Therapeutic Drug Monitoring of HIV Protease Inhibitors Using High-Performance Liquid Chromatography With Ultraviolet or Photodiode Array Detection

Abstract

Published data suggest that therapeutic drug monitoring of human immunodeficiency virus protease inhibitors would improve the management of antiretroviral therapy. The authors have developed a high-pressure liquid chromatographic assay allowing simultaneous determination of six protease inhibitors (ritonavir, saquinavir, indinavir, nelfinavir, amprenavir, and lopinavir), using carbamazepine as internal standard. Detection was based on a dual wavelength ultraviolet spectrophotometer and can be improved by the use of a photodiode array detector. Monitoring was performed 1 month after initiation of therapy or in instances of therapeutic failure, side effects, suspicion of noncompliance, drug interactions, or malabsorption. Trough concentrations were 0.15 to 13.6 mg/L for ritonavir, 0.06 to 9.7 mg/L for indinavir, 0.03 to 5.5 mg/L for saquinavir, and 0.15 to 4.15 mg/L for nelfinavir. Concentrations below the limit of quantification were observed in 63/438 (14%) of the patients. Target concentrations are not well established, and reported in vitro inhibitory concentrations may be of limited value. The authors therefore chose to compare observed concentrations with mean plasma concentrations reported in clinical trials. Observed saquinavir and indinavir concentrations were often below or close to these target concentrations, particularly when used as a single protease inhibitor. Concentration-controlled studies should now be used to select proper target concentrations for each protease inhibitor, either prescribed alone or in combination.

Therapeutic Drug Monitoring of the HIV/AIDS Drugs Abacavir, Zidovudine, Efavirenz, Nevirapine, Indinavir, Lopinavir, and Nelfinavir

“…Other reports showed a median trough concentration of nelfinavir of 0.96-1.5 Ìg/ ml, depending on dose and combination with saquinavir [20], or of 2.56 Ìg/ml [29]. The combination of nelfinavir with a low dose of ritonavir has been shown to increase nelfinavir exposure by 20-39% in healthy people [31].…”

“…Indinavir given without ritonavir has a half-life of 2 h. The trough concentrations for indinavir under steady Donnerer/Kronawetter/Kapper/Haas/ Kessler state conditions are reported to be 0.06-9.7 Ìg/ml, with a median of 0.64 Ìg/ml, when given in combination with ritonavir as a pharmacoenhancer [20]. Others reported a mean trough concentration for indinavir of 0.48 Ìg/ml [28] or around 1.0 Ìg/ml [18].…”

“…Indinavir: peak levels are achieved at 1-2 h, trough levels at 8-12 h [17,18]. Lopinavir: peak levels are achieved 2-4 h after ingestion [19], trough levels after 8 -12 h. Nelfinavir: peak levels are achieved at 1.5-3 h, trough levels at 8-12 h [20].…”

Simultaneous liquid chromatographic analysis of ritonavir, quinine and 3-hydroxyquinine in human plasma

“…In order to successfully conduct any therapeutic drug monitoring, a suitable analytical procedure must be available. Several assay methods are available for determination of ritonavir and quinine separately in biological fluids [7][8][9][10] but there is no reported method for the simultaneous determination of both drugs. Several studies have established associations between plasma concentrations of protease inhibitors and their antiviral effects [11][12][13], suggesting a role for therapeutic monitoring of these drugs.…”

Drug Monitoring and Viral Response to Lopinavir/Ritonavir or Saquinavir/Ritonavir Containing Regimens in Individuals Infected with the Human Immunodeficiency Virus Type1

“…CYP 450 is responsible for numerous interactions between PIs and other drugs. Serum concentrations are decreased by coadministration of CYP3A4 inducers or increased by CYP3A4 inhibitors (3). Certain combinations Therapeutic drug monitoring (TDM) is a helpful tool to avoid supratherapeutic antiretroviral serum levels, which might cause side effects (5-7).…”