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 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. Os, I. et al. Lancet. 1992 Feb 8;339(8789):372. 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. Systolic and Diastolic Blood Pressure after Randomization 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. 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 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 Paul G. Shekelle et al, JACC Vol. 41, No. 9, 2003 Effect of angiotensin-converting enzyme inhibitors on mortality in male and female patients with heart failure asymptomatic LV systolic dysfunction symptomatic HF Paul G. Shekelle et al, JACC Vol. 41, No. 9, 2003 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 Point estimates for hazard ratios for total mortality by gender and overall in CIBIS II, MERIT-HF and COPERNICUS. The beneficial effects of metoprolol CR/XL extend to women with heart failure, including women with clinically stable severe heart failure. Ghali et al., Circulation. 2002;105:1585 Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers Luzier et al.,Clin Pharmacol Ther 1999;66:594-601.) 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 risk Major vascular events LDL Reduction The Lancet May 17 2012; 673: 60367-5 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 Risk Factors for Myopathy/Myalgia • Increasing dose • Increasing concentration: • Increasing age, female • CYP450 interactions (pharmacokinetic) • Clinical conditions: • Poly-therapy • Transplanted • Diabetes • Hypothyroidism • History of muscular symptoms after LLT 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 Patients, No. Variable Cases of NewOnset DM Unadjusted HR Age-and Race/Ethnicit y-Adjusted HRa MultivariateAdjusted 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) 143 006 9166 (6.41) 1 [Reference] 1 [Reference] 1 [Reference] 6701 682 (10.18) 1.68 (1.56-1.82) 1.64 (1.52-1.78) 1.48 (1.36-1.61) 4133 394 (9.53) 1.74 (1.58-1.93) 1.75 (1.58-1.93) 1.45 (1.36-1.61) 143 006 9166 (6.41) 1 [Reference] 1 [Reference] 1 [Reference] Nonuser Potency of statin at baseline Low potency: lovastatin, fluvastatin, pravastatin High-potency: simvastatin, atorvastatin Nonuser aThe HRs were estimated from Cox PH models adjusting for age and race/ethnicity. 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. bThe Adapted from Culver AL et al. Arch Intern Med. 2012;172(2):144-152. 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 HIGHDOSE 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 CYP2C9 CYP2C19 Alprenolol Diclofenac Fluvastatin Hexobarbital Clopidogrel I Diazepam Mephenytoin CYP2D6 Amitriptyline Bufaralol Codeine Methylphenobarbital Debrisoquine N-desmethyldiazepan Omeprazol Dextromethorphan Tolbutamide Proguanyl Encainide Warfarin Phenytoin Flecainide Rosuvastatin Rosuvastatin Imipramine Metoprolol Mibefradil Nortriptyline Perhexiline Perphenazine Propafenone Propanolol Sparteine Thioridazine Timolol Modified from: Brower et al., In: Evans W.E. (Ed). Applied Pharmacokinetics. Principles of Therapeutic Drug Monitoring, 3rd ed., 1992 CYP3A4 Amiodarone Atorvastatin Cerivastatin Clarithromycin Cyclosporine A Diltiazem Erythromycin Ketoconazole Itraconazole Lovastatin Mibefradil Midazolam Nefazodone Nifedipine Protease inhibitors Quinidine Sildefanil Simvastatin Terbinafine Verapamil Warfarin 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