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
Paclitaxel a
Low 5 ± 2 88-98 b 5.5 ± 3.5 2.01 ± 1.2 31 ± 1 c — 0.85 ± 0.21 μM d
i Child
i Child
a
Metabolized by CYP2C8 and CYP3A, and substrate for P-glycoprotein. b Binding of drug to
dialysis filtration devices may lead to overestimation of protein binding fraction (88% suggested).
c Average accumulation t 1/2
; longer terminal t 1/2
up to 50 hours are reported. d Steadystate
concentration during a 250-mg/m 2 IV infusion given over 24 hours to adult cancer patients.
Paliperidone a
28 (oral ER) b,c 59 (51-67) 74 3.70 ± 1.04 d 9.1 d (oral ER) 28.4 ± 5.1 d 22 (2.0-24) d 10.7 ± 3.3 ng/mL d
(oral ER) b LD a LD e (oral ER) (oral ER) (oral ER)
25-49 days 13 days
(IM PP) f
(IM PP)
a
Paliperidone, otherwise known as the 9-hydroxy active metabolite of risperidone, is marketed
as an oral extended-release (ER) tablet (INVEGA) or in the form of its water-insoluble palmitate
ester as a once-monthly long-acting IM injection (INVEGA SUSTENNA). Paliperidone is a racemate;
its enantiomers have similar pharmacological profiles. The (+) and (–)-enantiomers of
paliperidone interconvert, reaching an AUC (+) to (–) ratio of ~1.6 at steady state. b High-fat/
high-caloric meal increased C max
and AUC by 60% and 54%, respectively. c No data on the
absolute bioavailability of IM paliperidone palmitate (IM PP). The initiation regimen for
INVEGA SUSTENNA (234 mg/156 mg in the deltoid muscle on day 1/day 8) produces paliperidone
concentrations matching the range observed with 6- to 12-mg oral ER paliperidone.
d
At steady-state during once-daily doses of 3 mg, assuming an average body weight of 73 kg.
Pantoprazole a
Reference: Sonnichsen DS, et al. Clinical pharmacokinetics of paclitaxel. Clin
Pharmacokinet, 1994, 27:256–269.
V z
is estimated from CL/F and t 1/2
. e Patients with moderate hepatic impairment showed a
modest increase in clearance and plasma free fraction with no significant change in unbound
AUC. f The apparent long terminal t 1/2
of paliperidone following IM depot injection reflects
the slow dissolution of paliperidone palmitate and release of active paliperidone.
References: Boom S, et al. Single- and multiple-dose pharmacokinetics and dose proportionality
of the psychotropic agent paliperidone extended release. J Clin Pharmacol, 2009,
49:1318–1330. Drugs@FDA. Invega label approved on 4/27/07; Invega Sustenna label
approved on 7/31/09. Available at: http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/.
Accessed on January 1, 2010.
77 (67-89) — b 98 2.8 ± 0.9 0.17 ± 0.04 1.1 ± 0.4 2.6 ± 0.9 2.5 ± 0.7 μg/mL c
b LD
a LD
i RD
i Aged
a
Pantoprazole is cleared primarily by CYP2C19 (polymorphic)-dependent metabolism. Poor
metabolizers (PM) exhibit profound differences in CL (lower) and t 1/2
(higher), compared to
extensive metabolizers (EM). Pantoprazole is available as a racemic mixture of (+) and (–)
isomers. In CYP2C19 EM, no significant differences in the pharmacokinetics of (+) and (–)
pantoprazole were observed, whereas in CYP2C19 PM, the CL of (–) pantoprazole was
significantly greater than that of (+) pantoprazole. b No unchanged drug recovered in urine.
c
Following a single 40-mg oral dose.
References: Drugs@FDA. Protonix label approved on 11/12/09. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 26,
2009. Huber R, et al. Pharmacokinetics of lansoprazole in man. Int J Clin Pharmacol Ther,
1996, 34:185–194. Pue MA, et al. Pharmacokinetics of pantoprazole following single intravenous
and oral administration to healthy male subjects. Eur J Clin Pharmacol, 1993,
44:575–578. Tanaka M, et al. Stereoselective pharmacokinetics of pantoprazole, a proton
pump inhibitor, in extensive and poor metabolizers of S-mephenytoin. Clin Pharmacol Ther,
2001, 69:108–113.