No abstract

We report the first case of a human immunodeficiency virus type 1 (HIV-1)-infected individual receiving combination antiretroviral therapy, which included ritonavir, who developed Cushing syndrome with profound complications after epidural triamcinolone injections. This case highlights the potential of ritonavir interactions even with local injections of a corticosteroid.

Midazolam is a common probe used to predict CYP3A activity, but multiple blood samples are necessary to determine midazolam's area under the concentration-time curve (AUC). As such, single sampling strategies have been examined. The purpose of this study was to assess the ability of single midazolam concentrations to predict midazolam AUC in the presence and absence of CYP3A modulation by Ginkgo biloba extract (GBE). Subjects received oral midazolam 8 mg before and after 28 days of GBE administration. Postdose blood samples were collected during both study periods and midazolam AUC determined. Linear regression was used to generate measures of predictive performance for each midazolam concentration. The geometric mean ratio (90% confidence intervals) of midazolam AUC 0-∞ post-GBE/AUC 0-∞ pre-GBE was 0.66 (0.49-0.84) (P = .03). Before and after GBE administration, optimal midazolam sampling times were identified at 3.5 to 5 hours and 2 to 3 hours, respectively. Single midazolam concentrations between 2 and 5 hours correctly predicted the reduction in midazolam AUC following GBE exposure, but confidence intervals were generally wide. Intersubject variability in CYP3A activity (either inherent or from drug administration) alters the prediction of optimal midazolam sampling times; therefore, midazolam AUC is preferred for assessing CYP3A activity in drug-drug interaction studies. Keywords Midazolam; Ginkgo biloba extract; drug interactions; CYP3ACytochrome P 450 (CYP) is a large group of enzymes responsible for phase I oxidative metabolism. CYP enzymes are located in various tissues throughout the body, with the liver being the largest source. Two intestinal CYP isoforms that account for approximately 70% of total intestinal CYP activity include CYP3A4 and CYP3A5. Because >50% of CYPmetabolized drugs are substrates for CYP3A, modulation of this enzyme is the source of numerous drug-drug interactions. 1 However, it is not practical to study each CYP3A substrate to determine its interaction potential with CYP3A-modulating medications. As such, various CYP3A probe drugs have been identified to detect and quantify potential CYP3A-mediated drug-drug interactions. 2Midazolam has been used extensively as a probe for determining CYP3A4 and 3A5 catalytic activity in vivo; it is metabolized by CYP3A4 and CYP3A5 to its primary metabolite, 1′- The purpose of this healthy volunteer study was to assess the ability of single postdose midazolam concentrations to independently predict CYP3A activity as determined by midazolam area under the concentration-time curve (AUC), in the presence and absence of a newly described CYP3A-modulating compound, and to assess potential limitations associated with this approach. This study was a nested substudy of a larger investigation that examined the influence of Ginkgo biloba leaf extract (GBE) on the pharmacokinetics of the HIV protease inhibitor combination lopinavir/ritonavir. NIH Public Access METHODS Study SubjectsTo be considered for study inclusion, subjects had to be 18 to 50 y...

Objective: To determine the influence of a two-week course of lopinavir-ritonavir on the pharmacokinetics of the triglyceride-lowering agent, gemfibrozil. Methods: The study was conducted as an open label, single-sequence pharmacokinetic study in healthy human volunteers. Gemfibrozil pharmacokinetic parameter values were compared using a students t test after a single 600 mg dose was administered to healthy volunteers before, and after two weeks of lopinavir-ritonavir (400/100 mg) twice daily. Results: Fifteen healthy volunteers (8 males) completed the study. All study drugs were generally well-tolerated and no subjects withdrew participation. The geometric mean ratio (GMR, 90% CI) for gemfibrozil area under the plasma concentration-time curve (AUC0-∞) after 14 days of lopinavir-ritonavir compared to baseline was 0.59 (0.52, 0.67) (P < 0.001). All 15 study subjects experienced a reduction in gemfibrozil AUC0-∞ after lopinavir-ritonavir (range: −6% to −74%). The GMRs for gemfibrozil apparent oral clearance (Cl/F) and maximum concentration (Cmax) were 1.69 (1.41, 1.97) and 0.67 (0.49, 0.86) after 14 days of lopinavir-ritonavir versus baseline, respectively (P < 0.0001 and 0.01, respectively). Gemfibrozil elimination half-life did not change after lopinavir-ritonavir administration (P = 0.60). Conclusion: Lopinavir/ritonavir significantly reduced the systemic exposure of gemfibrozil by reducing gemfibrozil absorption. Clinicians treating HIV-infected patients with hypertriglyceridemia should be aware of this drug interaction.

Background-Corticosteroids are cytochrome P450 3A4 substrates, which have been associated with toxicities in patients receiving cytochrome P450 3A4 inhibitors such as human immunodeficiency virus protease inhibitors. In a study in healthy volunteers, ritonavir significantly increased prednisolone exposure.