• Charlson Co-morbidity Score

• Total vancomycin dose > 4gm/day at any point in therapy


Primary Endpoint

• Incidence of nephrotoxicity

• Definition: Minimum 1.5 fold-increase in serum

creatinine

– Based on the maximum serum creatinine

value within the first 7 days of vancomycin

treatment from the serum creatinine

measured within 48 hours before initiating

vancomycin


Study Design/Population

• Single-center, retrospective, IRB-approved cohort

study

Inclusion Criteria

• Male or females age >18 yrs

• Admitted to Duke University Hospital 7/1/09-7/1/12

• Minimum of 48 hours of vancomycin

• Minimum four days of measured serum creatinine concentrations

• For the cohort of patients on concomitant PT: >48 hours of PT concurrently with vancomycin and PT initiated within 48 hrs of initiation of vancomycin

49


Population

• Serum creatinine >1.5 mg/dL or calculated creatinine

clearance <30 ml/min (based on Cockcroft-Gault

equation)

• Previous history of renal replacement therapy

• 1.5-fold increase in serum creatinine from that

measured at the time of hospital admission and

before the initiation of vancomycin

• Incomplete medical records

Exclusion Criteria


Methods

• Subjects and data obtained from electronic records

from the Duke Enterprise Data Unified Content

Explorer (DEDUCE)

• Patients in each group were selected through random

number generation

• Data collection:

• Demographics

• Medication orders for vancomycin and PT

• Concomitant nephrotoxins

• Vancomycin trough concentrations

• ICD-9 codes for conditions to calculate Charlson score

• Serum creatinine concentrations


Data Analysis

• Sample size

– 180 patients (90 in each group) for 80% power to detect the

minimal increase of 15%, assuming incidence of

nephrotoxicity in patients receiving vancomycin is 10%

• Statistical analysis

– Primary: chi-squared test with a one-sided p-value and

corresponding one-sided 95% confidence interval

– Secondary: univariate analysis to assess the effect of various

risk factors on the incidence of nephrotoxicity

– Multivariate logistic regression models were fitted to assess

the association of nephrotoxicity with the addition of PT

50


Population

Vancomycin

198 patients screened

99 patients included*

Vancomycin + PT

176 patients screened

1 duplicate encounter excluded

92 patients included* •Selected by

•random assignment


Results

Patient Demographics by Treatment Group

Description

Vancomycin

Monotherapy

n=99

Combination

Group

n=92 P=value

Male (%) / Female (%) 48 (47.1%) / 51

(57.3%)

54 (52.9%) / 38

(42.7%) 0.158

Age, yrs

Mean (SD)

Median (IQR)

56.3 (+15.9)

56.7 (46-68.8)

60.7 (+15.1)

62.0 (49-70.4)

0.054

Charlson Comorbidity Index

Median (IQR)

3 (2 – 5)

4 (2 – 5)

0.050

Concomitant nephrotoxins, n (%) 71 (77.8%) 74 (74.7%) 0.695


Results

Characterization of Infection Site by Treatment Group

Infection Site(s)

Vancomycin

Monotherapy (%)

n=99

Combination

Group (%)

n=92 P=value

Bone and Joint

CNS

Respiratory

Urinary Tract

Blood

Intra-abdominal

Other

15 (17.1)

7 (8.0)

25 (28.4)

13 (14.8)

15 (17.1)

4 (4.6)

9 (10.2)

15 (14.0)

3 (2.8)

33 (30.8)

25 (23.4)

8 (7.5)

14 (13.1)

9 (8.4)

0.053

51


Results

Diagnosis of Sepsis by Treatment Group

Sepsis Diagnosis

Vancomycin

Monotherapy

n=99

Combination

Group

n=92 P=value

None

Sepsis

Severe sepsis

Septic Shock

86.9

10.1

2.0

1.0

72.8

16.3

4.4

6.5

0.067


Results: Primary Endpoint

Wald Χ2=3.04, one-sided p-value = 0.041

Nephrotoxicity by Treatment Group

Endpoint

Vancomycin

Monotherapy

(n=99)

Combination

Group

(n=92)

Nephrotoxic 8 (8.08%) 15 (16.3%)

Non-nephrotoxic 91 (91.92%) 77 (83.7%)


Results: Secondary Endpoints

By univariate analysis

*All patients had vancomycin total daily dose ≤ 4gm/day

Risk of Nephrotoxicity in select subgroups

Description

Crude (Unadjusted)

Odds Ratio

95% CI

Age 0.98 0.95-1.01

Concomitant nephrotoxic agents 1.16 0.41-3.33

Vancomycin total dose ≥

4gm/day*

- -

Vancomycin trough ≥ 15 mcg/mL 3.67 1.07-3.02

52


Multivariate Analysis

*Based on one-sided analysis of the hypothesis

Risk of Nephrotoxicity

Description

Adjusted

Odds Ratio

p-value*

Addition of PT 2.48 0.032


Limitations

• Single center, retrospective cohort study

– Incomplete medical records

– Reliability of ICD-9 codes for Charlson score

• Lower incidence of nephrotoxicity than

postulated

– Vancomycin monotherapy: 8.08%

– Combination group: 16.30%


Conclusions

• Significant increase in nephrotoxicity was observed in the

combination group compared to the vancomycin

monotherapy

– Study results confirmed previous findings

• Steady-state vancomycin trough concentration ≥15mcg/ml

was shown to increase the occurrence of nephrotoxicity

(similar to previous studies)

53


Acknowledgements

• DUH Pharmacy Research Committee

• Statistical Support

– John Pura, MPH (Biostatistician)

• Residency Program Director

– Beth McLendon Arvik, PharmD

• Fellow Residents



• What are potential confounding factors that may

contribute to the development of nephrotoxicity

during vancomycin therapy?

A. Use of concomitant nephrotoxic agents

B. Steady-state trough concentrations ≤15mcg/ml

C. Advanced age

D. A and B

E. A and C


Co-Investigators:

Matthew Harris, PharmD, BCPS

Debra Sudan, MD

Matthew Ellis, MD

Tacrolimus Dose Requirements in African-

American and Caucasian Kidney Transplant

Recipients on Mycophenolate and Prednisone

Kristi J. Beermann, PharmD

PGY1 Pharmacy Practice Resident

54



• These individuals have the following to disclose

concerning possible financial or personal relationships

with commercial entities (or their competitors) that may be

referenced in this presentation:

– Resident: Kristi J. Beermann, PharmD: Nothing to Disclose

– Co-Investigator: Matthew Harris, PharmD, BCPS: Nothing to

Disclose

– Co-Investigator: Debra Sudan, MD: Nothing to Disclose

– Co-Investigator: Matthew Ellis, MD: Nothing to Disclose


Objective

• Identify tacrolimus doses needed to achieve

therapeutic tacrolimus concentrations in African-

American versus Caucasian patients


Background-Kidney Transplant

• In patients with end-stage renal disease, kidney

transplant is the preferred management approach

• Immunosuppression is necessary to prevent rejection

following kidney transplantation

– Tacrolimus, mycophenolate, and prednisone are commonly

used in combination

• The risk of kidney rejection is highest during the first

30 days following transplantation

N Engl J Med 1999 Dec 2;341(23):1725-30.

Nephrol Dial Transplant 2001 Sep;16(9):1905-9.

55


Background-Tacrolimus

• Dosed at 0.1 mg/kg/day in two divided doses for

kidney transplant rejection prophylaxis

– Goal tacrolimus concentration may range from 5

to 20 ng/mL, depending on certain factors

• Patient-specific factors, immunosuppressive agents

chosen, transplant center preference

• Studies suggest that African Americans may require

higher tacrolimus doses compared to Caucasian

kidney transplant recipients

Transplantation 2013 Feb 27;95(4):566-72.

Transplantation 2007 Apr 15;83(7):997-9.

Lancet 1996 Nov 23;348(9039):1446


Purpose

• Evaluate tacrolimus doses required to achieve


American versus Caucasian kidney transplant

recipients at day 30 after transplantation


Objectives

• Primary

– Compare tacrolimus dose requirements (mg/kg/day) needed

to achieve therapeutic tacrolimus concentrations (8-12

ng/mL) on day 30 after transplantation in African-American

and Caucasian patients

56


Objectives

• Secondary

– Describe tacrolimus dose requirements (mg/kg/day) at

hospital discharge (Day DC) and post-transplant days 60

and 90

– Describe renal function (MDRD) at Day DC, and post-

transplant days 30, 60, and 90

– Describe biopsy-proven acute rejection episodes throughout

the 90 days after transplantation

– Describe tacrolimus concentration-related adverse effects

between the two groups throughout the 90 days after kidney

transplantation

MDRD: Modification of Diet in Renal Disease


Study Design

• Single-center, retrospective cohort study of patients

admitted to Duke University Hospital for kidney

transplantation between January 1, 2008 and

June 30, 2012

• Subjects identified through the transplant allograft list

and electronic order entry records

• IRB approved


Study Population-Inclusion Criteria

• >18 years of age

• Maintained on standard immunosuppressive regimen

(tacrolimus, mycophenolate, and prednisone)

• Tacrolimus concentration between 8-12 ng/mL at day

30 following de novo kidney transplantation

57


Study Population-Exclusion Criteria

• Multi-organ transplant recipient

• Documentation of non-adherence

• Patient death or transplant nephrectomy

• Use of sublingual or buccal route of administration of tacrolimus

• Dialysis dependent

• Concomitant receipt of strong 3A4 inducer/inhibitor medications

or bile acid sequestrants

• Enrollment in interventional research studies

• Systemic infection

• Positive urine or blood cultures for polyomavirus

• Dose change within 5 days from day 30 transplant visit


Methods

• Experimental groups included African-American and

Caucasian kidney transplant recipients meeting the

inclusion criteria

• Sample size calculation

– 200 patients needed to detect a difference in the

total daily tacrolimus dose of 0.8 mg/day

• Assuming an alpha of 0.05 and 80% power


Baseline Demographics

African American

(N=85)

Caucasian

(N=62)

P-value

Age, years (mean +/- SD) 50 (13) 54 (11) 0.034

Gender ( % male) 48 71 0.006

Height, cm (mean +/- SD) 169 (15) 174 (9) 0.013

Weight, kg (mean +/- SD)

Day 30

84 (18)

84 (17)

0.927

Donor Status (%)

Living

SCD

DCD

ECD

DCD/ECD

21

73

6

14

7

45

87

5

3

5

0.002

0.113

Delayed Graft Function (%) 19 10 0.144

Induction Agent Used (%)

Steroids

Basiliximab

Thymoglobulin

Daclizumab

8

41

25

26

48

29

11

11

<0.001

SCD: Standard criteria donor, DCD: Donation after cardiac death, ECD: Expanded criteria donor

58


Total Tacrolimus Daily Dose at Day 30

P=0.005


Total Tacrolimus Daily Dose and

Concentration at Days DC, 60, and 90


Renal Function-MDRD

Day DC: P=0.05

Day 30: P=0.22

Day 60: P=0.098

Day 90: P=0.041

59


Adverse Events

• Biopsy-proven acute rejection through day 90

– 4 Caucasian subjects

• Acute cellular rejection of Banff grades IA, IB, and IIB

(two subjects)

– 1 African-American subject

• Acute cellular rejection of Banff grade IIA

• Documented concentration-related side effects

– Tremors: 10 subjects

– Headaches: 2 subjects

– Nephrotoxicity: 1 subject


Limitations

• Single-center, retrospective cohort study

• Inability to control for factors that may affect

tacrolimus concentrations

– Interacting medications, diet, timing of blood draw,

adherence

• Presence of cytochrome P-450 polymorphisms are

unknown

– Data suggest the presence of polymorphisms

induce the metabolism of tacrolimus


Conclusion

• African Americans required significantly higher total daily

tacrolimus doses than Caucasians at day 30 after de novo

kidney transplant

• African Americans required higher daily tacrolimus doses

than Caucasians at days 60 and 90 following transplant

• Renal function improved in both groups throughout the

study period

• Overall incidences of rejection and concentration-related

side effects were low

60


Acknowledgements



– Lan Lan, PhD

– John Pura, MPH


– Beth McLendon-Arvik, PharmD




• What was the difference in dose needed to achieve


American versus Caucasian patients in this cohort?

A) 0.03 mg/kg/day

B) 1 mg/kg/day

C) 0.1 mg/kg/day

D) There was no difference in total daily tacrolimus

doses between races


Association between Oversedation from Continuous

Intravenous Sedation and Extubation Failures in

Mechanically-Ventilated Patients in the Pediatric

Intensive Care Unit

Jennifer M. Cole, PharmD

PGY1 Pharmacy Resident


Durham, NC

Co-investigators: Travis Heath, PharmD, BCPS

David Turner, MD

61



These individuals have the following to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation:

• Jennifer Cole, PharmD: Nothing to Disclose

• Travis Heath, PharmD: Nothing to Disclose

• David Turner, MD: Nothing to Disclose


Objective

• Describe the relationship between oversedation and

extubation failure in critically-ill pediatric patients, and

state associated risk factors


Analgesia and Sedation in the Intensive Care Unit

Am J Health Syst Pharm. 2002 Jan 15;59(2):150-78.

New Horiz 1994;2(1):.64–74.

Am J Respir Crit Care Med 1999 Jun;159(6):1742-6.

• Provides anxiolysis and amnesia

• Improves tolerance to

mechanical ventilation

• Reduces stress response

• Prolongation of mechanical

ventilation

• ↑ rates of extubation failure

• ↑ risk for the development of

ventilator-associated pneumonia

• ↑ intensive care unit and hospital

length of stay

62


State Behavioral Scale (SBS) Scores

• Most common, reliable tool used to assess level of

sedation in mechanically-ventilated pediatric patients

• Scoring system includes assessment of the following:

• Respiratory effort

• Coughing

• Response to external stimulus

• Attention to caregiver

• Ability to console

• Movement Pediatr Crit Care Med 2006 Mar;7(2):107-14.


Score Description

-3 Unresponsive

-2 Responsive to noxious stimuli

-1 Responsive to gentle touch or voice

0 Awake and able to calm

+1 Restless and difficult to calm

+2 Agitated

State Behavioral Scale (SBS) Scores

Pediatr Crit Care Med 2006 March ; 7(2): 107–114.


Extubation Failure

• Defined as the need for reintubation within 48-72

hours after extubation

• Pediatric Intensive Care Units (PICU) rates range from

2.7% to 22%

• Risk factors in adults include:

• Upper airway obstruction

• Pulmonary insufficiency

• Cardiac dysfunction

• Neurological impairment

• Poor muscle strength

• Excessive sedation Pediatr Crit Care Med 2005 May;6(3):312-8.

63


Purpose

• Evaluate current sedation practices and their impact

on extubation failure in critically-ill pediatric patients


Objectives

• Primary Objective

• Determine whether an association exists between

oversedation from continuous intravenous sedation

and extubation failures in mechanically-ventilated

patients in the PICU

• Secondary Objective

• Identify risk factors associated with oversedation and

with extubation failure

• Age, gender, weight, average daily doses, glasgow coma scale

(GCS) prior to intubation, duration of mechanical ventilation,

duration of continuous infusion, extubation readiness test

failures


Study Design

• Retrospective, single-center, cohort study

• Large academic medical center

• IRB approved

• Subjects identified utilizing Duke Enterprise Data

Unified Content Explorer (DEDUCE)

• On-line research tool providing Duke investigators with

access to clinical information collected during patient care

64


Study Population

• PICU admission between 1/1/09 -10/31/12

• Mechanical ventilation ≥ 48 hours

• Benzodiazepine and/or opioid infusion ≥ 24 hours

Inclusion Criteria

• Benzodiazepine or opioid tolerance

• Continuous infusion neuromuscular blockade 7 days preceding extubation

• Extracorporeal membrane oxygenation

• Neurologically-devastated patients

• Death during admission

• Incomplete medical records

Exclusion Criteria


Patient Screening

129 patients identified

62 patients oversedated

46 patients not oversedated

Excluded

Tracheostomy: 11

Death: 7

Duration of infusion < 24 hours: 2

Neurologically-devastated: 1


Patient Population

Demographic Oversedated

(n=62)

Not Oversedated

(n=46) p value

Male Gender , n (%) 39 (62.90) 29 (63.04) 1.00

Age, years, mean (SD) 6.64 (7.11) 4.73 (6.02) 0.093

Weight Percentile for Age,

mean (SD) 44.46 (33.27) 31.82 (30.86) 0.076

Weight Percentile for Age,

median (range) 50 (3-95) 17.5 (3-90) -

Initial GCS*, mean (SD) 8.18 (4.02) 9.48 (3.59) 0.071

ERT* Failure, n (%) 13 (20.97) 8 (17.39) 0.642

Duration of Mechanical Ventilation,

days, mean (SD) 6.64 (4.94) 6.76 (4.92) 0.998

Duration of Mechanical Ventilation,

days, median (range) 5 (2-28) 5 (2-22) -

*GCS: Glasgow Coma Scale

*ERT: Extubation readiness test

65


Primary Diagnosis


Results

p value = 0.339

22.6%

n=7

n=14


Risk Factors for Oversedation

*log-transformed

Weight Percentile

Initial GCS

Duration of Opioid Infusion

Maximum Opioid Daily Dose*,

mg/kg/day

Maximum Benzodiazepine Daily Dose*, mg/kg/day

0 0.5 1 1.5 2

Adjusted Odds Ratio

66


Risk Factors for Extubation Failure

Initial GCS

Duration of Mechanical Ventilation

Maximum Opioid Daily Dose*, mg/kg/day

Maximum Benzodiazepine Daily Dose*,mg/kg/day

*log-transformed

0 0.5 1 1.5 2

Adjusted Odds Ratio


Limitations

• Retrospective, single-center

• Small sample size

• Not adequately powered to detect a difference

• Inconsistent documentation of SBS scores

• Outliers influence odds ratio


Conclusions

• More patients who were oversedated failed extubation

• Absolute difference of 7.36%

• Reevaluation of dosing

• Children with a higher weight percentile for age

• Benzodiazepine continuous infusions

67


Acknowledgements


• Keliana O’Mara, PharmD, BCPS


• Lan Lan, PhD

• John Pura, MPH


• Beth McLendon Arvik, PharmD




Which of the following is NOT included in the State

Behavioral Scale (SBS) scoring system?

A. Ability to console

B. Coughing

C. Sneezing

D. Respiratory drive


Impact of Intra-operative Acetaminophen

Administration on Post-operative Opioid

Consumption in Patients Undergoing Hip or

Knee Replacement

Doug Raiff, PharmD, BCPS

Co-investigators:

Cathy Vaughan, PharmD

Amber Jones, PharmD

Ellen Flanagan, MD

68


These individuals have the following to disclose concerning possible

financial or personal relationships with commercial entities (or their

competitors) that may be referenced in this presentation:

-Resident: Robert D. Raiff, PharmD, BCPS: Nothing to Disclose

-Co-Investigator: Cathy A. Vaughan, PharmD: Nothing to Disclose

-Co-Investigator: Amber M. Jones, PharmD: Nothing to Disclose

-Co-Investigator: Ellen M. Flanagan, MD: Nothing to Disclose



Presentation Objective

• State the potential benefit(s) of intravenous

acetaminophen use for surgical pain management in

hip and knee replacement patients


Background Information

• Acute post-operative pain is a major health issue

– Pain management is a focus of the recent Affordable Care Act

– 80% of surgical patients suffer from acute post-operative pain

• Opioids frequently utilized in this setting

– Associated with adverse events

• Pruritus, nausea/vomiting, constipation, respiratory depression

• Result in longer inpatient stays and increased cost

• Acute perioperative pain management guidelines

– Recently updated by American Society of Anesthesiologists

– Advocate use of multimodal approach to pain management

USDHHS, CMS. HCAHPS: Patients’ Perspectives of Care Survey. Available at:

http://www.cms.gov/HospitalQualityInits/30_HospitalHCAHPS.asp. Accessed April 2, 2013

Apfelbaum JL , et al. Anesth Analg 2003; 97:534-40

Oderda G. Pharmacotherapy 2012; 32(9 Pt 2):6S-11S

American Society of Anesthesiologists. Anesthesiology 2012; 116:248-73

69


Background: Intravenous (IV) Acetaminophen

• FDA-approval: November 2010

• Added to Duke University Hospital (DUH) formulary March 2011 with

restrictions for use

• Pharmacokinetics vs. oral acetaminophen (APAP)

– Cmax up to 70% higher with IV route

– Overall exposure (AUC) similar

• Two pivotal studies in post-operative pain patients

– Total hip or knee replacement and abdominal laparoscopic

– Both did not randomize patients until morning after surgery

Ofirmev [package insert]. Cadence Pharmaceuticals. San Diego, CA: Cadence Pharmaceuticals, Inc.; November 2010

Sinatra RS, et al. Anesthesiology 2005; 102:822-31

Wininger SJ, et al. Clin Ther 2010; 14:2348-69


Study Purpose

• Investigate the impact of IV APAP administered intra-

operatively on post-operative opioid consumption in

adult patients undergoing hip or knee replacement


Study Objectives

• Primary Objective

– Compare post-operative opioid consumption (in

oral morphine equivalents) during the 24 hours

following hip or knee replacement in adult patients

who received intra-operative IV acetaminophen

versus those that received no IV acetaminophen.

70


Study Objectives

• Secondary Objectives

– Report time (in minutes) spent in post-anesthesia

care unit (PACU) following hip or knee replacement

– Characterize use of adjunctive analgesics during

the 24 hours following hip or knee replacement

– Report incidence of oversedation (RASS score ≤ -

4) during the 24 hours following hip or knee

replacement

– Report incidence of need for opioid reversal

(naloxone bolus administration) during the 24

hours following hip or knee replacement


Study Design

• Single-center, retrospective cohort

• Adult patients at DUH who underwent hip or knee replacement

between July 1, 2010 and March 31, 2012

• Subjects identified via Duke Enterprise Data Unified Content

Explorer (DEDUCE) database query

– Search conducted using associated ICD-9 codes

• IRB approved: January 2013


Study Design

0-24 hours immediately after surgery completion

Opioid consumption documented in both patient groups

Time zero: Completion of hip or knee replacement

0-60 minutes prior to completion of procedure

Patient receives IV APAP Patient does not receive IV APAP

71


Study Population

Inclusion Criteria

• Patients ≥ 18 years old

• Underwent hip or knee replacement surgery at DUH from July 1, 2010 through March 31, 2012

• For the experimental group, patients received a 1 gram dose of IV APAP ≤ 1 hour prior to surgery completion

Exclusion Criteria

• Intra-operative IV ketamine

• Intra-operative IV non-steroidal anti-inflammatory drugs

• IV APAP dose other than 1 gram

• More than one IV APAP dose given during 24-hour study period


Methods

• IV APAP group: Patients receiving intra-operative IV APAP

meeting inclusion criteria

• Non-exposed group: Equal number of patients who did not

receive intra-operative IV APAP

• Random number generator applied to both groups

• Sample size calculation

– 87 patients per group needed to detect 30% difference in

24-hour oral morphine usage

• Assuming 80% power and 2-sided α level of 0.05

• Two-sided, unpaired t-test utilized

• All opioids converted to oral morphine equivalents

– Rounded to nearest 0.1 mg


Results

Screened for study eligibility (N = 431)

IV APAP

(N = 88)

Non-Exposed Group

(N = 88)

Excluded from study (N = 255)

Dose outside of time frame (N = 155)

Intra-operative ketamine (N = 67)

>1 dose during 24-hour study (N = 27)

Dose other than 1 gram given (N = 5)

Received intra-operative NSAID (N = 4)

72


Baseline Demographics


Primary Endpoint

Ora

l M

orp

hin

e E

qu

iva

len

ts (

mg

)

149.3 ± 98.7 147.2 ± 122.6


Length of PACU Stay

Le

ng

th o

f sta

y (

min

)

73


Utilization of Adjunctive Analgesics

*Gabapentin or pregabalin


Safety

Sessler CN, et al. Am J Respir Crit Care Med 2002; 166:1338-44

• No patients in the IV acetaminophen and non-

exposed groups experienced either of the following:

– RASS score of ≤ -4 during the 24 hours

immediately following surgery

• Scale ranges from +4 (combative) to -5 (unarousable)

• Score of -4 is associated with deep sedation

– Need for naloxone bolus administration for

opioid reversal


Study Limitations

• Single-center, retrospective cohort study

• Different percentages of hip and knee procedures

within each of the groups

• No control placed on adjunctive analgesia regimens

patients received during 24-hour post-operative

period

– Patients may have received different pain

medications based on health care provider

74


Conclusions

• No statistical difference in 24-hour opioid consumption in

adult hip and knee replacement patients who received

intra-operative IV APAP versus patients who received no

IV APAP

• No apparent difference in length of PACU stay

• No patients required naloxone boluses or met pre-

specified oversedation criteria

– Larger study needed to evaluate this endpoint

• Higher number of patients in non-exposed group used

adjunctive analgesics

– Possibly a reflection of differences in pain control

• Future directions……


Acknowledgements


– Beth McLendon-Arvik, PharmD


– John Pura, MPH

– Lan Lan, PhD


– Ann Scates-McGee, PharmD




• What was the difference in 24-hour post-operative

opioid consumption (oral morphine equivalents)

between patients who received intra-operative IV

APAP and those patients who received no IV APAP?

A. 100 mg

B. 50 mg

C. 20 mg

D. 2 mg

75


• Questions?

• Please complete the evaluations!

• Thank you for attending Spring

Symposium 2013!

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