Intravenous ganaxolone in pediatric super-refractory status epilepticus: A single hospital experience.

Synaptic GABAA receptor (GABAAR) internalization contributes to the drug resistant nature of super-refractory status epilepticus (SRSE). Ganaxolone is a 3ß-methylated synthetic analog of the endogenous neuroactive steroid, allopregnanolone, that has positive allosteric modulatory activity on synaptic and extrasynaptic GABAA receptors. Ganaxolone is currently in clinical trials to treat rare pediatric seizure disorders and established and refractory SE. Two pediatric patients with SRSE (age 17 and age 7) were treated under emergency investigational new drug (E-IND) applications with intravenous (IV) ganaxolone administered as an initial bolus and a maintenance infusion for up to 4.5 days with intermittent IV boluses as-needed followed by taper on day 5 and transitioned to chronic treatment using ganaxolone suspension. Adjunctive ganaxolone was effective in terminating SRSE in both patients, safely permitting IV anesthetics to be weaned. Seizure control has been maintained after transitioning to enteric ganaxolone. Further investigation of ganaxolone as a safe and effective treatment for SRSE is warranted.

Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis.

BACKGROUND: Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC). AIM: To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC. METHODS: Participants (5-17 years of age; 18-82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model. RESULTS: Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%-45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified. CONCLUSION: Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844.

The effect of sevelamer carbonate and lanthanum carbonate on the pharmacokinetics of oral calcitriol.

BACKGROUND: Lanthanum carbonate and sevelamer carbonate are non-calcium-based phosphate binders used to manage hyperphosphataemia in patients with chronic kidney disease (CKD). Patients with CKD may require intravenous or oral active vitamin D. We investigated the effects of lanthanum carbonate and sevelamer carbonate on the bioavailability of oral calcitriol. METHODS: This was a three-period, crossover study in healthy volunteers. Forty-one individuals were randomized to one of six possible sequences, each consisting of three treatment periods separated by washouts. The treatments were calcitriol (1 µg at lunch), calcitriol with lanthanum carbonate (3000 mg/day) and calcitriol with sevelamer carbonate (7200 mg/day). Serum calcitriol levels were assessed at baseline and throughout the study. RESULTS: Co-administration of lanthanum carbonate with calcitriol had no significant effect on area under the curve over 48 h (AUC(0-48)) for serum exogenous calcitriol [least-squares (LS) mean, calcitriol with lanthanum carbonate vs calcitriol alone: 429 pg h/mL vs 318 pg h/mL, respectively; P = 0.171]. Similarly, there was no significant effect on maximum concentration (C(max)). In contrast, co-administration with sevelamer was associated with a significant reduction in bioavailability parameters for calcitriol (calcitriol with sevelamer carbonate vs calcitriol alone, LS mean AUC(0-48): 137 pg h/mL vs 318 pg h/mL, respectively; P = 0.024; LS mean C(max): 40.1 pg/mL vs 49.7 pg/mL, respectively; P < 0.001). CONCLUSIONS: Sevelamer carbonate significantly reduces serum concentrations of exogenous calcitriol when administered concomitantly with oral calcitriol, whereas lanthanum carbonate has no significant effect. This should be considered when treating CKD patients who require phosphate binders and oral vitamin D.