Gemfibrozil concentrations are significantly decreased in the presence of lopinavir-ritonavir.

OBJECTIVE: The objective of this study was to determine the influence of a 2-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 Student t test after a single 600-mg dose was administered to healthy volunteers before and after 2 weeks of lopinavir-ritonavir (400/100 mg) twice daily. RESULTS: Fifteen healthy volunteers (eight males) completed the study. All study drugs were generally well tolerated and no subjects withdrew participation. The geometric mean ratio (90% confidence interval) for gemfibrozil area under the plasma concentration-time curve after 14 days of lopinavir-ritonavir compared with baseline was 0.59 (0.52, 0.67) (P < 0.001). All 15 study subjects experienced a reduction in gemfibrozil area under the plasma concentration-time curve after lopinavir-ritonavir (range, -6% to -74%). The geometric mean ratios for gemfibrozil apparent oral clearance and maximum concentration 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.

Iatrogenic Cushing syndrome after epidural triamcinolone injections in an HIV type 1-infected patient receiving therapy with ritonavir-lopinavir.

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.

Influence of antiretroviral drugs on the pharmacokinetics of prednisolone in HIV-infected individuals.

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. METHODS: We investigated the influence of antiretroviral (ARV) medications on prednisolone pharmacokinetics in 3 groups of 10 human immunodeficiency virus-infected subjects. One group received lopinavir/ritonavir, and another efavirenz, as part of their ARV regimen; a third group did not receive ARV medications. Each subject received a single 20-mg prednisone dose followed by serial blood sampling for prednisolone. Prednisolone pharmacokinetics were compared among the groups. RESULTS: Area under the concentration-time curve was significantly lower in efavirenz recipients versus subjects receiving lopinavir/ritonavir (geometric mean ratio = 0.60, P = 0.01). Average prednisolone area under the concentration-time curve was higher in subjects taking lopinavir/ritonavir versus subjects not on ARVs; however, this difference was not significant (P > 0.05). CONCLUSIONS: These data indicate that prednisolone concentrations may fluctuate widely when human immunodeficiency virus-positive individuals established on efavirenz therapy change to lopinavir/ritonavir or vice versa.

Limitations of using a single postdose midazolam concentration to predict CYP3A-mediated drug interactions.

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-infinity) post-GBE/AUC(0-infinity) 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.

Pharmacological enhancement of protease inhibitors with ritonavir: an update.

Advances in HIV treatment since the approval of the first antiretroviral (ARV) medication have occurred at a rapid pace. However, resistance to these medications can occur quickly owing to inadequate plasma concentrations resulting from poor adherence related to intolerable drug toxicities and complex dosing schedules. Drug-drug and drug-food interactions can also result in inadequate ARV drug exposure. Ritonavir is a potent cytochrome P450 3A4 inhibitor and low doses can be used in combination with almost all protease inhibitors to overcome most drug-drug and drug-food interactions. Little toxicity can be attributed to the addition of low-dose ritonavir to an ARV regimen, and most patients find that the added pills do not adversely affect adherence. This article reviews the pharmacological use of ritonavir for pharmacokinetic enhancement (or boosting) and updates the clinical use of boosted protease inhibitors.

Part XIII. Systemic antifungal therapy.

Until the last decade of the 20th century, intravenous amphotericin B deoxycholate was the only agent available to treat the relatively rare occurrence of serious systemic fungal infections. In response to an explosion in the incidence of systemic fungal infections, within a 15 year period, four new classes of antifungal agents were introduced: the triazoles, liposomal amphotericin B preparations, an allylamine, and echinocandins (Table 1). So an updated review of antifungal therapy is in order.

Darunavir: a second-generation protease inhibitor.

PURPOSE: The pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse events, dosage and administration, and place in therapy of darunavir are reviewed. SUMMARY: Darunavir is the most recent protease inhibitor (PI) to receive approved labeling from the Food and Drug Administration for the treatment of human immunodeficiency virus (HIV). Darunavir is unique among currently available PIs because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. Darunavir is well absorbed, and the bioavailability of darunavir increases by 30% when given with food. Darunavir is approximately 95% bound to plasma proteins. Darunavir is metabolized by and inhibits cytochrome P-450 (CYP) isoenzyme 3A4; therefore, darunavir is prone to CYP3A4-mediated drug-drug interactions. Two trials have demonstrated the clinical efficacy of darunavir in HIV-positive patients previously treated with antiretrovirals. One trial demonstrated a 2 log(10) decrease in plasma HIV RNA levels, compared with a decrease of <1 log(10) in the control group. Average increases in CD4+ T-cell counts for darunavir and control groups were 124 and 20 cells/mm(3), respectively. Adverse events reported from preliminary safety data indicate that darunavir has a similar safety profile to other currently available PIs. The recommended adult dosage of darunavir is 600 mg (two tablets) combined with ritonavir 100 mg every 12 hours with food. Darunavir should be used with caution in patients with hepatic dysfunction. No dosage adjustment is necessary for patients with mild or moderate renal dysfunction. CONCLUSION: Darunavir is a new HIV PI that retains virological activity in the presence of multiple protease mutations. As such, darunavir appears to be a useful component of optimized combination antiretroviral therapy for HIV-infected patients previously treated with antiretrovirals.