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Gender-related differences in pharmacokinetics and pharmacodynamics Petra A. Thürmann Philipp Klee-Institute of Clinical Pharmacology HELIOS Hospital Wuppertal.

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Presentation on theme: "Gender-related differences in pharmacokinetics and pharmacodynamics Petra A. Thürmann Philipp Klee-Institute of Clinical Pharmacology HELIOS Hospital Wuppertal."— Presentation transcript:

1 Gender-related differences in pharmacokinetics and pharmacodynamics Petra A. Thürmann Philipp Klee-Institute of Clinical Pharmacology HELIOS Hospital Wuppertal Chair of Clinical Pharmacology University Witten/Herdecke

2 Gender- or sex-specific differences in pharmacokinetics and -dynamics absorption, distribution, metabolism and elimination effect at the receptor level, efficacy and adverse drug reactions... and the enrolment of women in clinical trials with new and old drugs Blood level Time (min)

3 Women in clinical trials – an analysis of studies submitted to the FDA n=2.581 trials, n=334.551 Patients, excl. Studies with sex-specific drugs Evelyn B et al, FDA, 24.8.2001

4 Inclusion of women in clinical trials published in 2001 N = 239 trials with n = 15,880 patients/volunteers % clinical trials with… Clinical Pharmacology & Therapeutics (IF 5,6) British Journal of Clinical Pharmacology (IF 1,8) European Journal of Clinical Pharmacology (IF2,1) Fleisch, Fleisch & Thürmann, CP&T 2005

5 Reasons to exclude women from clinical trials Ethical reasons Potential risk of pregnancy Experience with thalidomide and diethylstilbestrol Juridical reasons Liability Methodological Reasons Inter-individual variability increases Interactions with oral contraceptives

6 Pharmakokinetics: sex-based differences Body weight is in average 10 kg lower in women when compared with men Women tend to have a higher percentage of body fat and – depending on the menstrual cycle – a variable water content Women metabolize endogenous sex hormones to a higher extent than men  liver function and metabolic capacity differ

7 Metabolism at the microsomal cytochrome P450 system CYP3A CYP2D6 CYP2C CYP1A2 CYP2E1 %

8 Sex-based differences in the expression of CYP3A4-mRNA and enzyme activity in human liver microsomes Wolbold R et al, Hepatology 2003 CYP3A4 mRNA-expressionCYP3A4 protein content in relation to verapamil-N-dealkylation

9 Tirilazad and subarachnoidal haemorrhage ++ = good recovery (Glasgow Outcome Scale) + = moderate – severe dysfunction (Glasgow Outcome Scale) % WomenMen P < 0,05 Kassell NF et al, J Neurosurg 1996

10 Plasma concentrations of tirilazad mesylate after 3 mg/kg i.v. Hulst LK et al, Clin Pharmacol Ther 1994 AUC (ng/ml*h) *P<0.05 m vs. w P < 0.05

11 Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with SAH Findings from previous multicenter clinical trials have suggested that tirilazad mesylate might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH). This beneficial effect, however, was greater in males than females, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of tirilazad in women with SAH. CONCLUSIONS: The authors conclude that high-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Although a significant reduction in the incidence of symptomatic vasospasm was observed in the treatment group, the primary end point (mortality rate at 3 months post-SAH) was not affected by the study drug. Lanzino G et al, J Neurosurg 1999

12 Pharmakokinetics of metoprolol – a CYP2D6 substrate Luizer et al, Clin Pharm Ther 1999 * * * p < 0,05 women versus men C max (ng/ml) AUC (ng/ml*h) Maximum plasma concentration * ** * Area under the concentration/time curve

13 Influence of oral contraceptives (OC) on the pharmacokinetics of metoprolol 0 400 800 1200 1600 AUC (ng/ml*h) 0 50 100 150 200 plasma concentration (ng/ml) maximum 0 1 2 3 4 5 metoprolol half life (h) 12 females with OC 11 females without OC Kendall MJ et al; Br J Clin Pharmacol 1982

14 Adverse drug reactions with betablockers resulting in hospitalisation CYP2D6- substrates: metoprolol, carvedilol, nebivolol, propranolol CYP2D6- independent betablockers: sotalol, bisoprolol, atenolol Thürmann et al, German Pharmacovigilance Study Group 2006

15 Population pharmacokinetics of 5-fluouracil Gusella et al, BJCP 2002

16 Women experience greater toxicity with fluorouracil- based chemotherapy for colorectal cancer % patients with ADRs severity grade  3 Sloan et al, J Clin Oncol 2002 ** * * * *p<0,001 N = 1,093 f + 1,355 m patients receiving 5-FU- based chemotherapy

17 Sex-based differences in pharmacokinetics Sex-based differences in pharmacokinetics have been demonstrated Influence of sex (hormones ?) on metabolism does exist for several pathways and enzymes Clinical relevance: in most cases slight over-/underdosing?

18 Women emerge from general anesthesia faster than men (Time (median, min) Gan TJ et al, Anaesthesiology 1999 N = 274 patients receiving propofol/alfentanil/NO

19 CNS: GABA-receptors and sex/gender complex interaction between GABA A receptors and sex hormones antinociceptive effects of progesterone via binding at the GABA A -receptor complex chronic administration of progesterone decreases the requirement of the narcotic halothane in rats  pregnant women require smaller minimal alveolar concentrations of volatile narcotics when compared with non-pregnant women Review: Pley et al, Acta Anaesthesiol Scand 2003

20 Influence of oral contraceptives (OC) on the effect of benzodiazepines AlprazolamLorazepam Reaction index Kroboth & McAuley, 1997

21 Sex / gender and requirements of opiates In patient-controlled analgesia men require approx. 40 % higher doses of morphine than women (n = 1,833 patients). In healthy volunteers (n = 20; 10 females) using electrostimulation to induce pain, the morphine con- centration to decrease pain by 50 % came to 42 nmol/l in women and 71 nmol/l in men. The required morphine concentration at the opiate receptor for pain control is about twice as high in men when compared with women. Women suffer more frequently than men from opiate- induced nausea and vomiting. Review: Pley et al, Acta Anaesthesiol Scand 2003

22 Gender differences in treatment response to sertraline vs. imipramine in chronic depression Response rate (%) n = 400 women n = 235 men P = 0.001 significant interaction for treatment*gender Kornstein et al, Am J Psychiatry 2000

23 Sex/gender-differences in the pharmacodynamis and effects of drugs Response to drugs can be sex-specific Differences can be observed even for those receptors and enzymes for which a sex- specific response is not expected! Clinical relevance?? Relevant for gender differences in drug efficacy and incidence of side effects?

24 Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Martin RM et al, BJCP 1998

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26 Gender-related differences in pharmacokinetics and pharmacodynamics Sex/gender-based differences in drug pharmacokinetics and effects do exist These differences are often small – but become apparent in larger cohorts Thus: during drug development sex- differences should be regarded –  and especially after drug approval!

27 Thank you for your attention!

28 Analysis of trials with known gender-sensitive drugs ?? Fleisch, Fleisch & Thürmann, CP&T 2005

29 Why do women live longer?

30 Geschlechtsspezifische Unterschiede in der Pharmakokinetik von Psychopharmaka CYP 1A2: geringere Aktivität bei Frauen als bei Männern. Dies führt zu etwa 35 % höheren Plasmakonzentrationen von Clozapin und Norclozapin bei Frauen im Vergleich zu Männern. Die Plasmakonzentrationen der SSRIs Fluvoxamin und Sertralin sind bei Frauen 70 – 100 % bzw. 50 – 70 % höher im Vergleich zu Männern, dies wird auf unterschiedliche Aktivitäten von CYP 1A2 und im Fall von Fluvoxamin auch auf CYP 2C19 zurückgeführt. Lane H-Y et al. J Clin Psych 1999; Meibohm B et al, Clin Pharmacokinet 2002

31 Drug development phases Phase I: absorption, distribution, metabolism, elimination, concentration/effect relationship, healthy volunteers Phase II: dose finding in selected patients, comparison versus placebo (approx. 200) Phase III: more patients (approx. 2,000), with concomitant diseases and comedication, comparison versus standard treatment Phase IV: safetey after marketing aproval, experience in a broad spectrum of patients

32 Hormonal Influences and efficacy of antidepressants (I) Martenyi et al, Eur Neuropsychopharmacol 2001

33 Hormonal Influences and efficacy of antidepressants (II) Martenyi et al, Eur Neuropsychopharmacol 2001

34 Age- and gender distribution of digitalis intoxications N = 123 Thürmann et al, Int J Clin Pharmacol Ther 2003 Men Women

35 Dry cough induced by ACE-inhibitors % Kubota et al, Eur J Clin Pharmacol 1996

36 % deltaQT Drug-induced QTc-prolongation in the isolated rabbit heart Ebert SN et al, 1998 10  M3,3  M *p < 0,05 * *


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