Penetration of HIV‐1 protease inhibitors into CSF and semen

Association of Saquinavir Plasma Concentrations with Side Effects but Not with Antiretroviral Outcome in Patients Infected with Protease Inhibitor-Susceptible Human Immunodeficiency Virus Type 1

“…2) was above the upper limit of 53.7 ng/ml of the in vitro IC 90 range (19) in all patients except for one, with a C min of 50 ng/ml. C min,saquinavir was below the proposed in vivo protein-binding corrected IC 95 of 278 ng/ml (3,24), but this was not predictive of the antiretroviral outcome. Although the plasma concentration-versus-time curves suggested a later T max in patients with therapy failure (Fig.…”

“…2 and Table 2) was not associated with therapeutic outcome in these patients, who either were antiretrovirally naïve or had a protease inhibitor-susceptible virus at baseline genotypic resistance testing, a poorer antiretroviral response with lower trough saquinavir concentrations was reported for patients who already had one failed protease inhibitor-containing therapy regimen (3). In that study, the values of C min were divided by the proposed protein-binding corrected "wild-type" IC 95 of saquinavir of 278 ng/ml (3,24), i.e., all values of C min by the same number, and the resulting ratio ranged from 0.12 to 3.24 (3), which agrees with the present range of this ratio of 0.18 to 7.91 (interquartile range, 0.83 to 3.1). This complements our advice to not monitor saquinavir plasma concentrations for antiretroviral efficacy in patients at the beginning of therapy with previously reported advice to do so in patients at later therapy stages (3).…”

Antiretroviral Tissue Kinetics: In Vivo Imaging Using Positron Emission Tomography

“…Suboptimal concentrations of antiviral drugs in target tissues can be the result of poor patient compliance with rigid and toxic drug regimens, drug interactions, and pharmacological barriers that limit the accessibility of drugs to critical target tissues and cell reservoirs. It is known that antiretroviral compounds have differential levels of penetration in certain anatomic compartments (45,46) and between subjects (43). While numerous examples of relationships between plasma pharmacokinetics of antiretroviral drugs and efficacy have been described (4,22), examples of relationships between pharmacokinetics and toxicity are limited.…”

Enantiomeric radiochemical synthesis of R and S (1‐(6‐amino‐9H‐purin‐9‐yl)‐3‐fluoropropan‐2‐yloxy)methylphosphonic acid (FPMPA)

“…It is known that antiretroviral compounds have differential penetrations in certain anatomic compartments 11,12 and between subjects 13 , raising the possibility that localized sub-optimal concentrations of one drug of the combination increases the probability of drug resistance strain generation 14 , a major cause of drug therapy failure in the population of HIV-1-infected patients. In order to be effective these drugs need to penetrate within cells, the intracellular concentration is the ultimate driving force to define antiviral efficacy.…”