Teresa P. McKaveney

Lung Deposition and Pharmacokinetics of Cyclosporine After Aerosolization in Lung Transplant Patients

AbstractPurpose. Aerosolized cyclosporine (aCsA) has proven to be an effective therapy for refractory acute and chronic rejection in lung transplant (LTx) patients. The objective of this study is to evaluate the lung deposition and systemic absorption of aCsA after aerosolized cyclosporine administration in LTx patients in the immediate postoperative period. Methods. Cyclosporine (CsA) was administered intravenously (1.0 mg/kg) to eight LTx patients, and multiple blood samples were collected over 24 h. At least 24 h later, aCsA (300 mg in propylene glycol) was administered to the same patients using nebulization and multiple blood samples were obtained again. Five patients had an additional inhalational gamma scintigraphy study with aCsA and 99MTc-labeled albumin to measure drug deposition. Results. Peak blood concentrations of CsA after aerosol administration ranged from 119-402 ng/ml, and concentrations at 24 h ranged from 9-48 ng/ml. The rate of decline in drug concentration in blood in the apparent elimination phase was notably slower after administration of aCsA than after IV infusion. Terminal disposition half life (t1/2 λz) values ranged from 4.1-9.9 h (mean 6.5 h) following IV administration and from 23.1 to 65.2 h (mean 40.7 h) following pulmonary administration, suggesting that drug absorption occurred throughout the 24-h sampling period following pulmonary administration. Deconvolution analysis indicated biphasic absorption of CsA from the lung in all patients, characterized by rapid initial absorption (absorption half-life 0.73 ± 0.38 h) over the first 4 to 6 h followed by slower, sustained absorption throughout the remainder of the sampling period (absorption half-life 16.2 ± 13.2 h). The absolute bioavailability of CsA after aerosol administration ranged from 5.4-11.2% (mean 8.2%) of the dose placed in the nebulizer. The total dose delivered to the lung estimated from scintigraphy ranged from 17.8-39.3 mg, and was in approximate agreement with the amount of drug absorbed, estimated using deconvolution. Essentially all drug deposited in the lungs was systemically absorbed. Conclusions. This study documents that cyclosporine can be effectively delivered by aerosolization to the lung of transplant patients in the early postoperative period. Part of the cyclosporine deposited in the lung is absorbed rapidly into systemic circulation and a portion is absorbed slowly but completely over a prolonged period.

Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population

Study Objective. To determine the long‐term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug‐resistant tuberculosis (MDRTB) after undergoing solid organ transplantation.

Tacrolimus Analysis: A Comparison of Different Methods and Matrices

We determined the trough blood and plasma concentrations of tacrolimus from the day of transplantation through 30 days posttransplantation in four liver and four kidney transplant patients by three different methods. The first method involved a solid phase extraction of the blood or plasma using Sep-Pak columns (SPs) followed by quantitation of tacrolimus using an enzyme-linked immunosorbent assay (ELISA); the second method involved a liquid-liquid extraction using methylene chloride (MC) followed by quantitation of tacrolimus using the ELISA, and the third method involved a high-performance liquid chromatography (HPLC) fractionation of the extract obtained from the solid-phase extraction and quantitation of tacrolimus in the fractions by ELISA. The trough plasma tacrolimus concentrations ranged from 0.1 to 5.2 ng/ml. While the trough plasma concentrations of tacrolimus were similar and independent of the method of analysis in kidney transplant patients and in liver transplant patients with normal biochemical profile, in patients with liver dysfunction, tacrolimus plasma concentrations were higher when measured by SP-ELISA and MC-ELISA methods as compared to the HPLC-ELISA method. In plasma samples obtained from liver transplant patients with liver dysfunction, the presence of some metabolites that cross-reacted with the antibody used in the ELISA could be documented in the HPLC fraction corresponding to the metabolites. This indicates that while tacrolimus metabolites that cross-react significantly with the antibody used in the ELISA do not accumulate in kidney transplant patients, they can appear in the plasma of patients with liver dysfunction. The trough blood tacrolimus concentrations in patients were significantly higher than the corresponding plasma concentrations and ranged from 1.4 to 107 ng/ml. The trough blood tacrolimus concentrations were similar and independent of the method of analysis in kidney and liver transplant patients, suggesting unchanged tacrolimus to be the major component in the blood. The HPLC fractions corresponding to the metabolites of tacrolimus did not contain any components that cross-reacted with the antibody used. This study documents that the methods used in this study for the analysis of blood concentrations of tacrolimus appear to be specific for the parent tacrolimus and can be used in future pharmacokinetic and clinical studies.

Adverse Drug Events Involving COX-2 Inhibitors

OBJECTIVE: To describe the types and severity of adverse drug-related events (ADEs) observed in patients receiving cyclooxygenase-2 (COX-2) inhibitors and to increase the awareness of risk factors that predispose patients to ADEs associated with COX-2 inhibitors. METHODS: A review of ADEs reported at the University of Pittsburgh Medical Center Presbyterian Hospital (UPMC-P) revealed significant events related to use of celecoxib or rofecoxib. A query of the internal ADE database was performed to identify ADEs involving COX-2 inhibitors from January 1999 to June 2002. A similar query was performed to identify ADEs involving nonselective nonsteroidal antiinflammatory drugs (NSAIDs) reported during this same time period. Utilization data were also collected. RESULTS: Forty-eight ADEs involving 24 patients receiving COX-2 inhibitors were reported and validated via the UPMC-P ADE review process compared with 38 events in 33 patients receiving nonselective NSAIDs. The types of ADEs reported as related to COX-2 inhibitors were similar to those reported in association with nonselective NSAIDs. Forty-two percent of ADEs (n = 20) involving COX-2 inhibitors and 45% of events (n = 17) involving nonselective NSAIDs were classified as severe. All patients receiving COX-2 inhibitors and 91% of patients receiving nonselective NSAIDs exhibited risk factors that increased their risk to experience an ADE; all but 1 of these patients were receiving outpatient COX-2 inhibitor therapy. CONCLUSIONS: The observed ADEs involving COX-2 inhibitors were similar to those associated with nonselective NSAIDs. Most events may have been preventable, highlighting the need for education regarding the appropriate use of COX-2 inhibitors.

In the lung aerosol cyclosporine provides a regional concentration advantage over intramuscular cyclosporine

BACKGROUND Acute rejection remains an almost universal complication among lung transplant recipients. Refractory rejection as well as chronic systemic immunosuppression is associated with significant morbidity and mortality. Recent studies suggest that aerosol cyclosporine may address these issues by effectively preventing acute cellular rejection while maintaining low systemic drug concentrations. This study was designed to evaluate the concentrations of cyclosporine in blood and lung tissue after aerosol and intramuscular administration. METHODS Lewis rats were divided into 4 experimental groups: Groups A (n = 33) and B (n = 30) received aerosol cyclosporine 3 and 5 mg/kg, respectively; Groups C (n = 33) and D (n = 30) received systemic cyclosporine 5 and 15 mg/kg, respectively. We used high-performance liquid chromatography to quantitate blood and lung tissue cyclosporine levels at timed intervals. We used the trapezoidal rule to approximate area under the concentration vs time curve (AUC). RESULTS Aerosol delivery of cyclosporine resulted in higher and more rapid peak drug levels in lung tissue samples than did systemic delivery. At an equivalent 5 mg/kg dose, the cyclosporine AUC was 3 times higher with aerosol delivery than with intramuscular delivery in lung tissue (477,965 vs 157,706 ng x hour/g, respectively). The lung tissue: blood AUC ratio was highest in the aerosol groups (27.3:1 and 17.4:1) compared with the intramuscular groups (8.1:1 and 9.4:1). CONCLUSION Local aerosol inhalation delivery of cyclosporine provides a regional advantage over systemic intramuscular therapy by providing higher peak concentrations and greater lung tissue exposure.

Retrospective Analysis of Hyperlipidemia Management in a Transplant Population

Study Objectives. To determine the prevalence of hyperlipidemia and the effectiveness of hyperlipidemia management in a large population of transplant recipients. A secondary objective was to assess the effect of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines on hyperlipidemia management compared with the effect from earlier guidelines.