Download - Dosing Regimen Individualization
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Dosing Regimen Individualization
Gender
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Gender physiological differences
1. Body Composition: percent body fat is 10% lower in men.
2. Hormonal: androgen vs. estrogen / progesterone influences.
3. Menstrual Cycle.
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Gender Differences
Absorption – no significant differences
Distribution – no significant differences
Renal elimination – no significant differences
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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
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Methylprednisolone0.6 mg/kg
Lew, …, Jusko. Clin Pharmacol. Ther. 54:402-414,1993.
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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
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Special considerations
1. Menopause.
2. Menstrual cycle.
3. Pregnancy.
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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
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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.
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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
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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
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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).
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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
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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
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Tobramycin
R. S. Kidd, MS Thesis, U. Tennessee. 1998
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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
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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
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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.
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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
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Pregnancy and Fenoterol
Tocolytic agent in pregnancy
CL is 85% by hepatic metabolism; high E
CL is blood flow limited
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Fenoterol 2 g/min iv infusion
Hildebrandt, et al. Eur. J. Clin. Pharmacol. 45:275,1993
nonpregnant
pregnant
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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