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A high-performance liquid chromatographic method for the determination of the HIV protease inhibitor saquinavir in human plasma, saliva, and cerebrospinal fluid is described. Saquinavir was extracted from samples using C2 extraction columns prior to ion-pair, reversed-phase high-performance liquid chromatography with ultraviolet detection at 239 nm. The method has been validated over the range of 2.5-4000 ng/ml using a 0.6-ml sample volume. This assay has been used for the analysis of saquinavir in plasma and saliva of HIV-1-infected patients.

OBJECTIVE: To report a hypersensitivity reaction to etoposide occurring in a patient after 2 months of drug therapy. CASE SUMMARY: a 20-year-old man with a diagnosis of testicular carcinoma was treated with bleomycin, etoposide, and cisplatin (BEP regimen). After dose 20 of etoposide, an exanthema was noted, which was attributed to etoposide. The patient had received 19 doses of etoposide during the previous 2 months without any sign of an allergic reaction. Rechallenging the patient with etoposide from another batch resulted in recurrence of the exanthema. DISCUSSION: Both etoposide and its excipient (polysorbate 80) are suspected of causing hypersensitivity reactions. Although the exact mechanism of the hypersensitivity reaction is not known, it is believed to be of nonimmunogenic origin. CONCLUSIONS: With a lower rate of infusion of etoposide and/or by premedication with antihistamines and/or corticosteroids, hypersensitivity reactions to etoposide might be prevented in patients with a history of hypersensitivity to this drug.

Zidovudine is the cornerstone of current antiretroviral treatment of human immunodeficiency virus (HIV) infection. Its use, however, frequently leads to adverse reactions, including myelosuppression. Zidovudine pharmacokinetics show large interindividual variation with indications of pharmacokinetic-pharmacodynamic relationships, but a clear therapeutic window has not yet been defined. Individualisation of zidovudine therapy with monitoring of drug concentrations might be desirable. This review considers (intracellular) monitoring of zidovudine and anabolites for individualisation of zidovudine therapy and the achievements in describing pharmacokinetic-pharmacodynamic relationships so far.

It has been hypothesized that didanosine has a low efficacy in the prevention and treatment of patients with the dementia complex of acquired immunodeficiency syndrome (AIDS) because "... the drug has not been detected in the cerebrospinal fluid". We investigated didanosine concentrations in cerebrospinal fluid (CSF) and plasma of four patients with AIDS who were using didanosine chronically. Didanosine levels, 4 h after the last drug administration, averaged 0.16 (+/- 0.03) mumol/l in CSF and 0.70 (+/- 0.27) mumol/l in plasma. When compared with historical data from patients using zidovudine, didanosine concentrations in CSF appeared to be approximately half (on a molar base) those of zidovudine concentrations in the CSF. Whether this difference in CSF levels is the explanation for the presumed lower efficacy of didanosine in the prevention and treatment of AIDS dementia complex remains to be proven. However, it is clear from this study, in contrast with earlier suggestions, that didanosine is able to pass the blood-CSF barrier in human immunodeficiency virus-infected individuals.

There is a growing interest in therapeutic drug monitoring (TDM) of protease inhibitors (PIs) as a potential tool to optimize the treatment of HIV-infection, as recently discussed in this journal [1]. A prerequisite for the introduction of TDM is the definition of minimal effective concentrations. To date, the target concentrations of the PIs are largely unknown. Proposed minimal effective concentrations for the PI saquinavir range from 100 to 200 ng ml−1[1]. Results from the CHEESE study, however, suggest that the threshold concentration may be even lower for antiretroviral naive HIV-1-infected patients concomitantly treated with zidovudine (AZT) and lamivudine (3TC). In the CHEESE study, antiretroviral naive patients were treated with saquinavir soft-gelatin capsules 1200 mg three times daily (or indinavir 800 mg three times daily), in combination with AZT 200 mg three times daily plus 3TC 150 mg twice daily [2]. To explore pharmacokinetic–pharmacodynamic (PK–PD) relationships, blood samples for the quantification of saquinavir were obtained at regular intervals. Plasma concentrations of saquinavir were determined with a sensitive and validated assay [3]. The accuracy of this assay was confirmed in a cross-validation with a commercial contract laboratory using a radioimmunoassay. Three patients experienced virological treatment failure prior to week 48 (one had two plasma saquinavir concentrations below 100 ng ml−1, one had no concentrations below 200 ng ml−1, and no saquinavir concentrations were available from the remaining patient). Twenty-two patients (median baseline plasma HIV-1 RNA concentration (viral load) 4.99 log10 copies/ml), completed 48 weeks follow-up. After 48 weeks, 19/22 patients (86%) had a plasma viral load below 50 copies/ml. A total of 151 plasma saquinavir concentrations were available ranging from undetectable (four samples from three patients) to 3792 ng ml−1 (median 145 ng ml−1) (Figure 1). Figure 1 Scatterplot of the saquinavir plasma concentrations (n=151) obtained from 22 HIV-1 infected patients at regular intervals during a 48 week period. The patients used saquinavir soft gelatin capsules 1200 mg three times daily plus zidovudine and ... No PK–PD relationships were observed, possibly due to a lack of statistical power. Surprisingly, however, a potent and durable suppression of viral replication (

Objective To investigate the normalized inhibitory quotient (NIQ) of lopinavir (LPV) as a predictor of 48-week virological responses to a lopinavir/ritonavir (LPV/RTV)-containing regimen in highly treatment-experienced patients. Design We calculated the NIQ for 59 patients who completed 48 weeks’ treatment and assessed the factors predicting a week-48 virological response. Methods The NIQ was calculated by dividing each subject's IQ (LPV Ctrough/fold change in LPV susceptibility, as assessed by VirtualPhenotype™) by a reference IQ (mean population LPV Ctrough/fold change in LPV IC50, as assessed by VirtualPhenotype™). HIV-1 RNA was assessed by NASBA (quantification limit: 80 copies/ml). The general linear model and multiple logistic regression, respectively, were used to estimate the independent predictors of a change in viral load and HIV-1 RNA Results The median (interquartile range) baseline levels of CD4+ cells and HIV-1 RNA were 251 (141–385) cells/μl and 4.85 (4.49–5.23) log10 copies/ml, respectively. The median NIQ was 2.2 (0.5–14). At week 48, the median decrease in HIV-1 RNA was 1.4 (0.59–2.79) log10 copies/ml ( PConclusion The LPV NIQ independently predicts virological responses to an LPV/RTV-containing regimen in highly treatment-experienced HIV-1-infected patients.