Prof. Alberto Corsini Università degli Studi di Milano

Farmacologia di genere

Prof. Alberto Corsini

Università degli Studi di Milano

• 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

Harris et al., N Engl J Med 2000; 343:475

Outline of the presentation

• Epidemiology

• Pharmacological treatment

- Ace inhibitor

- ß – blockers

- ASA

- Statins

• Pharmacological explanations

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

Outline of the presentation

• Epidemiology

• Pharmacological treatment

- Ace inhibitor

- ß – blockers

- ASA

- Statins

• Pharmacological explanations

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.

The Beneficial Effect of Ramipril on the Composite Outcome of

Myocardial Infarction, Stroke, or Death from Cardiovascular

Causes Overall and in Various Predefined Subgroups

Lindon M.H. Wing et al, N Engl J Med 2003;348:583-92.

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

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.

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.

Paul G. Shekelle et al, JACC Vol. 41, No. 9, 2003

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

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

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

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).

Outline of the presentation

• Epidemiology

• Pharmacological treatment

- Ace inhibitor

- ß – blockers

- ASA

- Statins

• Pharmacological explanations

Ghali et al., Circulation. 2002;105:1585

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

Curves of cumulative percentage of total mortality in

placebo arms in men and women

Ghali et al., Circulation. 2002;105:1585

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

Luzier et al.,Clin Pharmacol Ther 1999;66:594-601.)

Gender-related effects on metoprolol pharmacokinetics

and pharmacodynamics in healthy volunteers

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.)

Comparisons of blood pressure-lowering regimens against placebo

European Heart Journal (2008) 29, 2669–2680

Comparisons of blood pressure-lowering regimens against

less intensive control

European Heart Journal (2008) 29, 2669–2680

Outline of the presentation

• Epidemiology

• Pharmacological treatment

- Ace inhibitor

- ß – blockers

- ASA

- Statins

• Pharmacological explanations

• 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).

Ridker et al., N Engl J Med 2005;352:1293-304

Ridker et al., N Engl J Med 2005;352:1293-304

Ridker et al., N Engl J Med 2005;352:1293-304

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

Outline of the presentation

• Epidemiology

• Pharmacological treatment

- Ace inhibitor

- ß – blockers

- ASA

- Statins

• Pharmacological explanations

European Heart Journal (2011) 32, 1769–1818

Cholesterol Treatment Trialists’ (CTT) Collaboration

Lancet, November 9th, 2010; 6736(10) 61545-0

Effects on major vascular

events per 1·0 mmol/L

reduction in LDL

cholesterol, by baseline

prognostic factors

Lancet, 2010; 6736: 61545-0

The Lancet May 17 2012; 673: 60367-5

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

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

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

Number (%) of patients discontinuing lipid-lowering

medication in users of cerivastatin compared with users

of any other HMG-CoA reductase inhibitor

Arch Intern Med 2006;166:1842-1847

ASSOCIATION BETWEEN MEDICATION

THERAPY DISCONTINUATION AND MORTALITY

Ho PM et al. Arch Intern Med 2006;166:1842-1847

Percent change in lipid levels in male and

female patients

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

Percentage of LDL success rate by gender and risk group

Santos RD et al. Am H J 2009; 158 (5): 860-6

Individual LDL-C % Response to Atorvastatin 10mg/day

Pedro-Botet J et al. Atherosclerosis 158 (2001) 183-193

• 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

Culver A.L. et al, Arch Int Med, Jan 9th, 2012

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.

Lipids and other laboratory measurements

during the follow –up in Jupiter

Effect of rosuvastatin on composite

primary end point

RR of allocation to statin vs placebo in

women in relation to CVD

PRIMARY ENDPOINT IN PRE-SPECIFIED SUBGROUPS

WITHIN JUPITER TRIAL, STRATIFIED BY ACHIEVED LDL-C

Hsia J et al,

JACC, 57:

1666-75, 2011

Major adverse cardiac events curves at

30 days in high-dose statin vs control arms

Patti G Circulation 2011;123:1622-1632

PERIPROCEDURAL MYOCARDIAL PROTECTION BY HIGH-

DOSE STATIN ACROSS VARIOUS SUBGROUPS OF PATIENTS

Patti G et al, Circulation, 123: 1622-1632, 2011

Outline of the presentation

• Epidemiology

• Pharmacological treatment

- Ace inhibitor

- ß – blockers

- ASA

- Statins

• Pharmacological explanations

Gender differences in pharmacokinetics

Baggio G, Corsini A et al Clin Chem Lab Med 2013; 51(4): 713–727

Percentuale di massa magra e di grasso sul totale del peso

corporeo nell’uomo e nella donna in funzione dell’età

Mayersohn MB, 1994

SEX DIFFERENCES IN CYTOCHROME P450 ACTIVITY

Gandhi M et al, Annu. Rev. Pharmacol. Toxicol., 44: 499-523, 2004

GENDER DIFFERENCES IN PHASE I METABOLISM

Franconi F et al, Pharm Res, 55: 81-95, 2007

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

GENDER DIFFERENCES IN PHASE II METABOLISM

Franconi F et al, Pharm Res, 55: 81-95, 2007

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

CYP3A SUBSTRATES INCLUDED IN THE REVIEW

Greenblatt DJ and von Moltke L, J Clin Pharmacol, 48: 1350-1355, 2008

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

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