Combination vitamin D therapy in stage 5 chronic kidney disease.

OBJECTIVE: To review the data supporting combination therapy with vitamin D and vitamin D receptor activators (VDRAs) in patients with stage 5 chronic kidney disease (CKD). DATA SOURCES: Literature was searched using PubMed and EMBASE using the terms kidney disease, kidney failure-chronic, and vitamin D. Limits applied included humans, adults (19 years or older), and clinical trials (and related), with publication dates between January 1, 1980, and May 16, 2011. STUDY SELECTION AND DATA EXTRACTION: All English-language publications were analyzed for relevance. Studies appropriate to the objective were evaluated, including 3 prospective observational studies, 1 prospective cohort study, and 1 retrospective study. DATA SYNTHESIS: To our knowledge, there have been no randomized controlled trials evaluating the safety and efficacy of vitamin D supplementation in combination with VDRA therapy in patients with stage 5 CKD. Relatively small observational studies have demonstrated improvements in 25-hydroxyvitamin D (25-OHD) concentrations and markers of mineral and bone metabolism as well as reduced VDRA use in patients with stage 5 CKD. Not all patients in these studies were receiving VDRA therapy. Therapy was safe, with no patients exceeding the recommended upper limit for 25-OHD concentrations and only a small percentage experiencing transient/correctable hypercalcemia. CONCLUSIONS: Vitamin D supplementation to maintain 25-OHD concentrations at 20-30 ng/mL or higher with or without VDRA therapy is inexpensive, appears safe, and may have additional health benefits in patients with stage 5 CKD. Well-designed, randomized controlled trials are needed to determine the efficacy and safety of combination vitamin D therapy in patients with stage 5 CKD.

Quality of drug information database research for clinical decision support.

This commentary identifies studies that have compared commercially available DI databases, and discusses improvements in study methodology that might better guide clinicians in selecting resources for their practice setting. We also provide suggestions for future direction of research in this area with an eye towards clinical decision support systems (CDSS). The body of comparative research of commercially available DI databases is small, and provides little value to the average clinician when making purchasing decisions. Transparency of study methodology would allow readers to choose a database that best fits their practice needs. Future research must consider how DI resources are imbedded within CDSS, such that the alerts generated by the CDSS are consistent with the primary DI workhorse of the practice site. Cohesion between CDSS and DI resources needs to be a consideration in future DI resource comparative research.

Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers.

OBJECTIVES: This open-label, single-arm, pharmacokinetic (PK) study in HIV-seronegative volunteers evaluated the bioequivalence of rosuvastatin and lopinavir/ritonavir when administered alone and in combination. Tolerability and lipid changes were also assessed. METHODS: Subjects took 20 mg of rosuvastatin alone for 7 days, then lopinavir/ritonavir alone for 10 days, and then the combination for 7 days. Intensive PK sampling was performed on days 7, 17, and 24. RESULTS: Twenty subjects enrolled, and PK data were available for 15 subjects. Geometric mean (+/-SD) rosuvastatin area under the concentration time curve (AUC)[0,tau] and maximum concentration (Cmax) were 47.6 ng.h/mL (+/-15.3) and 4.34 ng/mL (+/-1.8), respectively, when given alone versus 98.8 ng.h/mL (+/-65.5) and 20.2 ng/mL (+/-16.9) when combined with lopinavir/ritonavir (P < 0.0001). The geometric mean ratio was 2.1 (90% confidence interval [CI]: 1.7 to 2.6) for rosuvastatin AUC[0,tau] and 4.7 (90% CI: 3.4 to 6.4) for rosuvastatin Cmax with lopinavir/ritonavir versus rosuvastatin alone (P < 0.0001). There was 1 asymptomatic creatine phosphokinase elevation 17 times the upper limit of normal (ULN) and 1 liver function test elevation between 1.1 and 2.5 times the ULN with the combination. CONCLUSIONS: Rosuvastatin low-density lipoprotein reduction was attenuated with lopinavir/ritonavir. Rosuvastatin AUC and Cmax were unexpectedly increased 2.1- and 4.7-fold in combination with lopinavir/ritonavir. Rosuvastatin and lopinavir/ritonavir should be used with caution until the safety, efficacy, and appropriate dosing of this combination have been demonstrated in larger populations.

Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury.

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means +/- standard deviations; age, 41 +/- 17 years; weight, 81 +/- 12 kg; creatinine clearance, 114 +/- 40 ml/min) received intravenous levofloxacin at 750 mg (n = 10 patients) or 500 mg (n = one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 +/- 3.2 liters/h, 7.8 +/- 1.6 h, and 93 +/- 31 mg . h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of < or =0.5 microg/ml and MICs of < or =1 microg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 microg/ml or any organism with a MIC of > or =2 microg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 microg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.

Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children.

The contemporary treatment of the child infected with human immunodeficiency virus (HIV) unavoidably requires combination therapy with antiretroviral agents and may include additional drugs for the prevention and treatment of opportunistic infections or other disease states. The current guidelines for the treatment of the HIV-infected child recommend that the same principles of treatment for adults should apply to children. However, the pharmacokinetic and pharmacodynamic characteristics of many agents and regimens used in adults have not been defined adequately in children, and large-scale clinical trials to establish safety and show efficacy have not been completed. Therefore, the clinician will be required to use agents with incomplete knowledge about their pharmacologic properties. The purpose of this article is to provide an overview of the pediatric pharmacologic principles, a review of the pharmacologic characteristics of selected antiretroviral agents in children, and a prospectus on the design of drug dosing regimens in children.