CLINICAL PERSPECTIVE ON MANAGING POLYPHARMACY IN...

CLINICAL PERSPECTIVE ON MANAGING POLYPHARMACY

IN THE ELDERLY Gianni Di Perri

Clinica di Malattie Infettive Università degli Studi di Torino

Ospedale Amedeo di Savoia

Ospedale Amedeo di Savoia

About Aging…… • General figures on aging and aging with HIV Polypharmacy • General figures about elderly, polypharmacy and HIV infection Drug disposition in the elderly • Absorption, distribution, metabolism, clearance Antiretrovirals pharmacokinetics in the elderly • Old and new ARVs In Perspective….


According to demographic predictions, in the year 2030 at least 20% of the western

societies will consist of subjects aged > 65

….including healthy people….

….but also people with chronic disorders affecting different organs….

….and people with chronic metabolic disorders ….

Changing populations: the proportion of elderly people in the general population is increasing

Gavazzi & Krause. Lancet Infect Dis 2002;2:659–666

Old (65–79 years) 2% 11% 15%

Very old (>80 years) <0.5% 4% 9%

1900 2030 2000 Data from Switzerland

Elderly (>65 years) 4% 13% 21%

1900 2030 2000

Data from USA

Men will soon live longer than women for the first time as they ditch their unhealthy lifestyles Boys born in 2000 will live to 87 - the same as girls Younger boys forecast to then outlive their female counterparts All due to a decline in heavy industry, fewer smokers and improved healthcare

Women on average live longer than men in all countries, with the exception of:Zimbabwe, Lesotho, Swaziland and Afghanistan. 52 52 49 50

http://en.wikipedia.org/wiki/Zimbabwe

http://en.wikipedia.org/wiki/Lesotho

http://en.wikipedia.org/wiki/Swaziland

http://en.wikipedia.org/wiki/Swaziland

http://en.wikipedia.org/wiki/Afghanistan

74,000

22%

30,000 12%

Età mediana alla diagnosi di AIDS per sesso ed anno

Survival of Patients with > 500 CD4+ T-cells/mm3 for > 5 years is similar to the general population

Standardized mortality ratio = mortality in HIV-infected patients / mortality in general population

Lewden C, et al J Acquir Immune Defic Syndr 2007; 46: 72-77

PIR = Patients with Immune recovery: antiretroviral experienced who had a nadir CD4+ count < 350/mm3 and reached a CD4+ count > 500/mm3, confirmed at censored time

nPIR = Patients with no immune recovery: antiretroviral experienced who started HAART after 31st December 1996 with a nadir CD4+ count < 350/mm3 and did not reach a CD4+ count > 500/mm3

Expected numbers of years left

courtesy of Giovanni Guaraldi, ISS, Rome, Sept. 2012


Prevalence and Risk of Polypharmacy among the Elderly in an Outpatient Setting: A Retrospective Cohort Study in the Emilia-Romagna Region, Italy (2011) Slabaugh SL, et al. School of Population Health Faculty Papers. Paper 44.

Outpatient Pharmacy database, 2007

Patient information available from a demographic file of approximately 1 million residents aged > 65 years (out of a total population of 4.459.246 = 22.4%)

The cohort was comprised of 887.165 elderly subjects who had at least 1 prescription filled during the study year

Duration of treatment for a given drug by using the WHO’s defined

daily dose (DDD)

Polypharmacy episode defined as overlapping treatment with 5 or more medications occurring for at least 1 day

Odds for exposure to polypharmacy were higher for: Older subjects Males Residents of urban areas


887.165 (88.7%)

112.835 (11.3%)

349.689 (39.4%)

537.476 (60.9%)

35% of polypharmacy intakers were exposed for > 100 days in the study year Top 3 classes of

medications: Antithrombotics Peptic ulcer disease &

G/Oe reflux disease ACE inhibitors


Adherence not measureable

Not including medications not reimbursed (benzodiazepines and over the counter drugs, eg. Herbal remedies, dietary supplements)

HIV-infected patients (commonly taking 3 antiretrovirals) aged less than 65 not included in the study

DDD definition: “the assumed average maintenance dose per day for a drug used for its main indication in adults” – substantial differences may exist between DDD and actually prescribed dose (e.g. antithrombotics)

Elderly often require more frequent dose adjustments due to decreased renal and/or hepatic function

LIMITATIONS

courtesy of Giovanni Guaraldi, ISS, Rome, Sept. 2012

Comparison of daily pill burden in HIV+ and HIV- subjects according to age

Guaraldi G, et al. CID 2011; 11: 1120-6


Increased pH Delayed emptying Decreased splachnic flow Decreased motility Decreased absorption surface

Reduced intestinal enzymes: • CYP3A4 • ABCB1 (Pgp)

GASTROINTESTINAL CHANGES ASSOCIATED WITH AGING

ATV RPV

PIs MVC

NNRTIs

BODY CHANGES ASSOCIATED WITH AGING

Decreased albumin increased Vd (albumin-bound drugs) Increased α1-acid glycoprotein (AAG) +/- decreased Vd (AAG-bound drugs) Decreased Pgp activity at blood-brain barrier Toornvliet R, et al. Clin Pharmacol Ther 2006; 79: 540-8 • Increased [ARV] > efficacy

• Increased CNS toxicity

LIVER CHANGES ASSOCIATED WITH AGING

Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003; Housset et al. Res Virol 1990; Banerjee et al. AIDS 1992; Blackard JT et al. J viral hepat. 2008; Hong F et al. Hepatology 2010.

Decrease in Liver size (up to 30%) (Maximal – Vmax) metabolic capacity is proportional to liver size, and its decrease with aging corresponds to decreased intrinsic clearance for oral drugs metabolized by the liver. This reduced metabolism can be counterbalanced by changes in plasma protein binding. Decrease in liver blood flow

10 30 50 70 90

2000

1500

1000

500 FHF

(ml/

min

) Age

Zoli M, et al. Age and Aging 1999; 28: 29-33

Decrease in enzymatic activity

• CYP3A4 • UGT seems to be preserved (conflicting data, 1.4 fold higher AUCs)

20 – 29 30 – 40 40 – 50 > 70 age // //

The antipyrine (phenazone) clearance rate declined after 40 years by a rate of 0.34 ml · min−1 per year toward old age (−29%, p < 0.001).

Half-life increased by 30% in old age

Age and cytochrome P450-linked drug metabolism in humans: An analysis of 226 subjects with equal histopathologic conditions. Sotaniemi EA, et al. Clin Pharmacol Ther 1997; 61: 331-9

P450 (nmol.gm-1) in liver biopsy from 226 subjects with comparable liver histology

RENAL CHANGES ASSOCIATED WITH AGING

Hallan SI, et al. Br Med J. 2006; 333:1047. Age (Yrs)

0

5

10

15

20

25

30

0 20s 30s 40s 50s 60s 70s 80s > 90

< 30

Prev

alen

ce (%

)

GFR (mL/min/1.73 m2):

10s

30-44 45-59

Decreased GFR “ kidney mass “ nephron size “ nephron number “ glomerular surface area “ tubular function “ renal blood flow

Age is a critical variable in the Cockroft-Gault and Modification of Diet in Renal Disease (MDRD) which are used for estimating GFR for drug dosing

PK parameter Age-related changes affecting PK

PK impact Predicted overall PK effect

ARVs potentially

affected

Absorption (Ka, F)

^ Gastric pH v Gastric emptying v Splanchnic flow v Intestinal CYP3A4 v Intestinal Pgp

v F < > F, v Ka < > F, v Ka ^ F ^ F

v F or ^ F v Ka

ATV RPV other PIs MVC

Distribution (Vd) v albumin ^ AAG ^ body fat v lean muscle & body water v transp prot activ.

^ Vd v Vd ^ Vd (lipophilic drugs) ^ Vd

^ VD NNRTIs PIs MVC

Metabolism (CL) v albumin ^ AAG v liver mass v hepatic flow

^ CL/F v CL/F v CL/F < > CL/F

v CL/F PIs NNRTIs MVC InSTIs

Excretion (CL) v renal function v transport process

v CL/F v CL/F

v CL/F

N/NtRTIs

Potential Impact of Age-related Changes on PK

Schoen C, et al. Expert Opin Drug Metabol Toxicol 2013


n = 37 in 18-30 y n = 40 in 45-79 y ART naïve (or < 14 days) on LPV/r + 2 Nukes to 192 weeks. [LPV] in n = 44 at 24, 36, 96 wks.

Data shown is difference at week 24 when controlled for adherence score. However the difference was not significant at week 36 and 96!

Age-related changes in exposure of Darunavir

ARTEMIS – DRV/r 800/100 qd

TITAN – DRV/r 600/100

Sekar VJ et al 2008

Darunavir – 18% increase in AUC

Age-related changes in exposure of Atazanavir

Regimen Effect of Age on AUC

Reference

ATV/r 200/100 mg at steady state in patients

AUC 34% higher in patients > 42 years

Avihingsanon A et al 2008

ATV 400 mg single dose in healthy volunteers

AUC 17% higher in ‘elderly’ vs young.

O’Mara E et al 2001

Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study Dumond JB, et al. HIV Medicine, 2013

6 patients aged > 55 yrs per arm: EFV/TDF/FTC vs ATV/r + TDF/FTC Intensive sampling

TDF FTC EFV TDF FTC ATV RTV

AUC 0-24h

0.92

1.75

1.05

0.9

1.31

0.88

1.19

Cmax

0.87

1.26

0.84

0.94

1.31

1.09

1.78

EFV/TDF/FTC ATV/r + TDF/FTC

Median ratios for each drug, by regimen, in comparison to literature values

73 retrospective PK studies with age as covariate. Schoen C, et al. Expert opin Drug Metabol Toxicol 2013

Drug n. of studies No association found

Positive findings

LPV/r 9 8 100% increase AUC from 25 to 60 years of age

ATV +/- RTV 9 8 Slower ATV CL in aged > 30 yrs

AMP 2 2

DRV 3 1 Slightly higher AUC with age in 2 studies

IDV 6 4 [IDV] higher in 40-50 yrs aged & lower in 50-60 yrs aged / increase in volume but no effect on CL

NFV 3 1 Reduced [M8] metabolte in older adults

RTV 7 6 Faster elimination rate in middle aged (40 yrs) vs younger adults (20 yrs)

SQV 2 1 Slower clearance with age

Protease Inhibitors

-Regazzi M et al. Antimicrob Agents Chemother. 2005; 49: 643

Changes in Nelfinavir PK with Cirrhosis CYP2C19 is exquisitely sensitive to the presence of liver disease Branch, R. A. 1998. Drugs in liver disease. Clin. Pharmacol. Ther. 64:462– 464.

Efavirenz No difference in PK

The effects of age on antiretroviral plasma drug concentration in HIV-infected subjects undergoing routine

therapeutic drug monitoring Winston A et al 2013

Data from 3589 TDM samples were available for 2447 subjects (404 were > 50 years)

As age increased, NNRTI concentrations remained constant but PI concentrations increased.

p = .004

p = .05

Croteau D, et al. CROI 2012, paper 592


Non-Nucleoside Reverse Transcriptase Inhibitors

Drug n. of studies

No association found

Positive findings

DLV 1 0 Correlation between age and intrinsic CL (large proportion of PK variability)

EFV 12 10 +/2 2 studies found an age effect on univariate not retained in multivariate

ETV 2 1 5% AUC increase per decade of age

NVP 12 8 1 study found a 1.56% increase in AUC per year after 35 years of age / 2 studies found decreases in CL with age / 1 study found changes in CL with age but < > not reported

RPV 1 1

<60 years N=36

≥60 years N=18

0

100

200

300

Teno

fovi

r CL/

F (L

/h)

<60 years N=36

≥60 years N=18

0.0

2.5

5.0

7.5

10.0

Teno

fovi

r AU

C 0-2

4 (m

g.h/

L)

<60 years N=36

≥60 years N=18

0.0

0.1

0.2

0.3

0.4

Teno

fovi

r C24

(ng/

ml)

p = 0.045 p = 0.046

p = 0.077

Cevik M et al EACS, Belgrqde; 2011

Tenofovir (TFV) pharmacokinetics (PK) in HIV infected individuals over 40 years of age

TDF

N=899 N=482

P<0.001

Torino, data on file, 2013

TDF TDF

TDF TDF TDF TDF

TDF treatment is associated to renal alterations; although mostly reported as reduction in Cr-based measures (GFR by CG or MDRD), most severe disturbances are on tubular function Post FA, et al. JAIDS 2010;5:49-57.

TDF-associated renal toxicity is proportional to pK exposure Rodríguez-Nóvoa S et al. AIDS 2010; 24: 1064–1066 Poizot-Martin I, et al. 18th CROI, Boston, 2011. Abstr. n. 842 Ezinga M, et al. CROI 2012, Paper #603

TDF intake also associated to reduction in BMD, possibly with a mechanism including increased PTH secretion Masiá M, et al. AIDS Research and Human Retroviruses. 2012, 28(3): 242-246 Cotter AG, et al. JCEM; (Feb, 22) 2013

Both glomerular and tubular functions decline with age and chronic TDF intake might particularly impact in the elderly Mayersohn M. Applied pharmacokinetics: principles of TDM. 3rd ed. Applied Therapeutics. Vancouver, WA, 1992

TDF pK exposures varies according to companion drugs Calcagno A, et al. AAC 2013;57:1840-3 Ramanathan S, et al. CROI 2013; Atlanta, GA. #529

Ramanathan S, et al. CROI 2013; Atlanta, GA. #529

TFV AUC (mean [%CV]) Severe Renal Impairment (eGFR 15-29 mL/min)

TAF 25mg (n=14) 2070 (47)

Normal Renal Function

EVG/COBI/FTC/TDF (n=62) 4400 (50)

ATV+RTV (n=26) 3940 (30)

DRV+RTV (n=12) 4630 (16)

LPV/r (n=45) 3500 (27)

RPV/FTC/TDF (n=24) 3610 (21)

EFV/FTC/TDF (n=30) 2280 (19)

TAF 25mg Severe Renal Impairment (15-29 mL/min) (n=14) TDF 300mg Normal Renal Function (n=24)

TAF

TDF

TAF PK in Severe Renal Impairment • Open-label, single-dose study evaluating TFV PK following TAF

administration in severe renal impairment vs. matched controls vs. TDF in normal renal function

TFV exposures from TAF 25 mg are significantly higher (~5.7-fold) in severe renal impairment vs. matched controls, but still lower vs. TDF 300mg in subjects with normal renal function

TAF 25mg Matched Controls (≥90 mL/min) (n=13)

* Historical data

1

10

100

0 6 12 18 24 48 96 144 Mean (SD)

50

500

Time (hr)

TFV

Conc

entr

atio

n (n

g/m

L)

43


Nucleoside/Nucleotide Reverse Transcriptase Inhibitors


Positive findings

ABV 1 1

3TC 3 2 Age, [Cr] or CrCL correlated with drug CL

TDF 4 - Age, [Cr] or CrCL correlated with drug CL

ddI 2 2

d4T 2 2

AZT 4 2 1 study found slower CL in pts < 30 / 1 study found decreased CL in pts > 50


Cell Entry and Integrase Inhibitors


Positive findings

MVC 3 2 Faster distribution rate in older pts with no impact on AUC

T-20 1 1

RAL 2 2

ELV 1 1

MVC

N=148 N=96


*

** **

***

***

*** ***

*** *** ***

*** ***

0

10

20

30

40

50

60

patie

nts

(%)

< 50 years

≥ 50 years

The therapeutic classes for potential DDIs in the ageing HIV population

Marzolini C et al. J Antimicrob Chemother 2011; 66: 2107-11

: 35% had DDI

: 51% had DDI

Drug prescriptions analysed for 1497 HIV-infected subjects; 477 age >50 y and 1020 age <50 y.

209 admissions in which an ARV was prescribed for HIV+ patient

Review of Records: 89 potential errors in 77 admissions

17 patients given HAART > 24h after admission

44 patients given incorrect dose or frequency

15 patients received < 3 antiretrovirals

13 patients received contraindicated combination of drugs

12 patients received contraindicated drug for > 24h*

1 error corrected within 24h

* 6 – Simvastatin + boosted PI 6 – PPI + Atazanavir

CID 2006; 43: 933-8

CONCLUSIONS • Based on available data, PK/PD parameters of most ARVs do not seem to

undergo clinically relevant modifications in the elderly

• A single exception might be TDF, whose clearance is further decreased in the elderly, but alternative solutions are available, including the development f the new pro-drug (TAF)

• Most uncertainty comes from the appropriate management of DDIs, whose likelihood increases with polypharmacy

• Newly marketed generics might put at risk the release of STRs (single-tablet regimens) with potentially more consequences on those patients already taking multiple medications

• More studies are required to better understand the full impact of aging on the management of polypharmacy, especially in patients with specific co-morbidities

Acknowledgments

THE UNIVERSITY of LIVERPOOL

TORINO: Stefano Bonora

Antonio D’Avolio

Mauro Sciandra

Marco Siccardi

Daniel Gonzalez de Requena

Lorena Baietto

Cristina Tettoni

Sabrina Audagnotto

Letizia Marinaro

Margherita Bracchi

Laura Trentini

Andrea Calcagno

Marco Simiele

Amedeo De Nicolò

Anna Lucchini

Filippo Lipani

Roberto Bertucci

Agostino Maiello

Bernardino Salassa

Francesco G. De Rosa

Chiara Montrucchio

Chiara Alcantarini

Chiara Cardellino

LIVERPOOL:

David Back

Saye Khoo

Andy Owen

Marco Siccardi

LONDON:

Marta Boffito

Anton Pozniak

ROMA:

Andrea Antinori

Emanuele Nicastri

Giuseppe Ippolito

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