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

Tamoxifen a
— <1 >98 1.4 b,c 50-60 b 4-11 days d 5 (3-7) 120 (67-183) ng/mL
a
Has active metabolites; 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen are
minor metabolites that exhibit affinity for the estrogen receptor that is greater than that of
parent trans-tamoxifen. The t 1/2
of all metabolites are rate limited by tamoxifen elimination.
b
CL/F and V area
/F reported. c The major pathway of elimination, N-demethylation, is catalyzed
by CYP3A. d t 1/2
consistent with accumulation and approach to steady state. Significantly
Tamsulosin a
100 12.7 ± 3.0 99 ± 1 0.62 ± 0.31 0.20 ± 0.06 6.8 ± 3.5 c 5.3 ± 0.7 d 16 ± 5 ng/mL d
b Food a RD a RD, b Aged a RD, Aged a Food a Food
a
Data from healthy male subjects. Metabolized primarily by CYP3A and CYP2D6. b CL/F
reduced, moderate renal impairment. Unbound AUC relatively unchanged. c Apparent t 1/2
after
oral dose in patients is ~14-15 hours, reflecting controlled release from modified-release granules.
d Following a single 0.4-mg modified-release oral dose in healthy subjects.
References: Matsushima H, et al. Plasma protein binding of tamsulosin hydrochloride in renal
disease: Role of α 1
-acid glycoprotein and possibility of binding interactions. Eur J Clin
Telithromycin a
57 (41-112) 23 (19-27) 70 14 (12-16) 3.0 (2.1-4.5) 12 (7-23) 1.0 (0.5-3.0) c 2.23 μg/mL c
b RD b
a
~35% of the dose is metabolized by CYP3A4. b CL/F reduced in patients with severe renal
impairment. c Following an 800-mg oral dose given once daily for 7 days.
References: Ferret C, et al. Pharmacokinetics and absolute oral bioavailability of an 800-mg
oral dose of telithromycin in healthy young and elderly volunteers. Chemotherapy, 2002,
Temsirolimus a
longer terminal t 1/2
s are observed. e Average C ss
following a 10-mg oral dose given twice
daily to steady state.
References: Lønning PE, et al. Pharmacological and clinical profile of anastrozole. Breast
Cancer Res Treat, 1998, 49(suppl 1):S53–S57. PDR54, 2000, p. 557.
Pharmacol, 1999, 55:437–443. van Hoogdalem EJ, et al. Disposition of the selective α 1A
-
adrenoceptor antagonist tamsulosin in humans: Comparison with data from interspecies scaling.
J Pharm Sci, 1997, 86:1156–1161. Wolzt M, et al. Pharmacokinetics of tamsulosin in
subjects with normal and varying degrees of impaired renal function: An open-label singledose
and multiple-dose study. Eur J Clin Pharmacol, 1998, 4:367–373.
48:217–223. Namour F, et al. Pharmacokinetics of the new ketolide telithromycin (HMR
3647) administered in ascending single and multiple doses. Antimicrob Agents Chemother,
2001, 45:170–175. Zhanel GG, et al. The ketolides: A critical review. Drugs, 2002,
62:1771–1804.
— 4.6 b — c 3.8 ± 0.6 d 3.3 ± 0.5 d 12.8 ± 1.1 — 595 ± 102 ng/mL e
a
Temsirolimus, a water-soluble ester analog of sirolimus or rapamycin, is available for IV use.
Following IV administration, temsirolimus is converted to sirolimus; blood AUC of sirolimus
is 3-fold higher than that of temsirolimus at the recommended dose of 25 mg for the treatment
of advanced renal cell carcinoma. Both temsirolimus and sirolimus inhibit mTOR kinase
activity and undergo oxidative metabolism mediated by CYP3A. b Recovery of radioactivity
after a single IV dose of [ 14 C]-temsirolimus. c Both temsirolimus and sirolimus partition extensively
into blood cells; a major fraction of temsirolimus and sirolimus in plasma is bound to
plasma proteins. d Based on CL of 16.1 ± 2.5 L/hr and V ss
of 232 ± 36 l at a dose of 25 mg,
assuming an average body weight of 70 kg. All pharmacokinetic assessments are based on
whole blood concentration. e Following the first dose of a 25-mg/wk regimen.
References: Atkins MB, et al. Randomized phase II study of multiple dose levels of CCI-779,
a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory
renal cell carcinoma. J Clin Oncol, 2004, 22:909–918. Drugs@FDA. Torisel label approved
on 5/30/07. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
Accessed on December 31, 2010.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
1981