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
Solifenacin a
90 3-6 98% b 9.39 ± 2.68 671 ± 118 52.4 ± 13.9 4.2 ± 1.8 c 40.6 ± 8.5 ng/mL d
b LD, RD c
b LD, RD c
a
Solifenacin is extensively metabolized by CYP3A. The 4R-hydroxy-solifenacin metabolite is
pharmacologically active but not likely to contribute to the therapeutic efficacy of solifenacin
because of low circulating levels. b Primarily bound to α 1
-acid glycoprotein. c Dosage reduction
is advised in patients with severe renal impairment (CL cr
<30 mL/min), in whom a 2-fold
reduction in clearance and prolongation in t 1/2
are expected. d At steady state following 21 days
of dosing with 10 mg once daily.
References: Drugs@FDA. VESIcare label approved on 11/18/08. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 27,
Sorafenib a
38-49 b Negligible 99.5 1.2-2.0 c 20-27 c 2.0-12.1 5.4-10.0 μg/mL
a LD d
a
Sorafenib undergoes oxidative metabolism mediated by CYP3A and glucuronidation mediated
by UGT1A9. b Oral bioavailability of NEXAVAR tablet relative to an oral solution.
Sorafenib bioavailability reduced by 29% when administered with a high-fat meal. c Range of
geometric means determined at steady state in three phase I studies in patients with advanced
refractory solid tumors at the dose level of 400 mg two times a day. d Sorafenib AUCs were
23-63% lower in patients with mild and moderate hepatic impairment compared to patients
with normal hepatic function.
Sotalol a
2009. Kuipers M, et al. Open-label study of the safety and pharmacokinetics of solifenacin in
subjects with hepatic impairment. J Pharmacol Sci, 2006, 102:405–412. Kuipers ME, et al.
Solifenacin demonstrates high absolute bioavailability in healthy men. Drugs, 2004, 5:73–81.
Smulders RA, et al. Pharmacokinetics and safety of solifenacin succinate in healthy young
men. J Clin Pharmacol, 2004, 44:1023–1033. Smulders RA, et al. Pharmacokinetics, safety,
and tolerability of solifenacin in patients with renal insufficiency. J Pharmacol Sci, 2007,
103:67–74.
References: Drugs@FDA. Nexavar label approved on 11-17-2007. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 27,
2009. Strumberg D, et al. Safety, pharmacokinetics, and preliminary antitumor activity of
sorafenib: A review of four phase I trials in patients with advanced refractory solid tumors.
Oncologist, 2007, 12:426–437.
60-100 70 ± 15 Negligible 2.20 ± 0.67 1.21 ± 0.17 7.18 ± 1.30 3.1 ± 0.6 1.0 ± 0.5 μg/mL b
b RD
a RD
a
Sotalol is available as a racemate. The enantiomers contribute equally to sotalol’s antiarrhythmic
action; hence, pharmacokinetic parameters for total enantiomeric mixture is
reported herein. β-adrenoreceptor blockade resides solely with S-(–)-isomer. b Following
80-mg, twice-a-day dosing to steady state.
References: Berglund G, et al. Pharmacokinetics of sotalol after chronic administration to
patients with renal insufficiency. Eur J Clin Pharmacol, 1980, 18:321–326. Kimura M, et al.
Pharmacokinetics and pharmacodynamics of (+)-sotalol in healthy male volunteers. Br J Clin
Pharmacol, 1996, 42:583–588. Poirier JM, et al. The pharmacokinetics of d-sotalol and d,lsotalol
in healthy volunteers. Eur J Clin Pharmacol, 1990, 38:579–582.