pulmonary hypertension

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PULMONARY ARTERIAL HYPERTENSION Jenny Chan PharmD Candidate c/o 2015 Harborview General Medicine E November 25, 2014

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Page 1: Pulmonary hypertension

PULMONARY ARTERIAL HYPERTENSIONJenny ChanPharmD Candidate c/o 2015Harborview General Medicine ENovember 25, 2014

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ROADMAP Pulmonary Arterial Hypertension (PAH)

Classification & Treatment Patient Case Drug Interactions with HIV medications Treatment Considerations in HIV patients

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WHO FUNCTIONAL CLASSIFICATION OF PATIENTS WITH PULMONARY HYPERTENSION

The Classification of Pulmonary Arterial Hypertension. Medscape. http://www.medscape.org/viewarticle/544175

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PULMONARY ARTERIAL HYPERTENSION TREATMENT

Galie et al. Updated Treatment algorithm of Pulmonary Arterial Hypertension. JACC. December 24, 2013:D60-72.

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PULMONARY ARTERIAL HYPERTENSION TREATMENT

Galie et al. Updated Treatment algorithm of Pulmonary Arterial Hypertension. JACC. December 24, 2013:D60-72.

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PATIENT CASE MJ is a 45 y/o female PMH: PAH, HIV, right-sided HF with preserved left

ejection fraction, hypothyroidism, HTN, hx of DVT and PE

Medication ListHIV regimen Pulmonary Hypertension• Abacavir 600 mg-Lamivudine 300

mg PO qHS• Darunavir 800 mg PO qHS• Ritonavir 100 mg PO qHS• Dapsone 100 mg PO daily

• Bosentan 62.5 mg PO MWF• Bosentan 62.5 mg PO BID

T/Th/S/Su

CHF Others• Bumetanide 4 mg PO BID• Spironolactone 25 mg PO daily• Potassium Chloride 40 mEQ PO BID• Atorvastatin 20 mg PO qPM

• Warfarin 2 mg PO T/W/Th/S/Su• Warfarin 1.5 mg M/F

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A CLOSER LOOK AT MJ MJ is NYHA/WHO Functional Class II. Currently she is only using bosentan for her PAH

• Bosentan 62.5 mg PO MWF• Bosentan 62.5 mg PO BID T/Th/S/Su

• What is the standard dosing of bosentan? • Initial: 62.5 mg PO BID for 4 weeks• Maintenance: 125 mg PO BID

• Why is her dose of bosentan lower than normal?• Darunavir and ritonavir are 3A4 inhibitors and may increase

the serum concentration of bosentan. • Trough concentrations of bosentan were increased 5-fold in

normal volunteers at steady state when coadministered with lopinavir/ritonavir.

• Package insert recommends starting with bosentan 62.5 mg daily or every other day and monitor tolerability.

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MJ’S CONDITION WORSENS Pulmonary consult suggests that her

pulmonary hypertension is exacerbating her CHF and suggest the addition of sildenafil or tadalafil

Which one is FDA approved for pulmonary hypertension? Both

At what doses? Sildenafil: 20 mg 3 times daily Tadalafil: 40 mg daily

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HOW DOES SILDENAFIL WORK FOR PULMONARY HYPERTENSION? MOA: selective inhibitor of phosphodiesterase

type 5 (PDE5) PDE5 is found in high concentrations in the

pulmonary arteries and corpora cavernosa. Normally, PDE5 degrades cGMP, which

promotes the relaxation of smooth muscle. PDE5 inhibition prolongs the vasodilatory

effects of NO in pulmonary hypertension by preventing the degradation of cGMP.

Barnett C and Machado R. Sildenafil in the treatment of pulmonary hypertension. Vasc Health Risk Manag. Dec 2006; 2(4): 411-422.

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MECHANISM

Figure 1. Barnett C and Machado R. Sildenafil in the treatment of pulmonary hypertension. Vasc Health Risk Manag. Dec 2006; 2(4): 411-422.

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WHAT IS THE PROBLEM WITH THE ADDITION OF SILDENAFIL? DRUG INTERACTIONS Darunavir--Sildenafil

Strong CYP3A4 inhibitors may increase the serum concentration of sildenafil (CYP3A4, CYP2C9 substrate)

Management: Avoid combination in PAH. Ritonavir—Sildenafil

Strong CYP3A4 inhibitors and weak CYP2C9 inhibitors may increase the serum concentration of sildenafil (CYP3A4, CYP2C9 substrate)

Management: Avoid combination in PAH.

Lexi-Comp Online Interaction Analysis.

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WHAT IS THE EXTENT OF THE INTERACTION ? Phase I randomized, open-label, two-way

crossover study 16 HIV-negative healthy males were randomized

to Treatment AB or Treatment BA Treatment A: single dose sildenafil 100 mg Treatment B: Darunavir 400 mg/ritonavir 100

mg BID for 8 days and on day 7, a single dose of sildenafil 25 mg was given

Sildenafil exposure was comparable between the two treatments despite a much lower dose of sildenafil used. Sildenafil 25 mg Cmax was 38% lower compared with sildenafil 100 mg Cmax.

Sekar V et al. Effect of repeated doses of darunavir plus low-dose ritonavir on the pharmacokinetics of sildenafil in healthy male subjects: phase I randomized, open-label, two-way crossover study. Clin Drug Investig. 2008; 28(8):479-85

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HOW TO MANAGE THIS INTERACTION? Switch the HAART therapy What is another protease inhibitor that can be used

instead of darunavir/ritonavir? Dolutegravir (Tivicay®)

MOA: Integrase inhibitor Dosing:

50 mg daily 50 mg BID if INSTI-experienced or INSTI-resistance

suspected Metabolism:

Substrate of UGTs, BCRP, P-gp, CYP3A (minor). Primarily metabolized in the liver via UGT1A1 with some

contribution from CYP3A. Inhibits: OCT2

No interactions identified with sildenafil via Lexi-Comp

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WHAT ARE OTHER PAH TREATMENT OPTIONS FOR MJ? Riociguat (Adempas ®)

Approved: Oct. 8, 2013 MOA: Soluble Guanylate Cyclase (sGC) Stimulator.

sGC is a NO receptor and riociguat stabilizes the binding between sGC and NO to increase the synthesis of cGMP which promotes vasodilation.

Dosing: Initial: 0.5-1 mg TID. Maximum dose: 2.5 mg TID

Metabolism: Extensive liver metabolism via CYP1A1, 3A, 2C8, 2J2 Substrate: P-gp, BCRP

Challenges: REMS Program for all females, prescribers and pharmacies must be certified, increased bleeding risk, symptomatic hypotension

Adempas Prescribing Information. http://labeling.bayerhealthcare.com/html/products/pi/Adempas_PI.pdf.Revised 9/2014.

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IS THERE A BENEFIT TO ADDING RIOCIGUAT TO BOSENTAN? Yes Phase 3, randomized controlled, double-blind

study in 443 patients with PAH. Eligible patients assigned to placebo, riociguat (2.5 mg TID max) or riociguat (1.5 mg TID max)

6-minute walk distance (meters) increased 27+58 (m) from baseline in patients on endothelin receptor antagonists compared to 32+74 (m) increase from baseline in treatment-naive patients so there is a benefit.

Ghofrani et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N ENGL J MED. 13 July 25. 369;4

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IS THERE A BENEFIT TO ADDING SILDENAFIL TO BOSENTAN? Yes In a small study in 8 Japanese patients with

PAH on bosentan and sildenafil 50 mg, the chronic use of bosentan decreased the plasma concentration of sildenafil.

However, there was a 12.4% decrease in mean pulmonary arterial pressure, 19.9% increase in CI and 25% decrease in derived pulmonary vascular resistance (PVR).

Hatano M et al. Acute effect of sildenafil is maintained in pulmonary arterial hypertension patientsChronically treated with bosentan. Int Heart J. 2011;52(4):233-9.

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FINAL PLAN FOR MJ Discontinued darunavir/ritonavir Started dolutegravir 50 mg BID due to

suspected INSTI resistance or previous INSTI use

Started sildenafil 20 mg TID