CLINICAL CASESDDI’S IN THE AGING HIV PATIENTS
MORE QUESTIONS THAN ANSWERS
Alice K. Pau, Pharm.D., FIDSA
National Institute of Allergy & Infectious Diseases
National Institutes of Health, USA
DISCLOSURE AND DISCLAIMER
• Financial Disclosure – None
• Disclaimer - The content of this presentation does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
DDI’S IN THE AGING PERSON WITH HIVA THERAPEUTIC CHALLENGE
Factors making DDI’s in the aging HIV population challenging –
• Multiple co-morbidities
• Polypharmacy – difficult to predict the end results of multiple interacting drugs
• Multiple providers –
• Inadequate communication between providers
• Insufficient awareness of potential DDI’s
• Physiologic changes associated with aging affecting the PK of different drugs
• Clinical consequences of DDI’s in this population – unknown
• Continuous advances in medicine, with newly approved drugs targeting older
populations – makes it more complicated in managing DDI in these patients
THE DIABETIC PATIENT
65 YO MALE WITH HIV, HBV, & TYPE II DM
• CD4 = 600-800, viral load <40 copies/mL x 8 yrs, while on EFV/TDF/FTC
• He was maintained on metformin 1000mg bid with good glycemic control
• In June 2016, in order to ”modernize” his regimen, ARVs were changed to
DTG + TAF/FTC
• HIV provider and HIV clinical pharmacist noted that the recommendation in
the TIVICAY product label stated that –
• “With concomitant use, limit the total daily dose of metformin to
1,000mg either when starting metformin or TIVICAY.”
• His metformin dose was reduced to 500mg bid
METFORMIN PHARMACOKINETICS
• Absolute oral bioavailability under fasting condition – 50-60%
• Highly hydrophilic, cannot passively diffuse across membrane, intestinal absorption
is paracellular
• No hepatic metabolism, no biliary excretion
• 90% of metformin is excreted unchanged in the urine within 24 hrs
• Renal clearance – by glomerular filtration & active tubular secretion (via OCT2
uptake into tubular cells, followed by secretion by MATE1 and MATE2-K)
• Cimetidine – an OCT2 and MATE1 inhibitor, increases metformin Cmax by 60% &
AUC by 40%
To what extent does dolutegravir, an OCT2 inhibitor, affect the PK
of metformin ?
DTG + METFORMIN PK STUDYS O N G I H , E T A L . ( V I I V S P O N S O R E D ) J A I D S 2 0 1 6 ; 7 2 : 4 0 0 - 7
2 cohorts (DTG 50mg q24h & DTG 50mg q12h)–
• Metformin (Met) 500mg q12h x 5 days
• Met 500mg q12h + DTG x 7 days
• Met 500mg q12h x 10 days
(Met + DTGq24) : Met
GMR (90% CI)
(Met + DTGq12) : Met
GMR (90% CI)
AUC0-𝞃 1.79 (1.65, 1.93) 2.45 (2.25, 2.66)
Cmax 1.66 (1.53, 1.81) 2.11 (1.91, 2.33)
CL/F 0.559 (0.518, 0.604) 0.409 (0.375, 0.447)
T 1/2 1.09 (0.954, 1.24) 1.114 (1.00, 1.29)
• One case of hypoglycemia – in metformin only phase
• No increase in AE during combined therapy
• Authors Conclusion – A dose adjustment in metformin
should be considered when co-administered with DTG,
esp. in those at risk of metformin toxicity
DTG & METFORMIN USE IN A REAL LIFE COHORTG E R V ASO NI C E T A L , J A I D S 2 0 1 7 ; 7 5 : E 2 4 - 26
• Retrospective analysis of glycemic control in a clinical cohort of 15 HIV patients
• Type II DM > 1 yr; metformin > 12 mon; started on DTG for > 6 months
• 92% Caucasians, 92% male, mean age = 59 yr, all received DTG 50mg once daily
• All pts maintained on same metformin doses
• No change in glycemic control after adding
DTG to metformin therapy
• No AE to metformin reported
• There is no known PK/PD relationship with
metformin and glycemic control
• Other drugs known to have DDI with
metformin– considered to be “not clinically
relevant”
OUR CASE
• July 2016 – DTG started, metformin dose reduced to 500mg BID
• Based on the product label’s recommendation, the prescriber was concerned about the “legal” implication of
increasing the metformin dose. He was started on insulin, DTG was changed to RAL.
THE CASE FOR CHANGING THE LANGUAGE IN THE PRODUCT LABEL
• Much confusion arises relating to the current label recommendation
• “With concomitant use, limit the total daily dose of metformin to 1,000mg either when starting metformin or TIVICAY.”
• PK/PD correlation of metformin is not well defined
• There is no evidence of increase in hypoglycemia when DTG is added to metformin, but hyperglycemia has been seen when metformin dose was reduced, per recommendation
• Instead of a blanket recommendation for dose reduction and a ”cap” to the total daily dose, consider changing the language to recommend
• “when DTG and metformin are used concomitantly, monitor for glycemic control and adverse effects of metformin”
THROMBOSIS IN A PATIENT WITH RENAL FAILURE
56 YO FEMALE, ESRD, ON HEMODIALYSIS, WITH RECURRENT AV FISTULA GRAFT THROMBOSIS,
REQUIRING CHRONIC ANTICOAGULATION
Antiretroviral Drugs
DRV 800/cobi 150mg QD
Abacavir 600mg QD
3TC 50mg QD
Anti-hypertensives
Nifedipine 90mg QD
Carvedilol 25mg BID
Clonidine 0.2 mg BID
Other meds
Mirtazapine 15mg qHS
Sevelamer (Renagel®️) 800mg TID
with meals
Cinacalcet 120mg QOD
Erythropoietin thrice weekly
Iron sucrose IV infusion as needed
Warfarin 5mg alt with 2.5mg qod
(started approximately 2 weeks
before clinic visit)
56 YO FEMALE ON HEMODIALYSIS….
• In clinic, she asked for “a cup of coffee” because she got up too early in the
morning and was “feeling really tired”
• CBC showed hemoglobin of 5.2 mg/dL
• She reported profuse nose bleed, almost daily since started on warfarin
• She was admitted for blood transfusion and hemodialysis
• She and her HIV doctor have recently seen advertisements on TV for these
new oral anticoagulants which do not require PT/INR monitoring
• Isn’t this a better option for her?
NEW DIRECT ORAL ANTICOAGULANTS (DOAC)
rivaroxaban
dabigatran
edoxaban
apixaban
MECHANISM OF ACTION OF DOACS
Indications –
• Venous thromboembolism
(VTE) prophylaxis
• Post op prophylaxis
• Non-ambulatory pts
• Treatment of
• Deep vein thrombosis
• Pulmonary embolism
• other VTE
• Stroke prevention in patients
with non-valvular atrial
fibrillation
WARFARIN VS. DOAC
Warfarin DOAC
Dosing Once daily dosing (variable)Twice daily - dabigatran, apixaban
Once daily – edoxaban, rivaroxaban
Dietary
restrictionsStable vitamin K intake Rivaroxaban take with food; none for others
Drug
interactionsCYP 2C9 substrate CYP 3A4 and/or P-gp substrates
Monitoring
parametersPT/INR Monitoring not required
Reversal
agent(s)Vitamin K
Idarucizumab – for dabigatran
Other DOACs – no approved reversing agent
PK CONSIDERATIONS OF DOAC
Rivaroxaban
(Xarelto™)
Apixaban
(Eliquis™)
Dabigatran
(Pradaxa™)
Dosing Once daily Twice daily Twice daily
Oral bioavailability 66% (100% with food) 50% 3-7%
T1/2 (hr) 5-9 hr
11-13 hr in older pts
12 hr 12-17 hr
Renal elimination 33% 27% 80%
Drug Interaction
Potential
CYP3A4 & P-gp
substrate
CYP3A4 & P-gp
substrate
P-gp substrate
Product label
recommendations Not recommended
with strong CYP3A4
and P-gp inhibitors or
inducers
• Not recommended
with strong
CYP3A4 or P-gp
inducers
• May reduce dose with
CYP3A4 or P-gp
inhibitors
• Not recommended
with strong P-gp
inducers
• With P-gp inhibitors –
reduce dose or avoid,
esp. in pts with renal
dysfunction
Dabigatran Dosing
based on –
• Indication
• Renal Function
• Concomitant P-
gp inducers or
inhibitors
EFFECT OF RTV AND COBI ON THE PK/PD OF DABIGATRAN
Brooks K, et al. CROI 2016, 2017
Gordon L, et al Circulation 2017
PK of
dabigatran
with and
without
RTV or
COBI
Brooks K, et al
CROI 2017
Gordon L, et al
Circulation
2017
RTV COBI
PK of
dabigatran
with and
without
RTV or
COBI
Brooks K, et al
CROI 2017
Gordon L, et al
Circulation 2017
RTV COBI
PD of
dabigatran with
and without
RTV or COBI
Brooks K, et al CROI
2017
Gordon L, et al
Circulation 2017
RTV COBI
CLINICAL RELEVANCE OF PK/PD OF DABIGATRAN +COBI
• In this healthy volunteer study (mean age 38 yr), COBI has a much more
profound effect, as a P-gp inhibitor, on the PK and PD of dabigatran as
compared to RTV
• Staggering of doses by 2 hours did not reduce P-gp inhibition
• Most likely mechanism is that COBI is a potent intestinal P-gp inhibitor,
whereas RTV is a mixed P-gp inducer and inhibitor
• The clinical relevance of this increase in dabigatran drug exposure &
prolonged thrombin time – unknown
• Therapeutic options – (1) avoid concomitant use; (2) space apart by > 2 hr?;
(3) reduce dabigatran dose?; (4) monitor thrombin time?
CONSIDERATIONS BEFORE SWITCHING
Advantages Disadvantages
Warfarin • Defined monitoring parameter
(PT/INR)
• Long term experience in dose
adjustment
• Experience with use in renal failure
• Reversible by Vit K
• Close monitoring required – cost, time
• Narrow therapeutic index
• Affected by dietary intake
• Multiple drug interaction potentials
DOAC • No routine monitoring required • No routine monitoring
• Drug interaction potential
• Not recommended in renal failure
• Lack of reversing agents (except for
dabigatran)
Decision – (1) Stayed on warfarin – with closer monitoring
(2) Switched from DRV/c to dolutegravir to avoid warfarin interactions
56 YO HIV+ FEMALE, ON HEMODIALYSISREMAIN ON WARFARIN
DRV/C SWITCHED TO DTG, CLOSE INR MONITORING
Antiretroviral Drugs
Dolutegravir 50mg QD
Abacavir 600mg QD
3TC 50mg QD
Anti-hypertensives
Nifedipine 90mg QD
Carvedilol 25mg BID
Clonidine 0.2 mg BID
Other meds
Mirtazapine 15mg qHS
Sevelamer (Renagel) 800mg TID with meals
Cinacalcet 120mg QOD
Erythropoietin thrice weekly
Iron sucrose IV infusion as needed
Warfarin dose adjusted according to PT/INR
• No more significant nose bleed
• However, viral rebound to 1,000 copies/mL
• Dolutegravir trough concentration – reported as “Trace”
56 YO HIV+ FEMALE, ON HEMODIALYSISVIRAL REBOUND ON DTG
ADHERENCE OR DDI?
Antiretroviral Drugs
Dolutegravir 50mg QD
Abacavir 600mg QD
3TC 50mg QD
Anti-hypertensives
Nifedipine 90mg QD
Carvedilol 25mg BID
Clonidine 0.2 mg BID
Other meds
Mirtazapine 15mg qHS
Sevelamer 800mg (Renagel) TID
with meals ???
Cinacalcet 120mg QOD
Erythropoietin thrice weekly
Iron sucrose IV infusion as needed
Warfarin dose adjusted according to
PT/INR
• No more significant nose bleed
• However, viral rebound to 1,000 copies/mL
• Dolutegravir trough concentration – reported as “Trace”
SEVELAMAR DRUG INTERACTIONS
• Sevelamar – non-absorbable phosphate-
binding cationic polymer
• Also served as bile acid sequestrant &
reduces LDL cholesterol
• Does not affect PK of digoxin, warfarin,
metoprolol
• Reduced absorption reported with
levothyroxine, cyclosporin, tacrolimus,
quetiapine, ciprofloxacin
• Its effect on INSTIs – unknown, but given
the mechanism of interaction, reduced
INSTI oral absorption is possible
Kays MB, et al. Am J Kid Dis. 2003; 42(6): 1253-9.
SUMMARY
• These 2 cases illustrated some of the many challenges in managing polypharmacy in the aging HIV patients
• Most DDI studies are performed in younger HIV-negative volunteers – data extrapolation may not always be possible – A special plea to companies and researchers – to do more DDI studies in the relevant patient population
• Product labels based on potential PK interaction should take into account the relevance of the interaction to PD of the study drug (as seen in the case of metformin label)
• As newer drugs continue to be approved for the aging population, there is a dire need to explore the interactions of these newer drugs with ARV
ACKNOWLEDGEMENTS
• Our patients - who keep me on my toes every day, who constantly challenge me with
new co-morbidities, new drug combinations, and new unanswered questions
• Lori Gordon, Pharm.D. & Kristina Brooks, Pharm.D. – Our former PK fellows
who introduced me to the fact that DOACs may soon replace warfarin
• Safia Kuriakose, Pharm.D. and Jomy George, Pharm.D. – My colleagues who
taught me about DOACs and sparked my interest in DDI in the older patients
• Marketing Departments of Pharmaceutical Companies - which educate me
everyday with TV ads of new drugs & let me know what our patients are watching
THANK YOU
