Presence of Tablet Remnants of Nevirapine Extended-Release in Stools and Its Impact on Virological Outcome in HIV-1-Infected Patients: A Prospective Cohort Study.

BACKGROUND: Nevirapine extended-release (NVP-XR) taken once daily remains an effective antiretroviral agent for patients infected with HIV-1 strains that do not harbor resistance mutations. Presence of tablet remnants of NVP XR in stools was reported in 1.19% and 3.05% of subjects in two clinical trials. However, the prevalence may have been underestimated because the information was retrospectively collected in the studies. METHODS: Between April and December 2014, we prospectively inquired about the frequency of noticing tablet remnants of NVP XR in stools in HIV-1-infected patients who switched to antiretroviral regimens containing NVP XR plus 2 nucleos(t)ide reverse-transcriptase inhibitors. Patients were invited to participate in therapeutic drug monitoring of plasma concentrations of NVP 12 or 24 hours after taking the previous dose (C12 and C24, respectively) of NVP XR using high-performance liquid chromatography. The information on clinical characteristics, including plasma HIV RNA load and CD4 lymphocyte count, at baseline and during follow-up was recorded. RESULTS: During the 9-month study period, 272 patients switched to NVP XR-based regimens and 60 (22.1%) noticed tablet remnants of NVP XR in stools, in whom 54.2% reported noticing the tablet remnants at least once weekly. Compared with patients who did not notice tablet remnants, those who noticed tablet remnants had a higher mean CD4 lymphocyte count (629 vs 495 cells/mm3, P = 0.0002) and a similar mean plasma HIV RNA load (1.57 vs 1.61 log10 copies/mL, P = 0.76) on switch. At about 12 and 24 weeks after switch, patients who noticed tablet remnants continued to have a similar mean plasma HIV RNA load (1.39 vs 1.43 log10 copies/mL, P = 0.43; and 1.30 vs 1.37 log10 copies/mL, P = 0.26, respectively), but had a lower median NVP C12 (3640 vs 4730 ng/mL, P = 0.06), and a similar median NVP C24 (3220 vs 3330 ng/ml, P = 0.95) when compared with those who did not notice tablet remnants. CONCLUSIONS: The presence of tablet remnants of NVP XR in stools is not uncommon in HIV-1-infected Taiwanese patients receiving NVP XR-based antiretroviral regimens, which does not have an adverse impact on the virological and immunological outcomes.

Persistence of nevirapine in breast milk after discontinuation of treatment.

The objective of this study was to serially quantitate the concentration of nevirapine in breast milk after discontinuation of treatment. Samples were collected from both breasts of a human immunodeficiency virus-infected patient for 3 weeks. Nevirapine was quantifiable for up to 17 days after discontinuation of therapy; total nevirapine concentrations remained above the 90% inhibitory concentration for 6 days, and no differences were observed between breasts.

Effect of system variables involved in packed column SFC of nevirapine as model analyte using response surface methodology: application to retention thermodynamics, solute transfer kinetic study and binary diffusion coefficient determination.

A multifactor optimization technique is successfully applied to study the effect of simultaneously varying the system variables on feasibility of nevirapine analysis by packed column supercritical fluid chromatography (PC-SFC). The optimal conditions were determined with the aid of the response surface methodology using 3(3) factorial designs. The method is based on methanol-modified carbon dioxide as the mobile phase at flow rate of 3.0 ml/min with elution through a JASCO Finepak SIL-5, [C18 (5-micron, 25 cm x 4.6 mm, i.d.)] column using photodiode array detection. The method has been successfully used to analyze commercial solid dosage form to assess the chromatographic performance of SFC system. The present work briefs the thermodynamic applications of PC-SFC with an emphasis on the results of nevirapine. The foremost of such applications is the determination of solute diffusion coefficient in supercritical mobile phase by Taylor-Aris peak broadening technique.

Determination of lamivudine/didanosine/nevirapine in human serum using capillary zone electrophoresis.

A combination of the anti-HIV drugs lamivudine (3TC), didanosine (ddI), and nevirapine were separated and quantitated in human serum with capillary zone electrophoresis (CZE). The effects of various factors such as run buffer concentration and pH on the separation were investigated. The optimized resolution was achieved with a run buffer containing 100 nM N,N-dimethyloctylamine in 80 mM phosphate buffer (pH 2.5). Diltiazem was chosen as the internal standard. All analytes were separated within 10 min at 30 degrees C with a voltage of +20 kV and UV detection at 210 nm.

Validation of a high-performance liquid chromatography method for the assay of and determination of related organic impurities in nevirapine drug substance.

Nevirapine (Viramune), a dipyridiodiazepinone, is a potent and highly specific nonnucleoside inhibitor of HIV-1 reverse transcriptase. This paper describes the validation of a specific, sensitive, and stability-indicating high-performance liquid chromatography method for the assay and determination of related organic impurities in nevirapine drug substance. This method uses a Supelcosil LC-ABZ column, a mobile phase of 20:80 (v/v) acetonitrile-25mM NH4H2PO4 (pH 5.0), and ultraviolet detection at a wavelength of 220 nm. This method was validated for specificity, linearity, accuracy, repeatability, detection limit, quantitation limit, stability of analyte solutions, robustness, and intermediate precision. Nevirapine is completely separated from all impurities. The method is shown to be linear with coefficients of determination r2 greater than 0.999. Average accuracy is 100.4% with a relative standard deviation of 0.7% for the assay. Accuracy ranges from 100.1 to 102.6% for related organic impurities. Repeatability is good, with relative standard deviations not more than 1.4%. The detection limit and the quantitation limit are determined to be 0.001 and 0.003%, respectively. Relative response factors of known organic impurities are determined, permitting the use of nevirapine at the 0.1% level as an external standard for the quantitation of these impurities. Analyte solutions are shown to be stable for at least 2 days at ambient temperature. The method is validated as robust, and intermediate precision is high. A system suitability test is developed and validated, and requirements are set.