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

1926
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
Emtricitabine a
Cap: 93 b 73 ± 4 c < 4 4.4 ± 0.8 c 3.5 ± 0.8 c 9.0 ± 0.9 c 2.0 ± 1.0 e 1.7 ± 0.8 μg/mL e
(78-99)
Sol: 75 b b RD d a RD d
a
Cleared primarily by renal excretion. b Data for capsule (Cap) and solution (Sol) formulations
presented. c Data from a 200-mg IV dose, as filed in NDA; V area
reported. d Study in patients
with mild to severe renal impairment and end-stage RD; CL reduced in parallel with decline in
CL cr
; removed by hemodialysis. e Following 200 mg, given once daily, to HIV-infected adults.
Enalapril a
41 ± 15 88 ± 7 b 50-60 4.9 ± 1.5 c 1.7 ± 0.7 c 11 d 3.0 ± 1.6 e 69 ± 37 ng/mL e
b LD b LD b RD, Aged, a RD, LD
CHF, Neo
a Child
i Fem
a
Hydrolyzed by esterases to the active metabolite, enalaprilic acid (enalaprilat); except when
noted, pharmacokinetic values and disease comparisons are for enalaprilat, following oral
enalapril administration. b For IV enalaprilat. c CL/F and V ss
/F after multiple oral doses of
enalapril. Values after single IV dose of enalaprilat are misleading because binding to ACE
leads to a prolonged t 1/2
, which does not represent a significant fraction of the CL upon multiple
dosing. d Estimated from the approach to steady state during multiple dosing. e Mean values
Enoxaparin a
References: Modrzejewski KA, et al. Emtricitabine: A once-daily nucleoside reverse transcriptase
inhibitor. Ann Pharmacother, 2004, 38:1006–1014. Drugs@FDA. Emtriva NDA
approved on 7/2/03. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/nda/
2003/21-500_Emtriva_BioPharmr_P2.pdf. Accessed May 17, 2010.
for enalaprilat following a 10-mg enalapril oral dose given daily for 8 days to healthy young
adults. The EC 50
for ACE inhibition is 5-20 ng/mL enalaprilat.
References: Lees KR, et al. Age and the pharmacokinetics and pharmacodynamics of chronic
enalapril treatment. Clin Pharmacol Ther, 1987, 41:597–602. MacFadyen RJ, et al. Enalapril
clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships. An overview.
Clin Pharmacokinet, 1993, 25:274–282.
SC: 92 — b — 0.3 ± 0.1 c 0.12 ± 0.04 c 3.8 ± 1.3 d 3 e ACLM: 145 ±
45 ng/mL e
b RD i RD a RD BCLM: 414 ±
87 ng/mL e
a
Enoxaparin consists of low-molecular-weight heparin fragments of varying lengths. b 43% is
recovered in urine when administered as 99 Tc-labeled enoxaparin; 8-20% anti-factor Xa activity.
c F, CL/F, and V area
/F for SC dose measured by functional assay for anti-factor Xa activity.
d
Measured by functional assay of anti-factor Xa activity. Using anti-IIa activity or displacement
binding assay gives a t 1/2
of ~1-2 hours. e Following a single 40-mg SC dose to healthy
adult subjects. High-affinity antithrombin III molecules: ACLM, above-critical-length
molecules (anti-factor Xa and IIa activity); BCLM, below-critical-length molecules (antifactor
Xa activity).
References: Bendetowicz AV, et al. Pharmacokinetics and pharmacodynamics of a low molecular
weight heparin (enoxaparin) after subcutaneous injection, comparison with unfractionated
heparin—A three way cross over study in human volunteers. Thromb Haemost, 1994, 71:305–313.
PDR54, 2000, p. 2561.