The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects. In the 0-6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47,779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary 14C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47,779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favouring the S-configuration of GP 47,779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.
Applying the European Medicines Agency's ABEL method at the nominal level of 0.05 inflates the type I error to an unacceptable degree, especially close to a CV wR of 30%. To control the type I error nominal levels ≤0.05 should be employed. Iteratively adjusting α is suggested to find optimal levels of the test.
Introduction
Currently, no universally accepted definition of extended half‐life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half‐life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII.
Aim
To identify the half‐life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose.
Methods
A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half‐life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen.
Results
Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half‐life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half‐life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL.
Conclusion
Based on this investigation, EHL rFVIII products should have a minimum half‐life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.
Validated two-stage frameworks can be applied without requiring the sponsor to perform own simulations-which could further improve power based on additional assumptions. Two-stage designs are both ethical and economical alternatives to fixed sample designs.
Continuous surface-relief diffractive optical elements for two-dimensional array generation (fan-out) are designed and fabricated. Separable and nonseparable solutions for the two-dimensional element design are compared. The phase-grating microstructures are generated by laser-beam writing lithography in a single exposure step and converted to nickel shims by electroplating, enabling low-cost replicas to be produced by using laboratory and commercial replication processes. Results are presented for a 9 x 9 fan-out diffractive optical element with a measured efficiency of 94% and an overall uniformity within ±8%; replicas in epoxy have the same efficiency and a uniformity of ± 15%.
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