Abstract
HIV protease inhibitors, as components of combination antiretroviral drug regimens, have substantially reduced the morbidity and mortality associated with HIV infection. They selectively block the action of the virus-encoded protease and stop the virus from replicating. In general, these drugs have poor systemic bioavailability and must be dosed with respect to meals for optimal absorption. Protease inhibitor-containing regimens require ingestion of a large number of capsules, are costly, and produce or are susceptible to metabolic drug interactions. Simultaneous administration of two protease inhibitors takes advantage of beneficial pharmacokinetic interactions and may circumvent many of the drugs' undesirable pharmacologic properties. For example, ritonavir increases saquinavir concentrations at steady state by up to 30-fold, allowing reduction of saquinavir dose and dosing frequency. Ritonavir decreases the systemic clearance of indinavir and overcomes the deleterious effect of food on indinavir bioavailability. These benefits reflect inhibition of presystemic clearance and first-pass metabolism; as well as inhibition of systemic clearance mediated by hepatic cytochrome P450 3A4. Several dual protease inhibitor combination regimens have shown great promise in clinical trials and are now recommended as components of salvage therapy for HIV-infected patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 649-674 |
| Number of pages | 26 |
| Journal | Annual Review of Pharmacology and Toxicology |
| Volume | 40 |
| State | Published - 2000 |
Fingerprint
Keywords
- Cytochrome P450
- Drug interactions
- P- glycoprotein
- Pharmacodynamics
- Pharmacokinetics
ASJC Scopus subject areas
- Pharmacology
- Toxicology
Cite this
Dual protease inhibitor therapy in HIV-infected patients : Pharmacologic rationale and clinical benefits. / Flexner, Charles Williams.
In: Annual Review of Pharmacology and Toxicology, Vol. 40, 2000, p. 649-674.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dual protease inhibitor therapy in HIV-infected patients
T2 - Pharmacologic rationale and clinical benefits
AU - Flexner, Charles Williams
PY - 2000
Y1 - 2000
N2 - HIV protease inhibitors, as components of combination antiretroviral drug regimens, have substantially reduced the morbidity and mortality associated with HIV infection. They selectively block the action of the virus-encoded protease and stop the virus from replicating. In general, these drugs have poor systemic bioavailability and must be dosed with respect to meals for optimal absorption. Protease inhibitor-containing regimens require ingestion of a large number of capsules, are costly, and produce or are susceptible to metabolic drug interactions. Simultaneous administration of two protease inhibitors takes advantage of beneficial pharmacokinetic interactions and may circumvent many of the drugs' undesirable pharmacologic properties. For example, ritonavir increases saquinavir concentrations at steady state by up to 30-fold, allowing reduction of saquinavir dose and dosing frequency. Ritonavir decreases the systemic clearance of indinavir and overcomes the deleterious effect of food on indinavir bioavailability. These benefits reflect inhibition of presystemic clearance and first-pass metabolism; as well as inhibition of systemic clearance mediated by hepatic cytochrome P450 3A4. Several dual protease inhibitor combination regimens have shown great promise in clinical trials and are now recommended as components of salvage therapy for HIV-infected patients.
AB - HIV protease inhibitors, as components of combination antiretroviral drug regimens, have substantially reduced the morbidity and mortality associated with HIV infection. They selectively block the action of the virus-encoded protease and stop the virus from replicating. In general, these drugs have poor systemic bioavailability and must be dosed with respect to meals for optimal absorption. Protease inhibitor-containing regimens require ingestion of a large number of capsules, are costly, and produce or are susceptible to metabolic drug interactions. Simultaneous administration of two protease inhibitors takes advantage of beneficial pharmacokinetic interactions and may circumvent many of the drugs' undesirable pharmacologic properties. For example, ritonavir increases saquinavir concentrations at steady state by up to 30-fold, allowing reduction of saquinavir dose and dosing frequency. Ritonavir decreases the systemic clearance of indinavir and overcomes the deleterious effect of food on indinavir bioavailability. These benefits reflect inhibition of presystemic clearance and first-pass metabolism; as well as inhibition of systemic clearance mediated by hepatic cytochrome P450 3A4. Several dual protease inhibitor combination regimens have shown great promise in clinical trials and are now recommended as components of salvage therapy for HIV-infected patients.
KW - Cytochrome P450
KW - Drug interactions
KW - P- glycoprotein
KW - Pharmacodynamics
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=0034128937&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034128937&partnerID=8YFLogxK
M3 - Article
C2 - 10836150
AN - SCOPUS:0034128937
VL - 40
SP - 649
EP - 674
JO - Annual Review of Pharmacology and Toxicology
JF - Annual Review of Pharmacology and Toxicology
SN - 0362-1642
ER -