title: Clinical pharmacokinetics of darunavir.
abstract: Darunavir (TMC114) is a newly developed HIV-1 protease inhibitor with potent antiviral activity against both wild-type and multidrug resistant HIV-1 strains. The drug is currently approved by the US FDA for antiretroviral treatment-experienced patients with limited therapeutic options. The approved dosage of darunavir is 600 mg in combination with ritonavir 100mg twice daily. Darunavir is rapidly absorbed after oral administration, reaching peak plasma concentrations after 2.5-4 hours. Absorption is followed by a fast distribution/elimination phase and a subsequent slower elimination phase with a terminal elimination half-life of 15 hours in the presence of low-dose ritonavir. Darunavir is approximately 95% plasma protein bound, mainly to alpha(1)-acid glycoprotein. Systemic exposure is increased by 30% when darunavir is taken with a meal. Darunavir is extensively and almost exclusively metabolised by cytochrome P450 (CYP) 3A4. Coadministration with small doses of the strong CYP3A4 inhibitor ritonavir results in an increase in darunavir bioavailability from 37% to 82%. Darunavir and its metabolites are mainly excreted in faeces (79.5%) and, to a lesser extent, in urine (13.9%). With regard to the necessary coadministration with low-dose ritonavir as a potent CYP3A4 inhibitor, coadministration of other substrates of CYP3A4 with darunavir/ritonavir requires caution or is even contraindicated. Guidance is derived from drug-drug interaction trials and experience from comparable ritonavir-boosted protease inhibitor regimens.
authors: Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany.
authors: Michael
authors: M
authors: Rittweger
authors: Keikawus
authors: K
authors: Arastéh
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001682:Biological Availability; D000069454:Darunavir; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir
references: Antimicrob Agents Chemother. 2005 Jun;49(6):2314-21
references: 15917527
references: Cardiovasc Drugs Ther. 2001;15(3):211-8
references: 11713888
references: J Antimicrob Chemother. 2004 Jan;53(1):4-9
references: 14657084
references: Drug Alcohol Depend. 2000 Dec 22;61(1):47-54
references: 11064183
references: AIDS. 2007 Mar 30;21(6):F11-8
references: 17413685
references: J Acquir Immune Defic Syndr. 2007 Sep 1;46(1):24-31
references: 17621237
references: Drug Metab Dispos. 1999 Dec;27(12):1488-95
references: 10570031
references: N Engl J Med. 1997 Sep 11;337(11):725-33
references: 9287227
references: J Virol. 2004 Nov;78(21):12012-21
references: 15479840
references: Expert Opin Drug Saf. 2002 May;1(1):5-17
references: 12904155
references: Clin Infect Dis. 2003 Aug 15;37(4):476-82
references: 12905130
references: Acta Psychiatr Scand Suppl. 1989;350:152-5
references: 2530776
references: AIDS. 2007 Feb 19;21(4):395-402
references: 17301557
references: N Engl J Med. 1998 Mar 26;338(13):853-60
references: 9516219
references: AIDS. 2007 Jul 11;21(11):1449-55
references: 17589191
references: Clin Pharmacokinet. 2002;41(14):1195-211
references: 12405866
references: Antimicrob Agents Chemother. 2001 Dec;45(12):3445-50
references: 11709322
references: Antimicrob Agents Chemother. 2003 Jan;47(1):350-9
references: 12499212
references: Clin Pharmacol Ther. 2002 Jul;72(1):1-9
references: 12151999
references: Lancet. 2007 Apr 7;369(9568):1169-78
references: 17416261
references: Br J Clin Pharmacol. 2007 Nov;64(5):655-61
references: 17610528
references: Br J Clin Pharmacol. 2008 Apr;65 Suppl 1:54-9
references: 18333866
references: J Med Chem. 2005 Mar 24;48(6):1813-22
references: 15771427
references: Int Clin Psychopharmacol. 1995 Sep;10(3):129-41
references: 8675965
references: J Clin Pharmacol. 2007 Apr;47(4):479-84
references: 17389557
references: J Clin Pharmacol. 2004 Nov;44(11):1273-81
references: 15496645
references: Antimicrob Agents Chemother. 2007 Mar;51(3):958-61
references: 17210768
references: J Acquir Immune Defic Syndr. 2006 Nov 1;43(3):278-83
references: 17079992
references: AIDS. 1999 Sep 10;13(13):1623-7
references: 10509562
references: Antimicrob Agents Chemother. 2004 Jun;48(6):2091-6
references: 15155205
references: Antivir Ther. 2005;10(3):375-92
references: 15918329