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A new solid-phase extraction (SPE) method has been developed and validated on a liquid chromatography (LC) coupled with a mass spectrometer for the determination of plasma concentrations of tenofovir (TNF) and emtricitabine (FTC) in HIV infected patients. Chromatographic separation was achieved with a gradient (acetonitrile and water with formic acid 0.05%) on an Atlantis 4.6 mm × 150 mm, reversed phase analytical column. Detection of TNF, FTC, and internal standard (IS) was achieved by electrospray ionization mass spectrometry (ESI-MS) in the positive ion mode. Calibration ranged from 15.6 to 4000 ng/mL for TNF and 11.7 to 3000 ng/mL for FTC. Plasma was analyzed, and the limit of quantitation was 15.6 ng/mL for TNF and 11.7 ng/mL for FTC; limit of detection was 2 ng/mL for TNF and 1.5 ng/mL for FTC. Mean recovery of TNF, FTC, and IS were 46.5% [relative standard deviation (RSD): 8.8%] and 88.8% (RSD: 1.0%), and 81.7% (RSD: 3.1%), respectively. The method did not show any significant interference with antiretrovirals or other concomitant drugs administered to patients, and no significant “matrix effects” were observed. The method was applied for the determination of antiretroviral plasma concentration of HIV-positive patients treated with FTC and/or TNF, in combination with various other antiretrovirals. [ABSTRACT FROM AUTHOR] more...

Background Early virological response (VR) to enfuvirtide-based salvage regimens at week 12 has been described as a predictor of long-term therapeutic success. The relationship between enfuvirtide plasma exposure and VR has not yet been investigated in the clinical setting. Our aim was to investigate the role of enfuvirtide plasma exposure as a determinant of early VR in the clinical setting. Methods Forty-two multidrug-experienced patients starting a salvage enfuvirtide-based regimen were prospectively evaluated over a 12 week period. HIV-RNA levels and enfuvirtide Ctrough were regularly measured. VR was considered as achievement of viral load (VL) undetectability and/or a decrease of more than 1 log at week 12. Results Optimized background score (OBS) and enfuvirtide Ctrough concentrations were associated with VL decrease at week 12. An OBS ≥2 and enfuvirtide Ctrough >2100 ng/mL were associated with VR. The pharmacokinetic/pharmacodynamic (PK/PD) analysis confirmed this exposure–response relationship both in the total population and in different groups according to OBS 50 were calculated for the OBS I0 (0.31 versus 0.21 log) and Imax (−2.64 versus −3.33 log). Conclusions Enfuvirtide plasma exposure and OBS were found to significantly influence the magnitude and rate of early VR. The PK/PD modelling of enfuvirtide concentrations was different in our clinical setting, compared with previous data obtained under trial conditions. Therefore, optimization of enfuvirtide plasma exposure could deserve further evaluation as a determinant of therapeutic response in HIV-positive patients. [ABSTRACT FROM AUTHOR] more...

Background: We aimed to compare the steady-state pharmacokinetic parameters and tolerability of Triomune 40 (stavudine 40 mg, lamivudine 150 mg and nevirapine 200 mg) and branded formulations of these drugs in HIV-infected Ugandans., Methods: This includes a randomized, open-label, cross-over study of HIV-infected patients stable on therapy for 1 month. Patients were randomized to generic or branded formulation. Plasma pharmacokinetics were assessed after 1 month. The following day, alternate formulation was administered, and 1 month later, drug pharmacokinetics were re-assessed. Plasma pharmacokinetics were determined using HPLC-UV detection. Similarity between steady-state pharmacokinetic parameters was assessed using the US Food and Drug Administration standards for bioequivalency testing. Tolerability was assessed using questionnaires., Results: Sixteen (10 females) patients completed the study. Median (IQR) age, weight and CD4 count were 37 (33.7-40) years, 65 (63.4-66) kg and 292 (220.7-344.5) cells/mm(3), respectively. All patients received co-trimoxazole. The geometric mean ratio (90% CI) for stavudine, lamivudine and nevirapine was 0.92 (0.78-1.08), 1.11 (0.95-1.30) and 0.84 (0.64-1.11), respectively, for C(max), and 0.83 (0.70-0.97), 1.06 (0.94-1.20) and 0.88 (0.71-1.10), respectively, for AUC. Stavudine plasma concentrations were significantly lower for the generic formulation. Pharmacokinetic parameter inter-individual variability ranged from 29% to 99%. There were no differences in tolerability for the two formulations., Conclusions: Pharmacokinetic profiles of generic and branded drugs were similar. Differences particularly with regard to stavudine were demonstrated. Surveillance of the quality of generic antiretroviral drugs in the target populations is needed. Capacity building for pharmacokinetic research in resource-limited settings is a priority. more...