DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Vincristine a
— 10-20 Low 4.92 ± 96.9 ± 22.6 ± 16.7 c — ~250-425 nM d
3.01 L/hr/m 2 55.7 L/m 2 c
a LD b
a LD b
i Child
a
Data from adult male and female cancer patients. Metabolized by CYP3A and excreted
unchanged into bile (substrate for P-glycoprotein). b CL reduced, cholestatic liver disease.
c
t 1/2
and V z
for terminal phase. Longer t 1/2
(~85 ± 69 hours) also reported. d Following a 2-mg
IV bolus dose.
References: Gelmon KA, et al. Phase I study of liposomal vincristine. J Clin Oncol, 1999,
17:697–705. Rahmani R, et al. Pharmacokinetics and metabolism of vinca alkaloids. Cancer
Vinorelbine
27 ± 12 a 11 87 (80-91) 21 ± 7 76 ± 41 b 42 ± 21 b 1.5 ± 1.0 c 114 ± 43 ng/mL c
b LD
1130 ± 636 ng/mL d
a
For liquid-filled gelatin capsules. b Elimination kinetics of vinorelbine follow a threecompartment
model with extensive tissue distribution. Values for the terminal elimination
phase are reported. c Following a single 100-mg/m 2 oral dose (gel capsule). d Following a single
30-mg/g IV infusion over 15 minutes.
Voriconazole a
96 <2 58 3.8 b 1.6 b 6.7 b PO: 1.1 d PO: 2356 ng/mL d
b Food b LD c a Food b Food
IV: 3621 ng/mL e
a
Metabolized mainly to an inactive N-oxide by CYP2C19 (major), CYP3A4, and CYP2C9.
b
Elimination is dose and time dependent. Pharmacokinetic parameters determined at steady
state are reported. Mean CL was reduced (64%), V ss
reduced (32%), and t 1/2
increased (16%)
with 12 days of twice-daily 3-mg/kg IV administration. Also, CL decreased 41% when dose
was increased from 200-300 mg twice daily. c CL reduced in patients with mild to moderate
hepatic insufficiency. d Following a 3-mg/kg oral dose given twice daily for 12 days.
e
Following a 3-mg/kg IV infusion over 1-hour given twice daily for 12 days.
Warfarin a
Surv, 1993, 17:269–281. Sethi VS, et al. Pharmacokinetics of vincristine sulfate in adult cancer
patients. Cancer Res, 1981, 41:3551–3555. Sethi VS, et al. Pharmacokinetics of vincristine
sulfate in children. Cancer Chemother Pharmacol, 1981, 6:111–115. van den Berg
HW, et al. The pharmacokinetics of vincristine in man: Reduced drug clearance associated
with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother
Pharmacol, 1982, 8:215–219.
Reference: Leveque D, et al. Clinical pharmacokinetics of vinorelbine. Clin Pharmacokinet,
1996, 37:184–197.
References: Boucher HW, et al. Newer systemic antifungal agents: Pharmacokinetics, safety
and efficacy. Drugs, 2004, 64:1997–2020. Purkins L, et al. The pharmacokinetics and safety
of intravenous voriconazole—A novel wide-spectrum antifungal agent. Br J Clin Pharmacol,
2003, 56(suppl):2–9. Purkins L, et al. Voriconazole, a novel wide-spectrum triazole: Oral
pharmacokinetics and safety. Br J Clin Pharmacol, 2003, 56(suppl):10–16.
93 ± 8 <2 99 ± l b 0.045 ± 0.024 c,d,e 0.14 ± 0.06 b,d 37 ± 15 f <4 g R: 0.9 ± 0.4 μg/mL g
b RD i Aged, AVH, CF i Aged, AVH i Aged, AVH S: 0.5 ± 0.2 μg/mL g
i Preg
a
Values are for racemic warfarin; the S-(–)-enantiomer is 3- to 5-fold more potent than the R-(+)-
enantiomer. b No difference between enantiomers in plasma protein binding or V area
. c CL of the
R-enantiomer is ~70% of that of the antipode (0.043 versus 0.059 mL · min −1 · kg −1 ).
d
Conditions leading to decreased binding (e.g., uremia) presumably increase CL and V. e The S-
enantiomer is metabolically cleared by CYP2C9 (polymorphic). f t 1/2
of the R-enantiomer is
longer than that of the S-enantiomer (43 ± 14 versus 32 ± 12 hours). g Mean steady-state, 12-hour
postdose concentrations of warfarin enantiomers following a daily oral dose of 6.1 ± 2.3 mg of
racemic warfarin given to patients with stabilized (1-5 months) anticoagulant therapy.
Reference: Chan E, et al. Disposition of warfarin enantiomers and metabolites in patients
during multiple dosing with rac-warfarin. Br J Clin Pharmacol, 1994, 37:563–569.
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
(Continued)
1989