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

Entacapone a
42 ± 9 b Negligible 98 10.3 ± 1.74 0.40 ± 0.16 0.28 ± 0.06 d 0.8 ± 0.2 e 4.3 ± 2.0 μg/mL e
a LD c
i RD, LD
a
Data from healthy male subjects. Eliminated primarily by biliary excretion. b The bioavailability
of entacapone appears to be dose dependent (increases from 29-46% over a 50- to 800-mg
dose range). c Increased bioavailability, moderate hepatic impairment with cirrhosis. d Value
represents the t 1/2
for the initial distribution phase, during which 90% of a dose is eliminated.
The terminal t 1/2
is 2.9 ± 2.0 hours. e Following a single 400-mg oral dose. No accumulation
with multiple dosing.
Eplerenone a
— 7 b 33-60 c 2.4 d 0.6-1.3 d 4-6 1.8 ± 0.7 e 1.0 ± 0.3 μg/mL e
b CHF, LD
a
Eplerenone is converted (reversibly) to an inactive ring-open hydroxy acid. Both eplerenone
(E) and the hydroxy acid (EA) circulate in plasma; concentrations of E are much higher than
EA. Irreversible metabolism is catalyzed predominantly by CYP3A4. Data for E in healthy
male and female volunteers reported; no significant gender differences. b Recovered as E and
EA following an oral dose. c Protein binding is concentration dependent over the therapeutic
range; lower at the highest concentration. d CL/F and V ss
/F reported. e Following a 50-mg oral
dose given once daily for 7 days.
Erlotinib a
References: Holm KJ, et al. Entacapone. A review of its use in Parkinson’s disease. Drugs,
1999, 58:159–177. Keränen T, et al. Inhibition of soluble catechol-O-methyltransferase and
single-dose pharmacokinetics after oral and intravenous administration of entacapone. Eur J
Clin Pharmacol, 1994, 46:151–157.
59 (55-66) — 93 (92-95) 1.0 ± 0.4 c 1.2 ± 0.25 f 36 g 2-4 h 1.1-1.7 μg/mL h
a Food b
a Smk d
i LD e
a
Erlotinib is cleared primarily by CYP3A- and CYP1A2-dependent metabolism.
b
Bioavailability increases to ~100% when taken with a meal; not recommended because food
effect is highly variable. c Calculated from a 25-mg IV dose; in a population pharmacokinetic
study of 150 mg, once daily, CL/F = 0.98 mL/min/kg. d Systemic exposure reduced by half
compared to nonsmokers. e Study in patients with moderate LD; no data for severe hepatic
impairment. f Calculated from a 25-mg IV dose; in a population pharmacokinetic study of
150-mg once daily, V/F = 3.5 L/kg. g Median t 1/2
in a patient population receiving 150-mg
orally once daily; a shorter t 1/2
of 13 hours was reported for a single 25-mg IV dose.
h
Following 150-mg given once daily to steady state.
References: Clinical Pharmacology and Biopharmaceutics Review. Application 21-437/S-002.
U.S. Food and Drug Administration Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra.cfm. Accessed July
9, 2010. Cook CS, et al. Pharmacokinetics and metabolism of [14C]eplerenone after oral
administration to humans. Drug Metab Dispos, 2003, 31:1448–1455. Product information:
Inspra TM (eplerenone tablets). Chicago, IL, Pfizer, 2004.
References: Frohna P, et al. Evaluation of the absolute oral bioavailability and bioequivalence
of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized,
crossover study in healthy subjects. J Clin Pharmacol, 2006, 46:282–290. Lu JF, et al.
Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship
in patients with non-small cell lung cancer. Clin Pharmacol Ther, 2006, 80:136–134.
Drugs@FDA. Tarceva NDA and label; label approved on 4/27/09. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva.cfm. Accessed
May 17, 2010.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
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