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Dosing Regimen Individualization

Dosing Regimen Individualization. Gender. Gender physiological differences. Body Composition: percent body fat is 10% lower in men. Hormonal: androgen vs. estrogen / progesterone influences. Menstrual Cycle. Gender Differences. Absorption – no significant differences

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Dosing Regimen Individualization

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  1. Dosing Regimen Individualization Gender

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

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

  4. Gender DifferencesMetabolism - CL

  5. Methylprednisolone0.6 mg/kg Lew, …, Jusko. Clin Pharmacol. Ther. 54:402-414,1993.

  6. Methylprednisolone, con’t acortisol suppression

  7. Special considerations • Menopause. • Menstrual cycle. • Pregnancy.

  8. Menopause & CYP3A4

  9. Menstrual cycleFollicular 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

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

  12. 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 Alfentanil – P450 3A4 probe • < 1% unchanged in urine • low E • QH independent • 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

  14. Menstrual Cycle: CLR R. S. Kidd, MS Thesis, U. Tennessee. 1998

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

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

  17. Pregnancy & Drug Distribution

  18. Pregnancy & CL

  19. Pregnancy & Drug Clearance

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

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

  22. Fenoterol PK Parameters

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