Transcript Dosing Regimen Individualization

Grapefruit: Inhibits CYP3A4
FFP of high-E drugs is
significantly elevated
when given with
grapefruit juice. Frozen
concentrate has more
pronounced effect than
fresh squeezed juice.
Bioavailability of felodipine and
nifedipine increase 100-280%
when coadministered with
grapefruit juice, compared with
water.
dihydroxybergamottin
Edwards, et al. Drug Metab. Disp. 24:1287, 1996.
Grapefruit Juice
Selective post-translational down regulation of CYP3A4
in intestine and liver increases FFP for:
Terfenadine
Midazolam
Saquinavir
Triazolam
Cyclosporin
Verapamil
Grapefruit: Inhibits CYP3A4
Rau et al., Clin Pharmacol Ther 61:401, 1997.
Differential block shunts more TF to
carboxylate and elevates TF, which is
cardiotoxic.
St. John’s Wort
•Herbal remedy used to treat depression
•Potent inducer of CYP3A4
•Reduces the AUC and Css of CYP3A4 substrates for lowE parenteral and all-E oral; e.g.:
•indinavir
•cyclosporin
•combined oral contraceptives
Vitamins
Pyridoxine
Reduces Css of
phenytoin and
phenobarbital
Folic Acid
Reduces Css of
phenytoin, but not
phenobarbital
Ascorbic Acid
Competitively inhibits
sulfate conjugation;
1 g/d  60% in F
for ethyinyl estradiol
Charcoalbroiled food
CYP1A2 is induced.
Significantly reduces
AUC, Css for all orally
administered drugs that
are CYP1A2 substrates.
Smoking Tobacco
Theophylline
Hunt, Jusko, Yurchak. Clin Pharmacol Therap 19:549
CYP1A2 is induced.
Significantly reduces
AUC, Css for CYP1A2
substrates.
Smoking Tobacco
Phenytoin
CYP2C9 & -19 not
induced.
Alcohol
Acute: (co-administration; “binge drinking”)
Competitive inhibition of drug metabolism
Chronic: prolonged heavy use
Induces CYP2E1: acetaminophen, theophylline
are example substrates
Induces glucuronyl transferase
Confounding variable: liver disease
Depletion of glutathione in liver by alcohol makes liver
more susceptible to acetaminophen damage
Dosing Regimen
Individualization
Liver Disease
Liver Disease or Involvement
AIDS
Cirrhosis
Acute & Chronic Hepatitis: A, B, and C
Biliary Tract: infection, gall stones
Cancer: liver, biliary tree
Drug-Induced Liver Disease
Welling and Pool. Effect of liver disease on drug metabolism and pharmacokinetics. Ch. 16 in Drug Induced Hepatotoxicity,
Cameron RG, et al., Eds. Springer-Verlag, 1996.
Westphal and Brogard. Drug Administration in Chronic Liver Disease. Drug Safety 17:47-73, 1997.
Pathology relevant to PK
Vascular
•fibrotic infiltration elevates resistance to blood flow,
and extrahepatic collateral veins develop (shunts).
Up to 60% of hepatic flow may bypass the liver.
•QH decreased in cirrhosis, but no change or
increased in hepatitis.
For high-E drugs, FFP is elevated and CLH is decreased;
e.g., meperidine, pentazocine, propranolol.
Pathology relevant to PK
Hepatic Cell Mass
Intrinsic Hepatocyte Function
moderate cirrhosis
 severe cirrhosis
severe cirrhosis
 viral and alcoholic hepatitis
 hepatitis
CLint,u may or may not be affected.
Pathology relevant to PK
Ascites
•Lymph in peritoneal cavity due to increased
retention of Na and fluid by kidneys, and elevated
hepatic blood pressure.
•Increases VE (normal = 8L) by 1-20 L, with an
average of about 4 L.
Renal Function Changes
•GFR reduced in cirrhosis w/ ascites.
Pathology relevant to PK
Protein Synthesis
•Liver is the site of synthesis of albumin and 1-AAG.
•Decreased rate of albumin synthesis is common,
which causes reduced plasma concentration of
albumin and elevated fup.
•Some liver diseases increase the synthesis rate of
1-AAG, although cirrhosis seems to decrease its
synthesis rate. So 1-AAG concentration in plasma
may increase, decrease, or not change.
Liver Function Tests
Not useful as guides to alter DR.
•Bilirubin
•Albumin
•Prothrombin Time
•Enzymes, e.g.:
•alkaline phosphatase
•aspartate aminotransferase
S/A Diagrams
albumin:
fup
 enzyme activity:
CLint,u
 blood flow and shunting: QH
Oral & low-E parenteral
Css
F DM/
Ko
fup
CLint,u
Css,u
High-E parenteral
Css
F DM/
Ko
QH
Css,u
fup
QH
t1/2
CL
V
CLint
fup
CLint,u
Case Study: Ceftriaxone
Stoeckel, Tuerk, Trueb, McNamara. Clin. Pharmacol. Therap. 36:500, 1984
Ceftriaxone – plasma protein
binding
KA,eq
[M-1 x 10-4]
nP
[M-1 x 10-4]
Normal [8]
3.91 ± 0.62
5.90 ± 0.46
0.050 ± 0.008
Fatty Liver
[5]
3.52 ± 0.35
5.11 ± 0.89
0.071 ± 0.021*
Cirrhosis
[4]
3.20 ± 0.35
4.56 ± 0.88
0.091 ± 0.020*
Cirrhosis w/
ascites [6]
2.13 ± 0.50* 3.39 ± 0.84* 0.161 ± 0.061*
Group [n]
* = Different from Normal, p < 0.05
fup
Ceftriaxone – PK Parameters
CL
[mL/min/kg]
Vss
[L/kg]
t1/2
[hr]
fe
[%]
Normal
0.226 ± 0.064
0.142 ± 0.017
8.4 ± 1.82
45.8 ± 6.8
Fatty Liver
0.207 ± 0.036
0.129 ± 0.022
9.7 ± 1.26
50.6 ± 10.6
Cirrhosis
0.235 ± 0.106
0.109 ± 0.035
8.0 ± 1.98
68.3 ± 14.8
Cirrhosis w/
ascites
0.390 ± 0.156* 0.288 ± 0.077*
9.7 ± 1.83
74.7 ± 3.9*
* = Different from Normal, p < 0.05
Ceftriaxone – PK Parameters
CLu
[mL/min/kg]
CLR,u
[mL/min/kg]
CLNR,u
[mL/min/kg]
Normal
4.59 ± 1.29
2.04 ± 0.46
2.55 ± 0.94
Fatty Liver
3.19 ± 0.71
1.58 ± 0.47
1.61 ± 0.45
Cirrhosis
2.70 ± 0.93*
1.84 ± 0.72
0.87 ± 0.48*
Cirrhosis w/
ascites
2.06 ± 0.85*
1.55 ± 0.67
0.52 ± 0.20*
* = Different from Normal, p < 0.05
Summary – Liver Disease
CL, both renal and
hepatic.
May require DR.
 FFP for high-E drugs
given p.o. due to
shunting and CLint,u.
May require DR.
fup for albumin-bound
drugs.
DR for high-E via
parenteral route.