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

Simvastatin a
≤5 Negligible 94 7.6 b — 2-3 AI: 1.4 ± 1.0 c AI: 46 ± 20 ngEq/mL c
a
Simvastatin is a lactone prodrug that is hydrolyzed to the active corresponding β-hydroxy
acid. Values reported are for the disposition of the acid. b The β-hydroxy acid can be reconverted
back to the lactone; irreversible oxidative metabolites are generated by CYP3A. c Data
for active inhibitors (AI, ring-opened molecule) and total inhibitors (TI) following a 40-mg
oral dose given once daily for 17 days to healthy adults.
Sirolimus a
TI: 1.4 ± 1.0 c
TI: 56 ± 25 ngEq/mL c
~15 b — 40 c 3.47 ± 1.58 d 12 ± 4.6 d 62.3 ± 16.2 d SD: 0.81 ± SD: 67 ± 23 ng/mL e
0.17 e
a Food b MD: 1.4 ± MD: 94-210 ng/mL e
a
Data from male and female renal transplant patients. All subjects were on a stable cyclosporine
regimen. Sirolimus is metabolized primarily by CYP3A and is a substrate for P-glycoprotein.
Several sirolimus metabolites are pharmacologically active. b Cyclosporine co-administration
increases sirolimus bioavailability. F increased by high-fat meal. c Concentrates in blood cells;
blood-to-plasma concentration ratio ~38 ± 13. d Blood CL/F, V ss
/F, and t 1/2
reported for oral
dose. e Following a single 15-mg oral dose (SD) in healthy subjects and 4- to 6.5-mg/m 2 oral
dose (with cyclosporine) given twice daily to steady state (MD) in renal transplant patients.
Sitagliptin a
References: Corsini A, et al. New insights into the pharmacodynamic and pharmacokinetic
properties of statins. Pharmacol Ther, 1999, 84:413–428. Desager JP, et al. Clinical pharmacokinetics
of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin
Pharmacokinet, 1996, 31:348–371. Mauro VF. Clinical pharmacokinetics and practical
applications of simvastatin. Clin Pharmacokinet, 1993, 24:195–202.
87 ± 5.2 73.1 ± 15.9 38 4.42 b – 13.9 ± 2.0 1.5 ± 1.3 1046 ± 286 nM d
b RD c
i LD
a
Cleared primarily by the kidney. b Renal clearance is ~350 mL/min, which indicates active
tubular secretion, possibly mediated by human Organic Anion Transporter-3 (OAT3) and
P-glycoprotein (ABCB1). c Apparent oral clearance increased by a respective 2.3-, 3.8- and
4.5-fold in patients with moderate (CL cr
= 30-50 mL/min) and severe (<30 mL/min) renal
insufficiency and in patients with end-stage RD requiring hemodialysis. d Following a single
100-mg oral dose. Plasma AUC increased by ~14% following daily doses of 100 mg at steady
state compared to the first dose.
References: Bergman A, et al. Absolute bioavailability of sitagliptin, an oral dipeptidyl
peptidase-4 inhibitor, in healthy volunteers. Biopharm Drug Dispos, 2007, 28:315–22.
References: Kelly PA, et al. Conversion from liquid to solid rapamycin formulations in stable
renal allograft transplant recipients. Biopharm Drug Dispos, 1999, 20:249–253. Zimmerman
JJ, et al. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral
dose administration. J Clin Pharmacol, 1997, 37:405–415. Zimmerman JJ, et al. The effect of
a high-fat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin).
J Clin Pharmacol, 1999, 39:1155–1161.
Bergman AJ, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a
dipeptidyl peptidase-4 inhibitor. Diabetes Care, 2007, 30:1862–1864. Drugs@FDA. Januvia
label approved on 7/22/08. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
index.cfm. Accessed on December 26, 2009. Migoya EM, et al. Effect of moderate hepatic
insufficiency on the pharmacokinetics of sitagliptin. Can J Clin Pharmacol, 2009,
16:e165–e170. Vincent SH, et al. Metabolism and excretion of the dipeptidyl peptidase 4
inhibitor [ 14 C]sitagliptin in humans. Drug Metab Dispos, 2007, 35:533–538.
1.2 e
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
1977