Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
RITONAVIR - CLINICAL PHARMACOKINETICS AND INTERACTIONS WITH OTHER ANTI-HIV AGENTS
Autore:
HSU A; GRANNEMAN GR; BERTZ RJ;
Indirizzi:
ABBOTT LABS,D4PK,AP13A,100 ABBOTT PK RD ABBOTT PK IL 60064
Titolo Testata:
Clinical pharmacokinetics
fascicolo: 4, volume: 35, anno: 1998,
pagine: 275 - 291
SICI:
0312-5963(1998)35:4<275:R-CPAI>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN LIVER-MICROSOMES; PROTEASE INHIBITOR; IN-VITRO; CYTOCHROME-P450 3A4; ANTIRETROVIRAL THERAPY; DRUG-INTERACTIONS; INFECTION; COMBINATION; METABOLISM;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
124
Recensione:
Indirizzi per estratti:
Citazione:
A. Hsu et al., "RITONAVIR - CLINICAL PHARMACOKINETICS AND INTERACTIONS WITH OTHER ANTI-HIV AGENTS", Clinical pharmacokinetics, 35(4), 1998, pp. 275-291

Abstract

Ritonavir is 1 of the 4 potent synthetic HIV protease inhibitors, approved by the US Food and Drug Administration (FDA) between 1995 and 1997, that have revolutionised HIV therapy. The extent of oral absorption is high and is not affected by food. Within the clinical concentration range, ritonavir is approximately 98 to 99% bound to plasma proteins, including albumin and alpha(1)-acid glycoprotein, Cerebrospinal fluid (CSF) drug concentrations are low in relation to total plasma concentration. However, parallel decreases in the viral burden have been observed in the plasma, CSF and other tissues. Ritonavir is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Four major oxidative metabolites have been identified in humans, but are unlikely to contribute to the antiviral effect. About 34% and 3.5% of a 600mg dose is excreted as unchanged drug in the faeces and urine, respectively. The clinically relevant t1/2 beta is about3 to 5 hours. Because of autoinduction, plasma concentrations generally reach steady state 2 weeks after the start of administration. The pharmacokinetics of ritonavir are relatively linear after multiple doses, with apparent oral clearance averaging 7 to 9 L/h.. In vitro, ritonavir is a potent inhibitor of CYP3A. in vivo, ritonavir significantly increases the AUC of drugs primarily eliminated by CYP3A metabolism (e.g. clarithromycin, ketoconazole, rifabutin, and other HIV protease inhibitors, including indinavir, saquinavir and nelfinavir) with effectsranging from an increase of 77% to 20-fold in humans. It also inhibits CYP2D6-mediated metabolism, but to a significantly lesser extent (145% increase in desipramine AUC). Since ritonavir is also an inducer ofseveral metabolising enzymes [CYP1A4, glucuronosyl transferase (GT), and possibly CYP2C9 and CYP2C19], the magnitude of drug interactions is difficult to predict, particularly for drugs that are metabolised bymultiple enzymes or have low intrinsic clearance by CYP3A. For example, the AUC of CYP3A substrate methadone was slightly decreased and alprazolam was unaffected. Ritonavir is minimally affected by Ether CYP3Ainhibitors, including ketoconazole. Rifampicin (rifampin), a potent CYP3A inducer, decreased the AUC of ritonavir by only 35%. The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals. Combination treatment of ritonavir with saquinavir and indinavir results in potent ans sustained clinical activity. Other important factors with combination regimens include reduced interpatient variability for high clearance agents, and elimination of the food effect on the bioavailability of indinavir.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 12:42:15