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
Riluzole a
64 (30-100) <1 98 5.5 ± 0.9 3.4 ± 0.6 14 ± 6 0.8 ± 0.5 c 173 ± 72 ng/mL c
b Food b
b LD
a
Eliminated primarily by CYPlA2-dependent metabolism; metabolites are inactive.
Involvement of CYP1A2 may contribute to ethnic (lower CL/F in Japanese) and gender
(lower CL in women) differences and inductive effects of smoking (higher CL in smokers).
b
High-fat meal. c Following a 50-mg oral dose given twice daily to steady state.
Risperidone a
PO: 66 ± 28 b 3 ± 2 b 89 c 5.4 ± 1.4 b 1.1 ± 0.2 3.2 ± 0.8 a,b R: ~l e R: 10 ng/mL e
IM: 103 ± 13 b RD, a Aged d a RD, a Aged d TA: 45 ng/mL e
a
The active metabolite, 9-hydroxyrisperidone, is the predominant circulating species in extensive
metabolizers and is equipotent to parent drug. 9-Hydroxyrisperidone has a t 1/2
of 20 ± 3
hours. In extensive metabolizers, 35 ± 7% of an IV dose is excreted as this metabolite; its
elimination is primarily renal and therefore correlates with renal function. b Formation of
9-hydroxyrisperidone is catalyzed by CYP2D6. Parameters reported for extensive metabolizers.
In poor metabolizers, F is higher; ~20% of an IV dose is excreted unchanged, 10% as the
9-hydroxy metabolite; CL is slightly <1 mL/min/kg, and t 1/2
is similar to that of the active
metabolite, ~20 hours. c 77% for 9-hydroxyrisperidone. d Changes in elderly subjects due to
Ritonavir a
References: Bruno R, et al. Population pharmacokinetics of riluzole in patients with amyotrophic
lateral sclerosis. Clin Pharmacol Ther, 1997, 62:518–526. Le Liboux A, et al. Singleand
multiple-dose pharmacokinetics of riluzole in white subjects. J Clin Pharmacol, 1997,
37:820–827. PDR58, 2004, p. 769. Wokke J. Riluzole. Lancet, 1996, 348:795–799.
decreased renal function affecting the elimination of the active metabolite. e Mean steady-state
C min
for risperidone (R) and total active (TA) drug, risperidone + 9-OH-risperidone, following
a 3-mg oral dose given twice daily to patients with chronic schizophrenia. No difference in
total active drug levels between CYP2D6 extensive and poor metabolizers.
References: Cohen LJ. Risperidone. Pharmacotherapy, 1994, 14:253–265. Heykants J, et al.
The pharmacokinetics of risperidone in humans: A summary. J Clin Psychiatry, 1994,
55(suppl):13–17.
— b 3.5 ± 1.8 98-99 SD: 1.2 ± 0.4 c 0.41 ± 0.25 c 3-5 c 2-4 e 11 ± 4 μg/mL e
a Food MD: 2.1 ± 0.8 c b LD d
b Child, LD d
a
Ritonavir is extensively metabolized primarily by CYP3A4. It also appears to induce its own
CL with single-dose (SD) to multiple-dose (MD) administration. b Absolute bioavailability
unknown (>60% absorbed); food elicits a 15% increase in oral AUC for capsule formulation.
c
CL/F, V area
/F, and t 1/2
reported for oral dose. d CL/F reduced slightly and t 1/2
increased
slightly, moderate liver impairment. e Following a 600-mg oral dose given twice daily to
steady state.
References: Hsu A, et al. Ritonavir. Clinical pharmacokinetics and interactions with other
anti-HIV agents. Clin Pharmacokinet, 1998, 35:275–291. PDR54, 2000, p. 465.