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

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APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
Table AII–1
Pharmacokinetic Data (Continued)
BIOAVAILABILITY URINARY BOUND IN CLEARANCE VOL. DIST. HALF-LIFE PEAK TIME PEAK
(ORAL) (%) EXCRETION (%) PLASMA (%) (mL/min/kg) (L/kg) (hours) (hours) CONCENTRATION
Sunitinib a
— b ~9 c P: 90 7.3-14.8 d 4.0 d 40-60 e P: 6.0 (0-8.3) P: 91.9 ± 42.3 ng/mL f
M: 95 M: 6.0 (0-24) M: 25.1 ± 11.0 ng/mL f
a
Sunitinib is metabolized primarily by CYP3A4 to produce its primary active metabolite
(SU12662), which is further metabolized by CYP3A4. Plasma AUC of (SU12662) (M) is
~30% that of the parent drug (P) at steady state. b Data on absolute oral bioavailability is not
available. c 16% of a radioactive dose of [ 14 C]-sunitinib is recovered in urine, of which 86.4%
is in the form of parent drug and active metabolite. d Average CL/F of 34-62 L/hr and V ss
/F of
2230 L in 135 healthy volunteers and 266 patients with solid tumors, and assuming an average
body weight of 77.6 kg. e Population estimate in 73 volunteers and 517 cancer patients.
f
Steady-state concentrations during once-daily dosing of 50 mg.
Tacrolimus
25 ± 10 a,b <1 75-99 c 0.90 ± 0.29 a 0.91 ± 0.29 a,d 12 ± 5 a 1.4 ± 0.5 e 31.2 ± 10.1 ng/mL e
i RD i RD, LD i RD i RD
b Food a LD a LD
a
Drug disposition parameters calculated from blood concentrations. Data from liver transplant
patients reported. Metabolized by CYP3A; also a substrate for P-glycoprotein. b A similar
bioavailability (F = 21 ± 19%) reported for kidney transplant patients; F = 16 ± 7% for normal
subjects. Low oral bioavailability likely due to incomplete intestinal availability.
c
Different values for plasma protein binding reported. Concentrates in blood cells; blood-toplasma
concentration ratio = 35 (12-67). d Slightly higher V ss
and t 1/2
reported for kidney transplant
patients. Because of the very high and variable blood-to-plasma concentration ratio,
Tadalafil a
References: Britten CD, et al. A phase I and pharmacokinetic study of sunitinib administered
daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol, 2008,
61:515–24. Drugs@FDA. Sutent label approved on 2/2/07. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
Accessed on December 30, 2009. Houk BE,
et al. A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary
metabolite (SU12662) in healthy volunteers and oncology patients. Clin Cancer Res,
2009, 15:2497–2506.
markedly different V ss
values are reported for parameters based on plasma concentrations.
e
Following a single 7-mg oral dose given to healthy adults. Consensus target C min
at steady
state are 5-20 ng/mL.
References: Bekersky I, et al. Dose linearity after oral administration of tacrolimus 1-mg
capsules at doses of 3, 7, and 10 mg. Clin Ther, 1999, 27:2058–2064. Jusko WJ, et al.
Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther, 1995,
57:281–290. PDR54, 2000, pp. 1098–1099.
— — 94 0.59 b 0.89 b 17.5 2 d 378 ng/mL d
b RD c
a
Eliminated primarily by CYP3A4-dependent metabolism. b CL/F and V/F reported. c AUC
increased in patients with mild or moderate (2-fold) and severe (4-fold) renal insufficiency.
d
Following a single 20-mg oral dose.
References: Curran M, et al. Tadalafil. Drugs, 2003, 63:2203–2212; discussion 2213–2214.
Product labeling: Cialis ® (tadalafil tablets). Bothell, WA, Lilly Icos, 2004.