1. Dosing Regimen Individualization Gender

2. Gender physiological differences 1.Body Composition: percent body fat is 10% lower in men. 2.Hormonal: androgen vs. estrogen / progesterone influences. 3.Menstrual Cycle.

3. Gender Differences Absorption – no significant differences Distribution – no significant differences Renal elimination – no significant differences

4. Gender Differences Metabolism - CL FemaleMalenote Diazepam-C tot referenceLowerOxidation Diazepam-C u referenceLower" OxazepamreferenceHigherGlucuronide AcetaminophenreferenceHigher" PropranololreferenceHigher Oxidation Conjugation PrednisolonereferenceLowerOxidation Me-PrednisolonereferenceLowerOxidation

5. Methylprednisolone 0.6 mg/kg Lew, …, Jusko. Clin Pharmacol. Ther. 54:402-414,1993.

6. Methylprednisolone, con’t n = 6M; 6FMenWomenp Age [yr]37.337.0 TBW [kg]80.656.2 IBW [kg]75.553.0 AUC [ng h/mL]213314430.02 CL [L/h]21.623.3NS CL / IBW [L/h/kg]0.2880.4470.02 V [L]80.156.1<0.02 V / IBW [L/kg]1.061.07NS IC 50 [ng/mL] a 1.690.11<0.02 a cortisol suppression

7. Special considerations 1.Menopause. 2.Menstrual cycle. 3.Pregnancy.

8. Menopause & CYP3A4 CYP3A4 Activity in Pre- and Post-Menopausal Women 0.145 mg/kg midazolam i.v. menopause:PrePostPost + EPost + E&P N10 Age [y]24.662.358.155.8 Weight [kg]61.567.866.663.6 AUC [ng h/mL23.2 a 32.5 b 30.9 b 30.1 a,b CL [L/h/kg]0.64 a 0.47 b 0.49 b 0.53 a,b V ss [L/kg]1.33 a 1.35 a 1.56 a 1.83 a t 1/2 2.26 a 2.86 a 3.32 a 3.96 a

9. Menstrual cycle Follicular phase: days 1-13; luteal phase: days 14-28. GI. Small (< ± 10%) changes in gastric emptying rate and small intestinal transit rate. Clinically insignificant impact on bioavailability and pharmacokinetics. Cardiovascular. HR, BP, cardiac output, plasma lipids, free fatty acid metabolism, and atrial natriuretic peptide fluctuations over the cycle have been observed, but do not produce clinically significant effects on drug PK. A.D.M. Kashuba and A.N. Nafziger. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin. Pharmacok. 34:203-218,1998.

10. Menstural Cycle: drug distribution Fluid compartment volumes: V P, V E, V R No significant variation over cycle Plasma binding proteins: Albumin:  1 AAG: No variation Elevated at menses Plasma lipids < ± 10% variability in cholesterol and triglycerides

11. Menstrual Cycle: drug metabolism CYP1A2 varies over the cycle; CYP3A4 does not. 10 20 30 CYCLE DAY 59% 28% CL Theophylline CL in 9 young asthmatic women CYP1A2

12. Alfentanil – P450 3A4 probe Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe. Kharasch ED - Anesthesiology - 1997 Jul; 87(1): 26-35 < 1% unchanged in urine low E Q H independent Day CL [mL/min/kg] V ss [mL/kg] 23.62303 133.81304 213.60299 9 nonsmoking, nonpregnant volunteers 26  5 yr normal menstrual cycle during the same cycle: days 2 (menstrual phase), 13 (estrogen peak), and 21 (progster. peak).

13. Menstrual Cycle: disease symptom severity Asthma Symptoms worsen late luteal phase;  2 receptor density secondary to rise in progesterone. Epilepsy -4 to +6 days of cycle, frequency of seizures increases. “catamenial epilepsy” Glaucoma Symptom severity fluctuates with cycle phase Bipolar illness allergies

14. Menstrual Cycle: CL R PHASE - DayCL CR (n=9) Follicular - 8112 ± 17 Ovulatory – 15119 ± 14 Luteal - 21125 ± 18 R. S. Kidd, MS Thesis, U. Tennessee. 1998

15. Tobramycin R. S. Kidd, MS Thesis, U. Tennessee. 1998

16. Pregnancy R. Loebstein, A. Lalkin, G. Koren. Pharmacokinetic changes during pregnancy and their clinical relevance. Clinical Pharmacokinetics 33:328-343, 1997. Pregnancy-induced maternal physiological changes with potential impact on PK: GFR , ,  Drug metabolism enzyme activity Total body water  8L Hypoalbuminemia   f up  GI motility   k a and possibly  F Nausea and vomiting   F first trimester

17. Pregnancy & Drug Distribution VPVP  50% V Body Water  8 L 60% in placenta, fetus, amniotic fluid; 40% in maternal tissues  V  plasma albumin f up  V   1 acid glycoprotein steroid & placental hormones  f up  V

18. Pregnancy & CL GFR  50% may need to  DR for renally cleared drugs such as digoxin, penicillin, lithium Progesterone Estrogen  some hepatic metabolism enzymes, e.g., phenytoin.  microsomal oxidase activity, e.g., theophylline & caffeine. f up  CL but  C ss,u Estrogen cholestatic effect that may inhibit biliary excretion.

19. Pregnancy & Drug Clearance Drug CL [mL/min] Pregnant Control Ampicillin450 ± 31370 ± 30 Cefuroxime282 ± 34198 ± 27 Imipenem973 ± 47338 ± 85 Piperacillin1538 ± 362540 ± 75 Azlocillin126195 Sotalol196 ± 24109 ± 7

20. Pregnancy and Fenoterol Tocolytic agent in pregnancy CL is 85% by hepatic metabolism; high E CL is blood flow limited

21. Fenoterol 2 g/min iv infusion Hildebrandt, et al. Eur. J. Clin. Pharmacol. 45:275,1993 nonpregnant pregnant

22. Fenoterol PK Parameters Group:PregnantNonpregnant n95 CL [mL/min]1,9902,127 V ss [L]21.340.9 MRT [min]9.216.6