In rheumatoid arthritis (RA), interleukin-6 (IL-6) concentration is elevated, which may cause reduced cytochrome P450 (CYP) activity and increased exposure (peak plasma concentration and area under the plasma concentration-vs.-time curve (AUC)) to certain drugs. Tocilizumab may reverse IL-6-induced suppression of CYP3A4 activity. In this study, exposure to simvastatin was significantly reduced at 1 and 5 weeks after tocilizumab infusion in 12 patients with RA. The mean effect ratio for simvastatin AUC(last) was 43% (90% confidence interval (CI), 34-55%) at 1 week after tocilizumab infusion (day 15) and 61% (90% CI, 47-78%) at 5 weeks after tocilizumab infusion, as compared with baseline (day 1); both ratios were significantly lower than the bioequivalence boundary (80-125%). Mean plasma C-reactive protein (CRP) levels normalized within 1 week after tocilizumab was initiated; the time course of tocilizumab's CRP-reducing effect paralleled that of simvastatin pharmacokinetics. The study findings suggest that caution should be exercised when starting tocilizumab in RA patients who are taking simvastatin.
Objective Enfuvirtide (ENF, T‐20, Fuzeon®) is the first of a novel class of HIV drugs which block gp41‐mediated viral fusion to host cells and has been recently approved by both the FDA and European Union. The objective of this study was to evaluate time stability of the pharmacokinetics (PK) of ENF and its metabolite and its antiretroviral activity (PD) in a group of HIV‐1 infected adolescents. Methods Twenty‐eight HIV‐1 infected adolescents (aged 12‐17 years) who completed 24 weeks of a 48–week treatment study were included in the analysis. These patients were dosed subcutaneously with ENF dose of 2 mg/kg (to a maximum dose of 90 mg) b.i.d. subcutaneously in combination with an optimized antiretroviral regimen. Plasma samples for determination of the Ctrough of ENF and its metabolite were collected at 12±2 hr post‐dose at various weeks. Blood samples for determination of HIV‐1 RNA viral load and CD4+ and CD8+ T cell count were collected up to 24 weeks. Results Mean ENF Ctrough was 3.2 μg/mL at week 1 and 2.4 μg/mL at week 24. Mean ENF Ctrough was stable over 24 weeks of treatment. Mean ENF metabolite Ctrough was stable from week 1 (0.29 μg/mL) to week 24 (0.22 μg/mL). Decline in plasma HIV‐1 RNA from baseline (5.19 log10 copies/mL) was −0.974 log10 copies/mL at week 24. The increase in CD4+ count from baseline (131 cells/mm3) was 148 cells/mm3 at week 24. The increase in CD8+ count from baseline (626 cells/mm3) was 398 cells/mm3 at week 24. Conclusion Dose of 2 mg/kg b.i.d. to a group of HIV‐1 infected adolescents achieved PK exposure which is stable over 24 weeks of treatment and comparable to that achieved in adults at 90 mg b.i.d. dose. Clinical Pharmacology & Therapeutics (2004) 75, P26–P26; doi:
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