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

Tolterodine a
EM: 26 ± 18 EM: Negligible T: 96.3 EM: 9.6 ± 2.8 EM: 1.7 ± 0.4 EM: 2.3 ± 0.3 EM: 1.2 ± 0.5 c EM: 5.2 ± 5.7 ng/mL c
PM: 91 ± 40 PM: <2.5 5-HM: 64 PM: 2.0 ± 0.3 PM: 1.5 ± 0.4 PM: 9.2 ± 1.2 PM: 1.9 ± 1.0 c
EM: a Food b LD b a LD PM: 38 ± 15 ng/mL c
a
Data from healthy adult male subjects. No significant gender differences. Tolterodine (T) is
metabolized primarily by CYP2D6 to an active (100% potency) metabolite, 5-hydroxymethyl
tolterodine (5-HM), in extensive metabolizers (EM); t 1/2
5-HM = 2.9 ± 0.4 hour. Also metabolized
by CYP3A to an N-desalkyl product, particularly in poor metabolizers (PM). b CL/F
reduced and AUC 5-HM unbound
increased, hepatic cirrhosis. c Following a 4-mg oral dose given
twice daily for 8 days. C max
of 5-HM was 5 ± 3 ng/mL for EM.
Topiramate a
>70 b 70-97 13-17 0.31-0.51 c 0.6-0.8 c 19-23 c 1.7 ± 0.6 f 5.5 ± 0.6 μg/mL f
a Child d
a RD
b RD e
a
Data from healthy adult male and female subjects and patients with partial epilepsy.
b
Estimate of bioavailability based on urine recovery of unchanged drug. c CL/F, V area
/F, and t 1/2
reported for oral dose. Patients receiving concomitant therapy with enzyme-inducing anticonvulsant
drugs exhibit increased CL/F and decreased t 1/2
. d CL/F increased, <4 years of age
(substantially), and 4-17 years of age. e CL/F reduced, moderate-to-severe renal impairment
(drug cleared by hemodialysis). f Following a 400-mg oral dose given twice daily to steady
state in patients with epilepsy.
Toremifene a
References: Brynne N, et al. Influence of CYP2D6 polymorphism on the pharmacokinetics
and pharmacodynamic of tolterodine. Clin Pharmacol Ther, 1998, 63:529–539. Hills CJ, et al.
Tolterodine. Drugs, 1998, 55:813–820. PDR54, 2000, p. 2439.
— Negligible 99.7 2.6 ± 1.2 L/hr/m 2 b 479 ± 154 L/m 2 b T: 148 ± 53 b T: 1.5-3 d T: 1.1-1.3 μg/mL d
a Aged DMT: 504 ± 578 b DMT: 3-6 d DMT: 2.7-5.8 μg/mL d
b LD, c RD
a Aged, LD
a
Data from healthy adult male and female subjects and female patients with breast cancer.
Toremifene (T) is metabolized by CYP3A to N-desmethyltoremifene (DMT), a metabolite
that accumulates in blood and has anti-estrogenic activity. Toremifene appears to undergo
enterohepatic recycling, prolonging its apparent t 1/2
. b CL/F, V area
/F, and t 1/2
reported for oral
dose. c CL/F reduced, hepatic cirrhosis or fibrosis. d Following a 60-mg oral dose given once
daily to steady state in patients with breast cancer.
References: Glauser TA, et al. Topiramate pharmacokinetics in infants. Epilepsia, 1999,
40:788–791. PDR54, 2000, p. 2209. Rosenfeld WE. Topiramate: A review of preclinical,
pharmacokinetic, and clinical data. Clin Ther, 1997, 19:1294–1308. Sachdeo RC, et al.
Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy
during monotherapy and concomitant therapy. Epilepsia, 1996, 37:774–780.
References: Anttila M, et al. Pharmacokinetics of the novel antiestrogenic agent toremifene in
subjects with altered liver and kidney function. Clin Pharmacol Ther, 1995, 57:628–635.
Bishop J, et al. Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal
patients with advanced breast cancer. Cancer Chemother Pharmacol, 1992,
30:174–178. Wiebe VJ, et al. Pharmacokinetics of toremifene and its metabolites in patients
with advanced breast cancer. Cancer Chemother Pharmacol, 1990, 25:247–251.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
1983