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 DifferencesMetabolism - CL

Female Male note

Diazepam-Ctot reference Lower Oxidation

Diazepam-Cu reference Lower "

Oxazepam reference Higher Glucuronide

Acetaminophen reference Higher "

Propranolol reference HigherOxidation

Conjugation

Prednisolone reference Lower Oxidation

Me-Prednisolone reference Lower Oxidation

Methylprednisolone0.6 mg/kg

Lew, …, Jusko. Clin Pharmacol. Ther. 54:402-414,1993.

Methylprednisolone, con’tn = 6M; 6F Men Women p

Age [yr] 37.3 37.0

TBW [kg] 80.6 56.2

IBW [kg] 75.5 53.0

AUC [ng h/mL] 2133 1443 0.02

CL [L/h] 21.6 23.3 NS

CL / IBW [L/h/kg] 0.288 0.447 0.02

V [L] 80.1 56.1 <0.02

V / IBW [L/kg] 1.06 1.07 NS

IC50 [ng/mL]a 1.69 0.11 <0.02acortisol suppression

Special considerations

1. Menopause.

2. Menstrual cycle.

3. Pregnancy.

Menopause & CYP3A4CYP3A4 Activity in Pre- and Post-Menopausal Women

0.145 mg/kg midazolam i.v.

menopause: Pre Post Post + E Post + E&P

N 10 10 10 10

Age [y] 24.6 62.3 58.1 55.8

Weight [kg] 61.5 67.8 66.6 63.6

AUC [ng h/mL 23.2a 32.5b 30.9b 30.1a,b

CL [L/h/kg] 0.64a 0.47b 0.49b 0.53a,b

Vss [L/kg] 1.33a 1.35a 1.56a 1.83a

t1/2 2.26a 2.86a 3.32a 3.96a

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.

Menstural Cycle:drug distribution

Fluid compartment volumes:

VP, VE, VR

No significant variation over cycle

Plasma binding proteins:

Albumin: 1AAG:

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.

10 20 30

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 - 1997 Jul; 87(1): 26-35

•< 1% unchanged in urine•low E•QH independent

DayCL

[mL/min/kg]

Vss

[mL/kg]

2 3.62 303

13 3.81 304

21 3.60 299

•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).

Menstrual Cycle:disease symptom severity

AsthmaSymptoms 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: CLR

PHASE - Day CLCR (n=9)

Follicular - 8 112 ± 17

Ovulatory – 15 119 ± 14

Luteal - 21 125 ± 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 33:328-343, 1997.

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

Pregnancy & Drug Distribution

VP 50% V

Body Water 8 L

60% in placenta, fetus, amniotic fluid; 40% in maternal tissues

V

plasma albumin fup V

1 acid glycoprotein

steroid & placental hormones

fup V

Pregnancy & CL

GFR 50%may need to DR for renally cleared drugs such as digoxin, penicillin, lithium

ProgesteroneEstrogen

some hepatic metabolism enzymes, e.g., phenytoin. microsomal oxidase activity, e.g., theophylline & caffeine.

fup CL but Css,u

Estrogencholestatic effect that may inhibit biliary excretion.

Pregnancy & Drug Clearance

DrugCL [mL/min]

Pregnant Control

Ampicillin 450 ± 31 370 ± 30

Cefuroxime 282 ± 34 198 ± 27

Imipenem 973 ± 47 338 ± 85

Piperacillin 1538 ± 362 540 ± 75

Azlocillin 126 195

Sotalol 196 ± 24 109 ± 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: Pregnant Nonpregnant

n 9 5

CL [mL/min] 1,990 2,127

Vss [L] 21.3 40.9

MRT [min] 9.2 16.6