Case-Based Drug Drug

Interactions:

Oncology

Alice Tseng, B.Sc.Phm., Pharm.D.,

FCSHP, AAHIVP

May 21st, 2014

Mr. K

• 36 yo Caucasian male, born in Toronto

– Diagnosed with HIV in Aug/10 (negative in 2009)

– CD4 460 cells/mm3, VL 2488 copies/mL

• Medical history:

– Depression, anxiety

– Smokes 1 ppd since age 10

– EtOH: 15-20 beers, 375 mL scotch/week

– Marijuana, cocaine

• Attended inpatient rehab (2010), dropped out after

learning of HIV diagnosis

Mr. K (con’t)

• 2010 to 2014

– Yearly visit to clinic – no ARVs

– Numerous visits to Emerg Dept (occupational

injuries, depression)

– On/off attendance at Narcotics Anonymous

– On clonazepam for anxiety

• March 2014

– Sober for >30 days, attending NA twice daily

– CD4 277, VL 6246

– cART: given Rx for rilpivirine/tenofovir/FTC in

January; finally started 5 days ago, feeling well

– Axillary lesion noted on clinical exam (cyst?)

• 1 week later: shingles, Rx acyclovir

• April 2014:

– presented to ER with night sweats, weight loss,

RUQ pain, enlarging R. axillary mass x 4 weeks

April 2014

• Axillary mass biopsy: Burkitt lymphoma

– Liver lesions, bilateral renal masses, bone

marrow involvement (60%); stage IV disease

• Patient admitted

• Oncology team wants to start

chemotherapy ASAP with CODOX-M-IVAC

• CODOX-M

Supportive Therapy

CODOX-M

(days 1, 2, 10)

IVAC

(days 1-5)

Dexamethasone 20 mg IV 10 mg IV

Granisetron 1 mg IV 1 mg IV

Domperidone 20 mg QID

• Other medications:

– hydromorphone, nicotine patch,

acetaminophen, pantoprazole, enoxaparin,

clonazepam, allopurinol

• Drug interactions???

Potential Impact of ARVs on Metabolism

of AntineoplasticsClass Agents P450 PIs/

cobicistat

NNRTIs

Camptothecins Irinotecan

Topotecan

3A4

CYP450 (minor)

↑

-

↓

↓ (?)

Taxanes Docetaxel

Paclitaxel

CYP3A4

CYP2C8>3A4

↑ ↓

Vinca Alkaloids Vinblastine

Vincristine

CYP3A4 ↑ ↓

Epipophyllotoxins Etoposide CYP3A4 ↑ ↓

Steroids Dexamethasone

Methylprednisolone

Prednisone

CYP3A4 ↑ ↓

Retinoid analogue Bexarotene CYP3A4 ↑ ↓

Alkylating Agents Cyclophosphamide

Ifosfamide

2B6*, CYP3A4

CYP3A4*

↓ ↑

*conversion to active metaboliteRubinstein et al. AIDS 2014:28:453-65. Spano et al. J Clin Oncol

2008;26:4834-42. Antoniou & Tseng. Clin Pharmacokin 2005;44:111-45.

Effect on Targeted Anticancer Drug

Pharmacokinetics by CYP3A4 Inhibition &

Induction

35

0

500

-82

86

-80

40

-380

360

-72*

300

-80

0-37

51

-46

310

-56

-400

-300

-200

-100

0

100

200

300

400

500

% c

ha

ng

e A

UC

Bortezomib

dasatinib

erlotinib

imatinib

lapatinib

nilotinib

soraf

enib

sunatinib

temsirolimu

s

Inhibitor (Ketoconazole) Inducer (RIF or *CBZ)

Deeken et al. Curr Opin Oncol 2009;21:445-54.

Antiretroviral-Antineoplastic

Pharmacodynamic Interactionsnausea, vomiting

PIs, cobicistat, AZT

Most

chemotherapeutics,

incl. cisplatin,

cyclophosphamide

hypersensitivity

abacavir

taxanes

skin reactions

NNRTIs, PIs

anthracyclines,

antimetabolites,

EGFR inhibitors

neuropathy

d4T, ddI

vinca alkaloids, taxanes,

platinum agents, bortezomib

cardiovascular

toxicity

PIs, abacavir(?)

anthracyclines,

trastuzumab,

antimetabolites

renal toxicity

Tenofovir, atazanavir,

indinavir

platinum agents,

mitomycin

hematologic toxicity

AZT

Most

chemotherapeutics,

incl. taxanes,

antimetabolites

diarrhea

Pis, cobicistat

Antimetabolites,

irinotecan

metabolic,

lipodystrophy

NRTIs, PIs

temsirolimus,

enzastaurin

QT

prolongation

Some PIs,

rilpivirine

Tyrosine kinase

inhibitors

Severe/Life-Threatening Toxicities due

to Interactions with Antiretrovirals

2010;69(1):99-101.

Eur J Haematol 2006;76:269-71. Am J Clin Oncol 2004;27:81-4.

Deleterious pharmacokinetic interaction

between bexarotene and efavirenz

• 70-year old man on efavirenz since 2006 with VL<50 for 12 years, received bexarotene 300 mg QD for a neoplastic disorder

• 2 months later, he developed virologic failure– EFV level was 595 ng/mL vs 1478 ng/mL at baseline (dose

400 mg/d)

– EFV dose doubled to 800 mg/d � level 1354 ng/mL

– bexarotene concentrations ↓ 50% vs. steady-state reference PK data, only partial efficacy on neoplastic lesions observed

• Hypothesis: negative 2-way interaction– induction of CYP3A4/P-gp by BXR � ↓ EFV

– induction of CYP3A4 by EFV � ↓ BXR

Desnoyer A et al. AIDS 2010;24(14):2296-8.

Mr. K: Potential Interactions

Antineoplastic

Agents

Antiretroviral Potential

Interaction

Pharmacokinetic vincristine,

prednisone,

cyclophosphamide

(CYP3A4 substrates)

PIs/cobicistat (3A4

inhibitors); NNRTIs

(CYP3A4 inducers)

possible ↑

toxicity/↓ efficacy

dexamethasone

(CYP3A4 inducer)rilpivirine ↓ rilpivirine

concentrations

pantoprazole

(gastric pH)

rilpivirine ↓ rilpivirine

absorption

Pharmacodynamic domperidone,

granisetron

rilpivirine ↑ QT risk?

cyclophosphamide,

ifosfamide,

cytarabine,

methotrexate

tenofovir possible ↑

nephrotoxicity

Serum Creatinine and eGFR Changes with

Antiretrovirals

Study Mean ↑ Scr (umol/L) Mean ∆ eGFR* Method

Dolutegravir SPRING 2 – 48 wks 12.3 ↓ 16.5 CG

SINGLE – 48 wks 12.3 ↓ 13.1 CG

Elvitegravir

(Stribild)

Study 102 – 96 wks 11.5 ↓ 13.8 CG

Study 103 – 96 wks 10.61 ↓ 12.3 CG

Raltegravir SPRING 2 – 48 wks 4.7 ↓ 5.4 CG

Rilpivirine ECHO – 48 wks 5.69-9.07 ↓ 8-11 MDRD

THRIVE – 48 wks 4.11-7.16 ↓ 5-9 MDRD

ATV/cobi Study 114 – 48 wks 11.5 ↓ 12.9 CG

ATV/ritonavir Study 114 – 48 wks 8 ↓ 9.1 CG

Cobi 150 mg§ Normal renal function 8.9 ↓ 9.9 CG

eGFR 50-79 mL/min 21.2 ↓ 11.9 CG

RTV 100 mg§ Normal renal function 0.9 ↑ 1 CG

§HIV-negative subjects; *CG: mL/min, MDRD: mL/min/1.73m2

Managing Antiretroviral-

Antineoplastic Interactions

• Hold/delay antiretroviral therapy during

chemo

• Modify/dose adjust chemotherapy

• Modify cART regimen

Holding/Delaying cART

During Chemotherapy?

• Potential advantages:

– Avoid drug interactions which may

compromise efficacy or ↑ toxicity

– Fewer pills, less side effects, better

adherence?

cART during chemotherapy: better

response rates and survivalStudy No/type of patients Outcome

Cortes et al. Cancer

2002(6)

13 patients

Prospective study investigating the use of

hyper-CVAD in patients with HIV-related

Burkitt Lymphoma

Nine out of 13 patients were on

cART during chemotherapy. All four

patients who did not receive cART

died

Antinori et al. AIDS

2001 (7)

44 patients

Retrospective study in patients who received

CHOP/m-BACOD for HIV-related NHL

Virological response to cART was

the only factor independently

associated with complete response

following chemotherapy

Vaccher et al. Cancer

2001 (8)

104 patients

Retrospective analysis of two prospective trials

in patients with HIV-related NHL

Patients on CHOP plus cART had

fewer opportunistic infections (18

vs. 52%, p=0.05) and longer OS

(38 vs. 85%, p=0.001) compared to

CHOP only arm

Hoffmann et al. AIDS

2003 (9)

203 patients

Retrospective observational study- patients

with AIDS-related lymphoma

Response to cART was associated

with prolonged survival. Patients

receiving cART were more likely to

achieve CR (71% vs. 48%,

p=0.006)

Barta et al. Blood

2013 (10)

1546 patients

Systematic review of 19 prospective clinical

trials-patients with HIV-related NHL

Concurrent use of cART with

chemotherapy was associated with

improved CR rates (OR 1.89,

P=0.005) and a trend towards

improved OS (HR 0.78, P=0.07)

17Slide courtesy of Dr. K. Ibrahim, St. Vincent’s Hospital, Sydney, Australia

Reinitiating HAART in Patients Previously

Assigned to Episodic Treatment Reduces But

Does Not Eliminate Excess Risk For OI or Death• Participants who reinitiated

continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels <400 copies/mL after 6 months), but CD4 cell counts after 6 months remained 140 cells/mm3 below baseline.

• The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death ↓after the recommendation to reinitiate continuous therapy from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P=0.033 for difference.

• The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4 cell counts for those who reinitiated therapy.

SMART Study Group. Ann Intern Med 2008;149:289-99.

Stopping Antiretroviral Therapy

• Drugs A & B have short t1/2,

cleared from body quickly

• Drug C has long t1/2, at

therapeutic/subtherapeutic level

for prolonged period =

FUNCTIONAL MONOTHERAPY

• Risk of resistance

• Drugs A, B & C have balanced

short t1/2, simultaneously

cleared from body quickly

• Lower potential for resistance

to develop

Taylor et al. AIDS 2007;21:1673-82.

Dose Adjustment Recommendations for

Targeted Anticancer Drugs

CYP Inhibitors CYP Inducers

Dasatinib ↓ to 20 or 40 mg/d, monitor

for toxicity.

Not recommended.

Erlotinib Caution, ↓ dose if toxicity. *↓ to 50 mg with RTV 100 mg (?)

May ↑ from 150 up to 450

mg/d.

Imatinib ↑ dose by at least 50% and

monitor

Lapatinib ↓ from 1250 to 500 mg/d. May ↑ from 1250 up to 4500

mg/d.

Nilotinib ↓ from 400 mg BID to QD;

monitor for QT prolongation.

Sunitinib ↓ in 12.5 mg increments

down to 25 mg/d.

↑ in 12.5 mg increments up

to 50 mg/d.

*Molto et al. IWCPHHT 2014, PP01.

Modifying/Dose-Adjusting

Chemotherapy?

• Often no guidelines on dose-adjusting chemotherapy agents in case of drug interactions

• Empiric dose adjustment not often done or not consistent from centre to centre

– Concern re: compromising chemotherapy efficacy

• Usual strategy is to monitor for toxicity, then reduce dose

– however, some toxicities may be irreversible and/or treatment-limiting

• Antineoplastic TDM not routinely available

Antiretroviral Therapy for Treatment-Naïve Individuals

NNRTI

Efavirenz

Rilpivirine

If VL<100,000,

CD4>200

NRTI backbone Tenofovir-FTC Abacavir/3TC (with DTG; or

EFV, ATVr if VL<100,000)

Abacavir/3TC

http://www.aidsinfo.nih.gov/guidelines/

PI

Atazanavir/r

Darunavir/r

Lopinavir/r

Integrase Inhibitor

Raltegravir

Dolutegravir

Elvitegravir/cobicistat

/tenofovir/FTC

If Clcr>70 mL/min

DHHS Rating Recommended Alternative

as of May 1/14

Greater Toxicity with PI-based cART vs

non-PI-based cART

• Neutropenia (grade 3 & 4)

– Cyclophosphamide, doxorubicin, etoposide (Bower et al.), sunitinib (Rudek et al.)

– Therapy for Hodgkin’s & non-Hodgkin’s lymphoma (Ibrahim et al.)

– Inverse correlation between ritonavir dose and mean nadir neutrophil (p<0.001) in

pts on vinblastine-based treatment for Hodgkin’s lymphoma (Cingolani et al.)

• Neurotoxicity (grade 3 & 4)

– Therapy for Hodgkin’s & non-Hodgkin’s lymphoma (Ibrahim et al.)

– CHOP for non-Hodgkin’s lymphoma (Vaccher et al.)

• Infections requiring hospitalization

– Cyclophosphamide, doxorubicin, etoposide (Bower et al.)

• Greater dose-limiting toxicity

– Sunitinib for refractory cancer (Rudek et al.)

[Bower et al. Blood 2004;104:2943-6. Cingolani et al. AIDS 2010;24:2408-12. Ibrahim et al. Blood 2013;122:3843.

Rudek et al. Cancer 2014;120:1194-202. Vaccher et al. Cancer 2001;91:155-63]

Antiretroviral Boosting

[Mathias et al. 11th IWCPHT 2010, #18; Mathias et al. CROI 2009, #40.Ramanathan et al. ICAAC 2009, #A1-1301;

Ramanathan al. 13th IWCPHT 2012, #P_08; Kakuda T al. 13th IWCPHT 2012, #O_20].

Cobicistat Ritonavir Comments

Elvitegravir 150/150 mg 150/100 mg EVG/co in Stribild; also

available separately

Atazanavir 300/150 mg 300/100 mg ATV/co NDA submitted to

FDA April 4, 2014

Darunavir 800/150 mg 800/100 mg DRV/co NDA submitted to

FDA April 1, 2014

Darunavir 600/150 mg

BID

600/100 mg

BID

• Cobicistat is a selective, mechanism-based inhibitor of

CYP3A subfamily (primarily CYP3A4 and CYP3A5)

• enhances the systemic exposure of CYP3A substrates where

bioavailability is limited and half-life is shortened by CYP3A-

dependent metabolism

Non-PI cART in HIV Patients Receiving

Chemotherapy

• Raltegravir with CHOP

– 55 yo male with newly diagnosed HIV (CD4 36, VL 18,700)

and large B-cell lymphoma

– Simultaneously started RAL, ABC/3TC and CHOP + IT MTX

– Maintained VL<50 throughout 6 CHOP cycles; no active

lymphoma 2 months after completion of chemotherapy

• Etravirine with BEACOPP:

– 46 yo male with Hodgkin’s lymphoma, CD4 912, VL<20 on

DRVr, TDF/FTC ; changed to RAL, ETV and TDF/FTC (M184V)

– Pt received 4 cycles @ full dose, then 2 cycles with ½ dose

vincristine (mild neuropathy), VL remained <20; recurrence

free @ 8 months post treatment

[Fulco et al. Ann Pharmacother 2010;44:377-82. Kurz et al. Int J STD AIDS 2014 [epub ahead of print].

Mr. K: ART Regimen

• Spoke with HIV specialist re: diagnosis and

plan

• Changed cART to tenofovir/emtricitabine

and raltegravir

Summary

• Concurrent ARV therapy is indicated for patients undergoing chemotherapy, especially with low CD4

• Drug interactions may ↑ toxicity/↓ efficacy of ARVs and/or antineoplastic agents

– pharmacodynamic (overlapping toxicity profiles)

– pharmacokinetic interactions via CYP450, P-gp

• Attempt to modify cART regimen

– avoid/minimize RTV or cobicistat use

– Preference for non-interacting ARVs (unboosted InSTI, RPV?)

– NB: prior resistance profile, ensure adequate potency

• Close monitoring, multidisciplinary team recommended

www.hivclinic.ca