Dosing Regimen Individualization Gender
Gender physiological differences 1.Body Composition: percent body fat is 10% lower in men. 2.Hormonal: androgen vs. estrogen / progesterone influences. 3.Menstrual Cycle.
Gender Differences Absorption – no significant differences Distribution – no significant differences Renal elimination – no significant differences
Gender Differences Metabolism - CL FemaleMalenote Diazepam-C tot referenceLowerOxidation Diazepam-C u referenceLower" OxazepamreferenceHigherGlucuronide AcetaminophenreferenceHigher" PropranololreferenceHigher Oxidation Conjugation PrednisolonereferenceLowerOxidation Me-PrednisolonereferenceLowerOxidation
Methylprednisolone 0.6 mg/kg Lew, …, Jusko. Clin Pharmacol. Ther. 54: ,1993.
Methylprednisolone, con’t n = 6M; 6FMenWomenp Age [yr] TBW [kg] IBW [kg] AUC [ng h/mL] CL [L/h] NS CL / IBW [L/h/kg] V [L] <0.02 V / IBW [L/kg] NS IC 50 [ng/mL] a <0.02 a cortisol suppression
Special considerations 1.Menopause. 2.Menstrual cycle. 3.Pregnancy.
Menopause & CYP3A4 CYP3A4 Activity in Pre- and Post-Menopausal Women mg/kg midazolam i.v. menopause:PrePostPost + EPost + E&P N10 Age [y] Weight [kg] 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/ a 2.86 a 3.32 a 3.96 a
Menstrual cycle Follicular phase: days 1-13; luteal phase: days 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: ,1998.
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
Menstrual Cycle: drug metabolism CYP1A2 varies over the cycle; CYP3A4 does not CYCLE DAY 59% 28% CL Theophylline CL in 9 young asthmatic women CYP1A2
Alfentanil – P450 3A4 probe Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe. Kharasch ED - Anesthesiology Jul; 87(1): < 1% unchanged in urine low E Q H independent Day CL [mL/min/kg] V ss [mL/kg] nonsmoking, nonpregnant volunteers 26 5 yr normal menstrual cycle during the same cycle: days 2 (menstrual phase), 13 (estrogen peak), and 21 (progster. peak).
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
Menstrual Cycle: CL R PHASE - DayCL CR (n=9) Follicular ± 17 Ovulatory – ± 14 Luteal ± 18 R. S. Kidd, MS Thesis, U. Tennessee. 1998
Tobramycin R. S. Kidd, MS Thesis, U. Tennessee. 1998
Pregnancy R. Loebstein, A. Lalkin, G. Koren. Pharmacokinetic changes during pregnancy and their clinical relevance. Clinical Pharmacokinetics 33: , 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
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
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.
Pregnancy & Drug Clearance Drug CL [mL/min] Pregnant Control Ampicillin450 ± ± 30 Cefuroxime282 ± ± 27 Imipenem973 ± ± 85 Piperacillin1538 ± ± 75 Azlocillin Sotalol196 ± ± 7
Pregnancy and Fenoterol Tocolytic agent in pregnancy CL is 85% by hepatic metabolism; high E CL is blood flow limited
Fenoterol 2 g/min iv infusion Hildebrandt, et al. Eur. J. Clin. Pharmacol. 45:275,1993 nonpregnant pregnant
Fenoterol PK Parameters Group:PregnantNonpregnant n95 CL [mL/min]1,9902,127 V ss [L] MRT [min]