The importance of therapeutic drug monitoring (TDM) for parenteral busulfan dosing in conditioning regimen for hematopoietic stem cell transplantation (HSCT) in children.

BACKGROUND: Series of observations indicate PK/PD variability challenging the accuracy of the body-weight based busulfan (Bu) dosing schedule for (HSCT) conditioning therapy. The purpose of this communication is to describe the frequency of dose changes in initially body-weight-based fixed IV Bu dose and to emphasize the importance of TDM. MATERIAL AND METHODS: Sixty-two children (ages 2 months-18 years) were treated with IV busulfan doses based on body weight for myeloablation. TDM utilizing a limited sample strategy (trough concentration immediately before the 5th dose, followed by samples immediately after the end of the 2-h infusion peak, 4 h, and 6 h from initiation of the infusion) was performed in 46 of 62 subjects. Busulfan concentrations were determined by high-performance liquid chromatography (HPLC). AUC was calculated according to the trapezoidal rule. RESULTS: We observed trough levels of 25-1244 µg/L, peak levels of 849-4586 µg/L, and AUC of 2225-12818 µg/L·h following body weight-based high-dose busulfan. The doses were changed in 54% of cases. AUC in 5 of 9 patients with VOD were within target, in 3 patients AUS was higher, and in 1 patient AUC was lower. One of the 2 patients with neurotoxicity had higher AUC. Engraftment was 100%, but relapse occurred in 25% of cases. CONCLUSIONS: Our results demonstrate that even with IV busulfan, intra-individual PK/PD variability is challenging. Although AUC does not necessarily correspond with outcomes (due to the role of other factors the fact that doses were changed in 54% of cases underlines the importance of TDM.

Topotecan vitreous and plasma levels and retinal toxicity after transcorneal intravitreal delivery in healthy albino rabbits: alternative retinoblastoma treatment.

AIM: To determine intravitreal and plasma concentrations and retinal toxicity after transcorneal intravitreal injection of 1 µg and 2 µg of topotecan (Hycamtin). METHOD: Twelve healthy albino rabbits were included in this in vivo experiment. Six anesthetized albino rabbits received a single transcorneal intravitreal injection of 1 µg (group A) or 2 µg (group B) of topotecan. Vitreous and blood samples were collected until 168 h. Left eyes were treated with the same volume of saline. Plasma and vitreous levels of topotecan were determined by high-performance liquid chromatography. Area under the plasma concentration time curve (AUC) was calculated using trapezoidal rule. Clinical evidence of toxicity was classified into four grades according to anatomical structures. Electroretinograms (ERGs) were recorded. RESULTS: Time to maximum concentration was observed up to 2 h after drug injection in group A whereas up to 1 h in group B. Low levels of topotecan were detected in plasma in both groups and in the vitreous humor of the contralateral eye in group B. Topotecan levels (mean vitreous AUC in group A 2.55 µg/mL.h and in group B 5.338 µg/mL.h) were detectable up to 6 h in both groups. We observed following structural changes in rabbit eyes: corneal vascularization, cataract, hemophthalmus, choroidal edema and focal retinal atrophy. Abnormal ERGs were obtained. CONCLUSION: Our findings proved that transcorneal intravitreal administration of 1 µg and 2 µg of topotecan results in potentially cytotoxic intraocular concentrations. More studies are needed to establish the safety of topotecan for retinoblastoma in children.

Sudden renal function deterioration in an elderly patient on vancomycin therapy for endocarditis.

Vancomycin is currently the drug of choice in meticillin-resistant Staphylococcus aureus (MRSA) infection. It is also used prophylactically in some situations in which the patient is at risk for endocarditis. It is often used in combination with other antibacterials in the treatment of endocarditis and is a potential nephrotoxin. Various consensus guidelines differ in their interpretation of vancomycin plasma concentrations. This paper describes a case of a 72-years old Caucasian female patient, who developed significant renal impairment when prescribed vancomycin in combination with penicillin for the treatment of endocarditis, caused by Streptococcus pneumoniae.

Antiepleptic drug interactions: a clinical case demonstration.

Epilepsy is a serious health disorder affecting both paediatric and adult population worldwide. Due to difficulties in identifying its aetiology, initial management is often guided by empiric therapy measures. Symptomatic control requires the use of antiepileptic drugs (AEDs), many of which have the potential for adverse drug interactions. Children are especially susceptible to drug interactions and frequently exhibit atypical adverse events, which may require special care. Aim. To demonstrate a case of a 15 year old girl suffering from refractory epilepsy with underlying focal cortical dysplasia (FCD), whose seizure deterioration was most probably associated with drug-drug interactions between prescribed common antiepileptic drugs, namely valproic acid, phenobarbital or the prodrug primidon and carbamazepine.

Intravitreal carboplatin concentration and area under concentration versus time curve after intravitreal and periocular delivery.

PURPOSE: To determine platinum (Pt) concentrations and area under the concentration versus time curve (AUC) of the vitreous humor after periocular or transcorneal intravitreal administration of carboplatin in rabbits. METHODS: Eighteen albino rabbits were included in an in vivo experiment. Each animal received a single dose of either 30 mg of carboplatin by periocular injection (POI30 group: n = 6) or 15 mg by periocular injection (PI15 group: n = 6), or 0.05 mg by transcorneal intravitreal injection (TII group: n = 6), respectively, into the right eye. Vitreous humor from the right eyes and plasma samples were collected post dose at 1, 2, 6, 24, 48, 168, and 336 hours or 448 hours, respectively. Flameless atomic absorption spectroscopy was employed to analyze total platinum concentrations in blood and vitreous humor. AUC was calculated using the trapezoidal rule. RESULTS: Pt concentration was mostly < 1 mg/L (0-3.15 mg/L) in the vitreous humor samples and > or = 2 mg/L (2.33-7.3 mg/L) in the blood samples 1 hour after administration in POI groups. Markedly higher Pt concentrations were found 1 hour after intravitreal (TII) administration (10.285-66.759 mg/L) and decreased below 1 mg/L no less than 168 hours after administration. The mean AUC for Pt in vitreous humor was significantly lower (p = 0.0001) after both POI30 and P0I15 administration compared to TII route (8.955 +/- 2.464 mg/L/min). CONCLUSIONS: These findings proved that intravitreal carboplatin delivery enables the achievement of relatively stable concentrations and AUC of platinum in the rabbit vitreous humor. This moreover suggests that transcorneal intravitreal delivery of carboplatin aiming to treat retinoblastoma vitreous seeding is a promising mode of chemotherapy.

Cyclosporine use in miscellaneous clinical settings other than organ transplantations: is there any evidence for target levels?

BACKGROUND: Cyclosporine, once a corner stone in organ transplantation for decades, its use is expanded to treat several autoimmune conditions despite lacking profound evidence for its advantages. The aim of the retrospective study was to evaluate differences in trough blood levels of cyclosporine in some clinical indications other than transplantation. MATERIAL/METHODS: Blood cyclosporine trough levels determined by fluorescent polarization immunoassay (FPIA) TDx Abbott Diagnostics for TDM purpose in one year period was pooled from laboratory data-base. Total of 304 levels from 45 patients (26 males: 19 females) aged 2-62 years, who were on oral cyclosporine daily maintenance dose for conditions like systemic lupus erythematosus (SLE), atopic dermatitis (ADS), idiopathic thrombocytopenic purpura (ITP), dermatopolymyositis (DMS), and cardiomyopathy (CMP) were included. RESULTS: Cyclosporine trough was undetectable in 27 occasions, with maximum1213 microg/L, mode 74 ug/L, median 91 ug/L, mean 104.4+/-119.5 ug/L SD, and SE 6.85 respectively. Despite poorly de fi ned target, most clinicians desired trough concentrations not exceeding 100 microg/L, aiming to reduce toxicity. In this respect, nearly 35% were above this point, whereas 8% were below the detection limit of the method. There were no significant differences in concentrations within diagnostic groups except for ADS versus ITP (p<0.0039). CONCLUSIONS: Extended use of cyclosporine in several autoimmune diseases is promising. However, no evidence-based target levels in miscellaneous indications. Studies are needed to demonstrate overall benefits of CSA in relation to trough level and dynamic indicators (biomarkers) like expression of IL-2 and its receptor as targeted cell products in the future.