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
Ramelteon a
1.8 b <0.1% 82 883 ± 857 c P: 1.3 ± 0.5 e P: 1.6 ± 0.5 P: 6.9 ± 7.8 ng/mL e,f
b Aged M: 2.3 ± 0.5 e M: 110 ± 29 ng/mL e,f
b LD d a Aged a Aged
i RD
a
Ramelteon undergoes primary oxidative metabolism followed by glucuronidation as secondary
metabolism. CYP1A2 is the major enzyme involved in oxidative metabolism; CYP3A and
CYP2C9 also are involved as minor enzymes. Remarkable elevation in C max
and AUC were
observed with the concurrent administration of the strong CYP1A2 inhibitor fluvoxamine.
The M-II metabolite contributes to the hypnotic effects of ramelteon. M-II has 1/5th to 1/10th
the affinity of ramelteon as an agonist for the melatonin receptors (MT-1 and MT-2); however,
it circulates at 20- to 100-fold higher concentrations relative to ramelteon. b Poor systemic
availability of ramelteon is due to extensive first-pass metabolism. C max
and AUC are elevated
by a high-fat meal; T max
is slightly delayed. c Intersubject variability is notably large.
Ramipril a
R (R): 28 b R (R): <2 c R: 73 ± 2 R (R): 23 d — R (R): 5 ± 2 R (R): 1.2 ± 0.3 g R (R): 43.3 ±
10.2 ng/mL g
RT (R): 48 b RT (R): 13 ± 6 c RT: 56 ± 2 RT: — e RT (R): 9-18 f RT (R): 3.0 ± 0.7 g
a
Hydrolyzed to its active metabolite, ramiprilat (RT). Pharmacokinetic data for ramipril (R)
and RT following oral and IV R administration are presented. b Based on plasma AUC of R
and RT after IV and oral R administration. c Following an oral dose of R. d CL/F of R calculated
from reported AUC data. e No data available; mean renal CL of RT is ~1.1 mL/min/kg.
f
t 1/2
for the elimination phase reported. A longer terminal t 1/2
of ~120 hours most likely corresponds
to the release of drug from ACE; contributes to the duration of effect, but does not
contribute to systemic drug accumulation. g Following a single 10-mg oral dose.
Ranitidine
d
Four- and 10-fold elevation in AUC in mild and moderate hepatic impairment. e P = parent
drug; M = M-II metabolite. f C max
following a single 16-mg oral dose of ramelteon in young
adult subjects. There is no measurable accumulation of parent drug or active metabolite
because of their short elimination t 1/2
.
References: Drugs@FDA. Rozerem label approved on 10/20/08. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
Accessed on August 23, 2009. Greenblatt DJ,
et al. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a
hypnotic agent acting via melatonin receptors MT 1 and MT2. J Clin Pharmacol, 2006,
47:485–496. McGechan A, et al. Ramelteon. CNS Drugs, 2005, 19:1057–1065.
a RD RT (R): 24.1 ±
5.6 ng/mL g
References: Eckert HG, et al. Pharmacokinetics and biotransformation of 2-[N-[(S)-l-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(lS,3S,5S)-2-azabicyclo
[3.3.0]octane-3-carboxylic acid
(Hoe 498) in rat, dog and man. Arzneimittelforschung, 1984, 34:1435–1447. Meisel S, et al.
Clinical pharmacokinetics of ramipril. Clin Pharmacokinet, 1994, 26:7–15. PDR58, 2004, p.
2142. Song JC, et al. Clinical pharmacokinetics and selective pharmacodynamics of new
angiotensin converting enzyme inhibitors: An update. Clin Pharmacokinet, 2002, 41:207–224.
Thuillez C, et al. Pharmacokinetics, converting enzyme inhibition and peripheral arterial
hemodynamics of ramipril in healthy volunteers. Am J Cardiol, 1987, 59:38D–44D.
52 ± 11 69 ± 6 15 ± 3 10.4 ± 1.1 1.3 ± 0.4 2.1 ± 0.2 2.1 ± 0.31 a 462 ± 54 ng/mL a
a LD b RD b RD, Aged i Cirr, RD a RD, Cirr, Aged
i RD b Burn b Burn i Burn
a
Following a single 150-mg oral dose given to healthy adults. IC 50
for inhibition of gastric
acid secretion is 100 ng/mL.
Reference: Gladziwa U, et al. Pharmacokinetics and pharmacodynamics of H 2
-receptor
antagonists in patients with renal insufficiency. Clin Pharmacokinet, 1993, 24:319–332.