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
Modafinil, A Armodafinil
— Rac: 3.7 ± 15 Rac: 60 — b — b Rac: 13.6 ± 2.6 Rac: 2.5 ± 1.0 e Rac: 4.6 ± 0.7 μg/mL e
— Arm: <10 — — c — c Arm: 13.0 ± 2.6 Arm: 1.8 Arm: 5.4 ± 1.6 μg/mL e
b LD d , Aged
a LD d
a
Modafinil is available either as a racemic mixture or as the pure (R)-enantiomer armodafinil.
Pharmacokinetic data after dosing of racemate (Rac) or armodafinil (Arm) is reported. Modafinil is
extensively metabolized in the liver to two major metabolites, modafinil acid and modafinil sulfone.
b
CL/F = 0.72 ± 0.10 mL/min/kg and V/F = 0.77 ± 0.11 L/kg after an oral dose of racemic modafinil.
c
The exposure to Arm is 40% higher than that of racemic modafinil after equal oral doses. Arm
CL/F = 0.47 mL/min/kg and V/F = 0.6 L/kg. d Study in patients with moderate to severe liver impairment
receiving oral racemic modafinil; CL/F reduced by 60% and steady-state concentrations doubled
in patients with liver impairment. e Following a 200-mg single oral dose of modafinil or Arm.
Montelukast a
62 <0.2 >99 0.70 ± 0.17 0.15 ± 0.02 4.9 ± 0.6 3.0 ± 1.0 d 542 ± 173 ng/mL d
b LD b
a LD b
i Child c
a
Data from healthy adult subjects. No significant gender differences. Montelukast is metabolized
by CYP3A4 and CYP2C9. b CL/F is reduced by 41%, mild to moderate hepatic impairment
with cirrhosis. c Similar plasma profile with 5-mg chewable versus 10-mg tablet in
adults. d Following a single 10-mg oral dose.
Morphine a
References: Wong YN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of
the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin
Pharmacol, 1999, 39:30–40. Wong YN, et al. Open-label, single-dose pharmacokinetic study
of modafinil tablets and tolerability of modafinil tablets: Influence of age and gender in normal
subjects. J Clin Pharmacol, 1999, 39:30–40. Drugs@FDA. Nuvigil label approved on
06/15/07. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
Accessed May 17, 2010.
References: PDR54, 2000, p. 1882. Zhao JJ, et al. Pharmacokinetics and bioavailability of
montelukast sodium (MK-0476) in healthy young and elderly volunteers. Biopharm Drug
Dispos, 1997, 18:769–777.
PO: 24 ± 12 4 ± 5 35 ± 2 24 ± 10 3.3 ± 0.9 1.9 ± 0.5 IM: 0.2-0.3 c IV: 200-400 ng/mL c
IM: ~100 b AVH, i Aged, LD, i LD, Neo i LD, RD, Child PO-IR: 0.5-1.5 c IM: ~70 ng/mL c
LD, Alb Child b
b Neo, Burn, b RD a Neo, Prem PO-SR: 3-8 c PO-IR: 10 ng/mL c
RD, Prem
PO-SR: 7.4 ng/mL c
a
Active metabolite, morphine-6-glucuronide; Urinary excretion = 14 ± 7%; t 1/2
= 4.0 ± 1.5 hours.
Steady-state ratio of active metabolite to parent drug after oral dosing = 4.9 ± 3.8. In renal failure,
t 1/2
increases to 50 ± 37 hours, resulting in significant accumulation of active glucuronide
metabolite. b Decreased in children undergoing cardiac surgery requiring inotropic support.
c
Following a single 10-mg IV dose (bolus with 5-minute blood sample), a 10-mg/70-kg IM,
a 10-mg/70-kg immediate-release oral (PO-IR) dose, or a 50-mg sustained-release oral dose
(PO-SR). Minimum analgesic concentration is 15 ng/mL.
References: Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity:
Morphine, methadone and naloxone. Clin Pharmacokinet, 1976, 1:219–230. Glare PA, et al.
Clinical pharmacokinetics of morphine. Ther Drug Monit, 1991, 13:1–23.