Adherence to, and patient convenience of, prolonged-release tacrolimus in stable kidney and liver transplant recipients after conversion from immediate-release tacrolimus in routine clinical practice in Switzerland.

AIMS OF THE STUDY: Non-adherence to immunosuppressive therapy in patients following solid organ transplantation is associated with an increased risk of transplant rejection and graft loss. A high pill burden can adversely affect patients’ implementation of their treatment regimens and may lead to omitting doses of medication. The aim of this study was to investigate medication implementation adherence in liver and kidney transplant recipients converted from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus. METHODS: This multicentre, non-interventional, observational, 12-month study evaluated implementation adherence in routine practice at five hospitals in Switzerland. Patients attended four clinical visits: at baseline (pre-conversion), and then at week 2, month 6 and month 12 post-conversion. Implementation was defined as consistently taking medication at the correct time and at the correct dose in order to achieve target tacrolimus trough levels. Implementation adherence was evaluated in three ways: using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) interview questionnaire (at baseline and month 12), investigator-rated patient adherence (recorded at all visits), and tacrolimus trough levels (assessed throughout the study; sub-therapeutic levels were predefined by the investigator on an individual patient basis, over-therapeutic levels were defined as tacrolimus trough levels >15 ng/ml). The primary composite endpoint was non-adherence according to the BAASIS at month 12, any post-conversion investigator adherence rating of “poor”, or sub-therapeutic or over-therapeutic tacrolimus trough levels at month 6 or 12. Secondary endpoints included: individual components of the composite non-adherence primary endpoint, tacrolimus pill burden, patient satisfaction, and adverse drug reactions. RESULTS: Seventy-five patients received prolonged-release tacrolimus; 68 patients (46 kidney and 22 liver transplant recipients) completed the study. Of these 68 patients, 24 had missing data for at least one component of the primary endpoint; therefore, data for the primary composite endpoint were evaluable for 44 patients. Most (81.8%; 36/44) patients were non-adherent for the composite endpoint. Sub-therapeutic tacrolimus trough levels outside of the predefined therapeutic range were the largest contributor to the composite endpoint, and were detected in 62.0% (31/50) of patients. Overall non-adherence according to the BAASIS was similar pre-conversion (30.7%) and at 12 months post-conversion (28.3%). Investigators rated adherence as “poor” for two patients. Prolonged-release tacrolimus decreased tacrolimus pill burden in 66.7% of patients. All patients were very satisfied / satisfied with prolonged-release tacrolimus; 75.0% found it easier to remember to take prolonged-release versus immediate-release tacrolimus. Twenty percent of patients reported adverse drug reactions, with infections being the most frequently reported (9.3%). CONCLUSION: Overall, 1-year non-adherence rates were similar following conversion from immediate-release to prolonged-release tacrolimus; however, prolonged-release tacrolimus intake was more convenient. No new safety signals were detected.

Haemodialysis in massive caffeine intoxication.

Caffeine is the most widely consumed psychoactive substance worldwide. Intoxication causes central nervous system and haemodynamic complications, which have significant mortality rates. We report the case of a 39-year-old woman who ingested ∼0.5 mol (100 g) of pure caffeine, leading to a peak serum concentration of 2.95 mmol/L (574 mg/L). Three consecutive haemodialysis sessions caused serum caffeine reduction rates of 66, 46 and 45%, indicating that the unbound caffeine fraction is not dose linear in this high serum caffeine concentration range. Aggressive and repeated haemodialysis sessions may be of benefit in cases of severe caffeine intoxication.

Ocular penetration of caspofungin in a rabbit uveitis model.

BACKGROUND: Little is known about the ocular penetration of echinocandin antifungals. We studied the ocular distribution of systemically administered caspofungin in a rabbit uveitis model. METHODS: Caspofungin (1 mg/kg per day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 days starting 24 h after induction of unilateral uveitis by intravitreal endotoxin injection. Caspofungin concentrations were determined by high-performance liquid chromatography in the cornea, aqueous humor, vitreous humor, and serum 4, 8, 16, and 24 h after administration of a single dose and 24 h after the last of seven doses. RESULTS: The mean caspofungin concentration in the aqueous of the inflamed eye 4 and 8 h after single-dose administration was 1.30 +/- 0.39 microg/ml and 1.12 +/- 0.34 microg/ml, respectively. Drug concentrations decreased to 0.24 +/- 0.09 microg/ml at 16 h and 0.26 +/- 0.14 microg/ml at 24 h. In the vitreous of inflamed eyes drug levels were undetectable at all time points. No drug was found in the aqueous of inflamed eyes 24 h after the last of seven repeated doses, and the vitreous only contained trace amounts. In the corneas of inflamed eyes concentrations reached 1.64 +/- 0.48 microg/g at 4 h, peaked at 2.16 +/- 1.14 microg/g at 8 h, and declined to 1.87 +/- 0.52 microg/g and 1.49 +/- 0.48 microg/g at 16 and 24 h, respectively. After repeated dosing, corneal concentrations of caspofungin were 0.8 and 1.0 microg/g and below the limit of detection in two of four animals. In non-inflamed eyes no drug was detectable in the aqueous and vitreous humor, and the corneas at any time point. CONCLUSIONS: In our model, caspofungin reached therapeutically relevant levels in the aqueous and cornea but not in the vitreous humor of inflamed eyes. Intraocular drug deposition was critically dependent on a disrupted blood-eye barrier. These findings suggest a limited role for caspofungin in the treatment of fungal endophthalmitis.