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

1988
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
Venlafaxine, a Desvenlafaxine b
10-45 V: 4.6 ± 3.0 V: 27 ± 2 22 ± 10 d 7.5 ± 3.7 d 4.9 ± 2.4 V: 2.0 ± 0.4 V: 167 ± 55 ng/mL e
ODV: 29 ± 7 c ODV: 30 ± 12 c i Aged, Fem i Aged, Fem, 10.3 ± 4.3 c ODV: ODV: 397 ± 81
LD, RD 2.8 ± 0.8 c ng/mL e
b LD, RD
i Aged, Fem
a LD, RD
a
Venlafaxine (V) is available as a racemic mixture; antidepressant activity resides with the
l-(–)-enantiomer and its equipotent O-desmethyl metabolite (formation catalyzed by
CYP2D6—polymorphic). Parameters for the derived O-desmethylvenlafaxine (ODV) are
included. b O-Desmethyl metabolite is marketed as desvenlafaxine in an extended-release
formulation as a successor to V. It has a higher oral bioavailability (80%), with a T max
of 7.5
hours. Desvenlafaxine has a much lower CL (3.5 mL/min/kg) and a smaller V ss
(3.4 L/kg). Its
reported t 1/2
matches that observed for metabolite derived from V. c Values for ODV after
Verapamil a,b
V dosing. d CL/F and V ss
/F reported. e Mean data for V and ODV, following a 75-mg oral dose
(immediate-release tablet) given three times daily for 3 days to healthy adults. T max
for an
extended-release formulation is 5.5 (V) and 9 (DV) hours.
References: Klamerus KJ, et al. Introduction of a composite parameter to the pharmacokinetics
of venlafaxine and its active O-desmethyl metabolite. J Clin Pharmacol, 1992,
32:716–724. PDR54, 2000, p. 3237.
Oral: 22 ± 8 <3 90 ± 2 15 ± 6 c,d 5.0 ± 2.1 4.0 ± 1.5 c IR: 1.1 e IR: 272 ng/mL e
SL: 35 ± 13 a Cirr a Cirr, a Cirr a Cirr, XR: 5.6-7.7 e XR: 118-165 ng/mL e
Aged, Obes
Aged, Obes
a Cirr i RD, Atr a, i Atr Fib a, i Atr Fib a, i Atr Fib
Fib, Aged
i RD i RD, Child i RD, Aged, i RD, Child
Obes
a
Racemic mixture; (–)-enantiomer is more active. Bioavailability of (+)-verapamil is 2.5-fold
greater than that for (–)-verapamil because of a lower CL (10 ± 2 versus 18 ± 3 mL/min/kg).
Relative concentration of the enantiomers changes as a function of route of administration.
b
Active metabolite, norverapamil, is a vasodilator but has no direct effect on heart rate or P-R
interval. At steady state (oral dosing), AUC is equivalent to that of parent drug (t 1/2
= 9 ± 3
hours). c Multiple dosing causes a greater than 2-fold decrease in CL/F and prolongation of t 1/2
in some studies, but no change of t 1/2
in others. d Verapamil is a substrate for CYP3A4,
CYP2C9, and other CYPs. e Mean data following a 120-mg oral conventional tablet (IR) given
twice daily or range of data following a 240-mg oral extended-release (XR) dose given once
daily, both for 7-10 days to healthy adults. EC 50
for prolongation of P-R interval after an oral
dose of racemate is 120 ± 20 ng/mL; the value for IV administration is 40 ± 25 ng/mL. After
oral administration, racemate concentrations >100 ng/mL cause >25% reduction in heart rate
in Atr Fib, >10% prolongation of P-R interval, and >50% increase in duration of exercise in
angina patients. A level of 120 ± 40 ng/mL (after IV administration) was found to terminate
reentrant supraventricular tachycardias.
Reference: McTavish D, et al. Verapamil. An updated review of its pharmacodynamic and
pharmacokinetic properties, and therapeutic use in hypertension. Drugs, 1989, 38:19–76.