We studied the effect of rifampicin on steady-state pharmacokinetics of nevirapine and the impact of increasing the dose of nevirapine on its peak (Cmax) and trough (Cmin) levels in 13 HIV-infected patients on regular antiretroviral treatment with nevirapine-containing regimens (200 mg twice daily). A baseline pharmacokinetic study was conducted and repeated after 1 week of daily rifampicin (450/600 mg). The study was repeated in 7 of 8 patients who had subtherapeutic Cmin nevirapine levels after increasing nevirapine dose to 300 mg twice daily. Liver function was monitored. Rifampicin caused significant reductions in Cmax (42%), Cmin (53%), and exposure (46%) of nevirapine (P <.01). The Cmin of nevirapine fell below the therapeutic range of 3 microg/ml in 8 of 13 patients. An increase of nevirapine to 300 mg twice daily raised Cmin to therapeutic range in all 7 patients without exceeding the toxic level of 12 microg/mL. There were no clinical or laboratory adverse events. Our findings suggest that decreased bioavailability of nevirapine because of rifampicin coadministration could be overcome by increasing the dose of nevirapine from 200 to 300 mg twice daily without short-term adverse events. Further studies to evaluate the long-term safety of higher dose of nevirapine are required.

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Background and Objectives:A variety of demographic factors, sex, and degree of immunosuppression can influence antiretroviral drug concentrations. The authors studied the influence of immune status, sex, and body mass index (BMI) on the steady-state pharmacokinetics of nevirapine delivered as a fixed-dose combination in HIV-1-infected patients in India. Methods: Twenty-six HIV-1-infected adult patients undergoing treatment with nevirapine-based highly active antiretroviral therapy regimens participated in the study. Pharmacokinetic variables were compared between patients divided based on CD4 cell counts, sex, and BMI. Results: Patients with higher BMI had lower peak and trough concentration and exposure of nevirapine than those with lower BMI; none of the differences in the pharmacokinetic variables of nevirapine between the various patient groups was statistically significant. Conclusions: Patients' immune status, sex, or BMI had no impact on the pharmacokinetics of nevirapine. Plasma nevirapine concentrations were maintained within the therapeutic range of the drug in the majority of the patients.Keywords: pharmacokinetics; nevirapine; India; immune status; sex; BMI Access to antiretroviral drugs for HIV-1-infected patients in developing countries is a global public health priority. The World Health Organization currently recommends first-line therapy with 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-NRTI (NNRTI)⎯a combination with good efficacy, tolerability, simplicity, and low cost. 1 Generic fixed-dose combinations (FDCs) of such regimens are widely regarded as crucial for scaling up AIDS treatment in developing countries. Two triple-drug combinations consisting of nevirapine and lamivudine with either stavudine or zidovudine as the third agent are available as FDCs in the developing world. A vast majority of HIV-infected patients in India receive nevirapine-based highly active antiretroviral therapy (HAART), the common co-drugs being lamivudine and stavudine. 2 A few studies have reported the effectiveness and safety of generic FDCs for treatment of HIV-1-infected adults. [2][3][4][5] It has been suggested that a variety of demographic factors such as age, body size, and weight can influence antiretroviral drug concentrations. 6 Sex-based differences in the pharmacokinetics of nevirapine have also been observed. 7 Keating et al reported that malabsorption correlates significantly with the degree of immunosuppression. 8 We undertook a study to obtain information on the pharmacokinetics of nevirapine in HIV-infected patients on treatment with FDCs in India, as well as the influence of immunological status, sex, and body mass index (BMI) on the pharmacokinetics of these drugs, as very limited information is available on this aspect. Methods PatientsThe study participants were composed of HIV-infected patients of ethnic Indian origin who were participating in a controlled clinical trial and were being followed

Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). The present work reports the design and synthesis of a hybrid of the precursors of rifampicin and clofazimine, which led to the discovery of a novel Rifaphenazine (RPZ) molecule with potent anti-TB activity. In addition, the efficacy of RPZ was evaluated in-vitro using the reference strain Mtb H37Rv. Herein, 2,3 diamino phenazine, a precursor of an anti-TB drug clofazimine, was tethered to the rifampicin core. This 2,3 diamino phenazine did not have an inherent anti-TB activity even at a concentration of up to 2 µg/mL, while rifampicin did not exhibit any activity against Mtb at a concentration of 0.1 µg/mL. However, the synthesized novel Rifaphenzine (RPZ) inhibited 78% of the Mtb colonies at a drug concentration of 0.1 µg/mL, while 93% of the bacterial colonies were killed at 0.5 µg/mL of the drug. Furthermore, the Minimum Inhibitory Concentration (MIC) value for RPZ was 1 µg/mL. Time-kill studies revealed that all bacterial colonies were killed within a period of 24 h. The synthesized novel molecule was characterized using high-resolution mass spectroscopy and NMR spectroscopy. Cytotoxicity studies (IC50) were performed on human monocytic cell line THP-1, and the determined IC50 value was 96 µg/mL, which is non-cytotoxic.

Background Malabsorption of drugs from the gastro‐intestinal tract due to HIV enteropathy and concurrent infections could lower the bioavailability of anti‐tuberculosis (TB) drugs in HIV infected individuals. Our aim was to study the pharmacokinetics of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) in HIV infected Indian subjects. The D‐xylose absorption test was also performed in all the patients. Method We studied 13 patients with smear positive pulmonary TB, 13 with HIV & diarrhoea and 14 with HIV & TB. Rifampicin (450mg), INH (600mg), PZA (1500mg) and EMB (1200mg) were administered orally. The plasma levels of RMP and INH at different time points and urinary levels of all drugs/metabolites were estimated. Results A significant decrease in peak concentrations of RMP in HIV & diarrhoea and HIV & TB patients was observed when compared to patients with TB, the values being 3.23, 3.27 & 8.27μg/ml respectively (P<0.001). Significant decrease in AUC of RMP was also observed in HIV patients. The bioavailability of INH was reduced in rapid acetylators in HIV patients with and without TB. The urinary excretion of all four drugs/metabolites and D‐xylose was reduced in both HIV groups of patients. Conclusion Patients with HIV & TB and/or diarrhoea have decreased bioavailability of first line anti‐TB drugs. This could have implications for TB treatment of HIV infected patients. Clinical Pharmacology & Therapeutics (2004) 75, P29–P29; doi: