prof. alberto corsini università degli studi di milano
TRANSCRIPT
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Farmacologia di genere
Prof. Alberto Corsini
Università degli Studi di Milano
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• Women have been less enrolled in clinical trials
• A gender-specific analysis usually is not included in
the evaluation of results
• Uncertainty in gender differences in results
• ADRs are higher in females than in males.
Gender differences in pharmacology have to be
considered to improve drug safety, efficacy and to
optimize medical therapy
Franconi et al., Pharmacological Research 55 (2007) 81
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Harris et al., N Engl J Med 2000; 343:475
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Outline of the presentation
• Epidemiology
• Pharmacological treatment
- Ace inhibitor
- ß – blockers
- ASA
- Statins
• Pharmacological explanations
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ASSOCIATION OF RISK FACTORS WITH ACUTE MYOCARDIAL
INFARCTION IN MEN AND WOMEN AFTER ADJUSTEMENT FOR
AGE, SEX AND GEOGRAPHIC REGION
Yusuf S et al, Lancet, 364:937-952, 2004
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Outline of the presentation
• Epidemiology
• Pharmacological treatment
- Ace inhibitor
- ß – blockers
- ASA
- Statins
• Pharmacological explanations
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Os, I. et al. Lancet. 1992 Feb 8;339(8789):372.
In a Norwegian multicentre comparison of nifedipine with
lisinopril in mild-to-moderate hypertension 828 patients took
part.
Nearly three times more women than men spontaneously
reported cough with lisinopril (12.6% vs 4.4%, p=00027),
whereas such a difference was not apparent with nifedipine
(2.8 % vs 3.0%).
Thus, cough caused by lisinopril seems to be more common
in women and non-smokers.
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The Beneficial Effect of Ramipril on the Composite Outcome of
Myocardial Infarction, Stroke, or Death from Cardiovascular
Causes Overall and in Various Predefined Subgroups
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Lindon M.H. Wing et al, N Engl J Med 2003;348:583-92.
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There were no differences between the groups in the change in
diastolic blood pressure at any time point.
The pattern of blood-pressure reduction with the two treatments was
similar among men and among women.
Lindon M.H. Wing et al, N Engl J Med 2003;348:583-92.
Systolic and Diastolic Blood Pressure after Randomization
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Primary End Points among All Subjects,
Male Subjects, and Female Subjects
Lindon M.H. Wing et al, N Engl J Med 2003;348:583-92.
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The observation that the rate of events among male subjects was almost
twice that among female subjects is highly consistent with current data on
morbidity and mortality.
Men have a higher cardiovascular risk than women, and ACE-inhibitor
treatment may be of particular advantage in subjects with high
cardiovascular risk because of factors that influence the atherosclerotic
process, such as stability of plaque and endothelial function.
Lindon M.H. Wing et al, N Engl J Med 2003;348:583-92.
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Paul G. Shekelle et al, JACC Vol. 41, No. 9, 2003
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Paul G. Shekelle et al, JACC Vol. 41, No. 9, 2003
Effect of ACE Inhibitors on Mortality From Heart Failure
in Male and Female Patients
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Paul G. Shekelle et al, JACC Vol. 41, No. 9, 2003
Effect of angiotensin-converting enzyme inhibitors on
mortality in patients with heart failure
Male
Female
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Effect of angiotensin-converting enzyme inhibitors on
mortality in male and female patients with heart failure
Paul G. Shekelle et al, JACC Vol. 41, No. 9, 2003
symptomatic HFasymptomatic LV
systolic dysfunction
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In a post hoc subgroup analysis, studies were divided into those
treating symptomatic HF (CONSENSUS, SOLVD Treatment, and
TRACE) compared with those treating asymptomatic LV systolic
dysfunction (SAVE, SOLVD Prevention, and SMILE).
The pooled analysis included 1,079 women in the symptomatic HF
studies and 1,294 women in the asymptomatic HF studies.
Men clearly benefit when treated with ACE inhibitors for either
symptomatic or asymptomatic LV systolic dysfunction. The evidence
indicates that women with symptomatic HF probably benefit when
treated with ACE inhibitors, although the benefit may be somewhat
less than that seen in men (RR= 0.90; 95% CI: 0.78 to 1.05).
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Outline of the presentation
• Epidemiology
• Pharmacological treatment
- Ace inhibitor
- ß – blockers
- ASA
- Statins
• Pharmacological explanations
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Ghali et al., Circulation. 2002;105:1585
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Kaplan-Meier estimates of cumulative % of combined end point (time to first event)
of all-cause mortality/all-cause hospitalization in women (top) and men (bottom).
Ghali et al., Circulation. 2002;105:1585
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Curves of cumulative percentage of total mortality in
placebo arms in men and women
Ghali et al., Circulation. 2002;105:1585
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The beneficial effects of metoprolol CR/XL extend to women with heart failure,
including women with clinically stable severe heart failure.
Point estimates for hazard ratios for total mortality by gender
and overall in CIBIS II, MERIT-HF and COPERNICUS.
Ghali et al., Circulation. 2002;105:1585
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Luzier et al.,Clin Pharmacol Ther 1999;66:594-601.)
Gender-related effects on metoprolol pharmacokinetics
and pharmacodynamics in healthy volunteers
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Summary
Gender-related differences in the
pharmacokinetics of metoprolol
enantiomers, results in greater
drug exposure in females.
However, concentration–effect
relationships did not differ
between men and women.
The differences were the result
of gender specific differences in
metoprolol pharmacokinetics.
Luzier et al.,Clin Pharmacol Ther 1999;66:594-601.)
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Comparisons of blood pressure-lowering regimens against placebo
European Heart Journal (2008) 29, 2669–2680
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Comparisons of blood pressure-lowering regimens against
less intensive control
European Heart Journal (2008) 29, 2669–2680
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Outline of the presentation
• Epidemiology
• Pharmacological treatment
- Ace inhibitor
- ß – blockers
- ASA
- Statins
• Pharmacological explanations
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• Low-dose ASA lowers the risk of a first MI, with little effect on that
of stroke. Few similar data are available in women.
• 39,876 healthy women (age 45 or more) received 100 mg ASA on
alternate days or placebo and were monitored for 10 for a first
MACE (nonfatal myocardial infarction, nonfatal stroke, or death
from cardiovascular causes).
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Ridker et al., N Engl J Med 2005;352:1293-304
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Ridker et al., N Engl J Med 2005;352:1293-304
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Ridker et al., N Engl J Med 2005;352:1293-304
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The gender differences in benefits associated with
aspirin may reflect:
• the later onset of CVD in women
• the greater proportion of ischemic strokes among
women compared with men
• the relatively small incidence of MI among women
and stroke among men,
• the gender differences in aspirin metabolism
• the fact that aspirin resistance is more common in
women than men
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Outline of the presentation
• Epidemiology
• Pharmacological treatment
- Ace inhibitor
- ß – blockers
- ASA
- Statins
• Pharmacological explanations
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European Heart Journal (2011) 32, 1769–1818
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Cholesterol Treatment Trialists’ (CTT) Collaboration
Lancet, November 9th, 2010; 6736(10) 61545-0
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Effects on major vascular
events per 1·0 mmol/L
reduction in LDL
cholesterol, by baseline
prognostic factors
Lancet, 2010; 6736: 61545-0
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The Lancet May 17 2012; 673: 60367-5
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Is there evidence
for a benefit of
statin therapy in
people at low risk
of vascular disease
?
Cholesterol Treatment Trialists' (CTT)
Collaborators; Lancet. 2012 Aug 11;
380(9841):581-90
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Effects on major vascular events per 1.0 mmol/L reduction in
LDL cholesterol at different levels of risk, by gender
The Lancet May 17 2012; 673: 60367-5
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Predicted 5-year benefits of LDL cholesterol reductions
with statin treatment at diff erent levels of riskMajor vascular events
The Lancet May 17 2012; 673: 60367-5
LDL Reduction
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Number (%) of patients discontinuing lipid-lowering
medication in users of cerivastatin compared with users
of any other HMG-CoA reductase inhibitor
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Arch Intern Med 2006;166:1842-1847
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ASSOCIATION BETWEEN MEDICATION
THERAPY DISCONTINUATION AND MORTALITY
Ho PM et al. Arch Intern Med 2006;166:1842-1847
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Percent change in lipid levels in male and
female patients
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SHARP: Major Atherosclerotic Events subdivided by baseline characteristics
Baigent C. et al.The Lancet, Online Publication, 9 June 2011 doi:10.1016/S0140-6736(11)60739-3
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Percentage of LDL success rate by gender and risk group
Santos RD et al. Am H J 2009; 158 (5): 860-6
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Individual LDL-C % Response to Atorvastatin 10mg/day
Pedro-Botet J et al. Atherosclerosis 158 (2001) 183-193
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• Increasing dose
• Increasing concentration:
• Increasing age, female
• CYP450 interactions (pharmacokinetic)
• Clinical conditions:
• Poly-therapy
• Transplanted
• Diabetes
• Hypothyroidism
• History of muscular symptoms after LLT
Risk Factors for Myopathy/Myalgia
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Culver A.L. et al, Arch Int Med, Jan 9th, 2012
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Association Between DM Risk and Statin Use
Status at Baseline in Participants of the WHI
Adapted from Culver AL et al. Arch Intern Med. 2012;172(2):144-152.
Variable
Patients,
No.
Cases of
New-
Onset DM
Unadjusted
HR
Age-and
Race/Ethnicit
y-Adjusted
HRa
Multivariate-
Adjusted HRb
Taking statin medications at baseline
Yes 10 834 1076 (9.93) 1.71 (1.61-1.83) 1.69 (1.58-1.80) 1.48 (1.38-1.59)
No 143 006 9166 (6.41) 1 [Reference] 1 [Reference] 1 [Reference]
Years of statin medication use
<1.0 3614 360 (9.96) 1.74 (1.57-1.94) 1.71 (1.54-1.90) 1.46 (1.30-1.64)
1.0-2.9 3650 365 (10.00) 1.72 (1.55-1.91) 1.67 (1.51-1.86) 1.42 (1.26-1.59)
≥3.0 3570 351 (9.83) 1.68 (1.51-1.87) 1.68 (1.51-1.87) 1.57 (1.40-1.77)
Nonuser 143 006 9166 (6.41) 1 [Reference] 1 [Reference] 1 [Reference]
Potency of statin at baseline
Low potency: lovastatin, fluvastatin,
pravastatin
6701 682 (10.18) 1.68 (1.56-1.82) 1.64 (1.52-1.78) 1.48 (1.36-1.61)
High-potency: simvastatin, atorvastatin
4133 394 (9.53) 1.74 (1.58-1.93) 1.75 (1.58-1.93) 1.45 (1.36-1.61)
Nonuser 143 006 9166 (6.41) 1 [Reference] 1 [Reference] 1 [Reference]
aThe HRs were estimated from Cox PH models adjusting for age and race/ethnicity.bThe HRs were estimated from Cox PH models, adjusting for age, race/ethnicity, education, cigarette smoking, BMI, physical activity, alcohol intake, energy
intake, family history of DM, hormone therapy use, study arms, and self-report of cardiovascular disease at baseline.
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Lipids and other laboratory measurements
during the follow –up in Jupiter
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Effect of rosuvastatin on composite
primary end point
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RR of allocation to statin vs placebo in
women in relation to CVD
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PRIMARY ENDPOINT IN PRE-SPECIFIED SUBGROUPS
WITHIN JUPITER TRIAL, STRATIFIED BY ACHIEVED LDL-C
Hsia J et al,
JACC, 57:
1666-75, 2011
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Major adverse cardiac events curves at
30 days in high-dose statin vs control arms
Patti G Circulation 2011;123:1622-1632
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PERIPROCEDURAL MYOCARDIAL PROTECTION BY HIGH-
DOSE STATIN ACROSS VARIOUS SUBGROUPS OF PATIENTS
Patti G et al, Circulation, 123: 1622-1632, 2011
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Outline of the presentation
• Epidemiology
• Pharmacological treatment
- Ace inhibitor
- ß – blockers
- ASA
- Statins
• Pharmacological explanations
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Gender differences in pharmacokinetics
Baggio G, Corsini A et al Clin Chem Lab Med 2013; 51(4): 713–727
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Percentuale di massa magra e di grasso sul totale del peso
corporeo nell’uomo e nella donna in funzione dell’età
Mayersohn MB, 1994
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SEX DIFFERENCES IN CYTOCHROME P450 ACTIVITY
Gandhi M et al, Annu. Rev. Pharmacol. Toxicol., 44: 499-523, 2004
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GENDER DIFFERENCES IN PHASE I METABOLISM
Franconi F et al, Pharm Res, 55: 81-95, 2007
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Human Cytochrome P450 Isoenzymes Known to Oxidize
Clinically Used Drugs
Modified from: Brower et al., In: Evans W.E. (Ed). Applied Pharmacokinetics.
Principles of Therapeutic Drug Monitoring, 3rd ed., 1992
CYP2C9 CYP2C19 CYP2D6 CYP3A4
AlprenololDiclofenacFluvastatinHexobarbitalN-desmethyldiazepan
TolbutamideWarfarin
Rosuvastatin
Clopidogrel
DiazepamIMephenytoinMethylphenobarbital
OmeprazolProguanylPhenytoin
Rosuvastatin
AmitriptylineBufaralolCodeineDebrisoquineDextromethorphanEncainideFlecainideImipramineMetoprololMibefradilNortriptylinePerhexilinePerphenazinePropafenonePropanololSparteineThioridazineTimolol
AmiodaroneAtorvastatinCerivastatinClarithromycinCyclosporine ADiltiazemErythromycinKetoconazoleItraconazoleLovastatinMibefradilMidazolamNefazodoneNifedipineProtease inhibitors
QuinidineSildefanilSimvastatinTerbinafineVerapamilWarfarin
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GENDER DIFFERENCES IN PHASE II METABOLISM
Franconi F et al, Pharm Res, 55: 81-95, 2007
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GENDER HAS A SMALL BUT
STATISTICALLY SIGNIFICANT EFFECT ON
CLEARANCE OF CYP3A SUBSTRATE DRUGS
Greenblatt DJ and von Moltke L, J Clin Pharmacol, 48: 1350-1355, 2008
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CYP3A SUBSTRATES INCLUDED IN THE REVIEW
Greenblatt DJ and von Moltke L, J Clin Pharmacol, 48: 1350-1355, 2008
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INDIVIDUAL FEMALE/MALE CLEARANCE RATIOS FOR CYP3A
SUBSTRATE DRUGS ACROSS A SERIES OF 14 STUDIES OF
PARENTERAL ADMINISTRATION OR INTRAMUSCULAR AND 24
STUDIES OR ORAL ADMINISTRATION
Greenblatt DJ and von Moltke L, J Clin Pharmacol, 48: 1350-1355, 2008
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Conclusions
• Sex-based differences in bioavailability, distribution, metabolism and
elimination contribute to interindividual pharmacokinetic variability.
• They stem from variations between men and women in body weight,
plasma volume, gastric emptying time, plasma proteins, cytochrome
P450 activity, drug transporter function and excretion activity.
• Sex-determined variations in pharmacodynamics are more difficult to
study.
• These differences have obvious relevance to the efficacy and side
effect profiles of various medications in the two sexes
• The biologic basis of differences in PK and PD between sexes should
be considered before starting any therapy