Extended-release preparation, administration

In nonacute situations, phenytoin may be initiated in adults at oral doses of 5 mg/kg/day and titrated upward. Subsequent dosage adjustments should be done cautiously because of nonlinearity in elimination. Most adult patients can be maintained on a single daily dose, but children often require more frequent administration. Only extended-release preparations should be used for single daily dosing. 

The sodium salt of valproate is marketed in Europe as a tablet and is quite hygroscopic. In Central and South America, the magnesium salt is available, which is considerably less hygroscopic. The free acid of valproate was first marketed in the USA in a capsule containing corn oil the sodium salt is also available in syrup, primarily for pediatric use. An enteric-coated tablet of divalproex sodium is also marketed in the USA. This improved product, a 1 1 coordination compound of valproic acid and sodium valproate, is as bioavailable as the capsule but is absorbed much more slowly and is preferred by many patients. Peak concentrations following administration of the enteric-coated tablets are seen in 3-4 hours. Various extended-release preparations are available not all are bioequivalent and may require dosage adjustment. 

In general the opioid analgesics can enhance the CNS depressant effects of alcohol, which has been fatal in some cases this appears to be a particular problem with dextropropoxyphene. Alcohol has been associated with rapid release of hydromorphone and morphine from extended-release preparations, which could result in potentially fatal doses. Acute administration of alcohol and methadone appears to increase the blood levels of methadone. The bioavailability of dextropropoxyphene is increased by alcohol... 

The bioavailabilities of cefadroxil, cefalexin, cefixime, cefprozil, and cefradine are not affected by food. Cefaclor may be given without regard to food but absorption of an extended-release preparation may be increased by food. The bioavailabilities of cefetamet pivoxii and cefuroxime axetil may be increased by administration with food. 

Each simulation included 100 hypothetical subjects. The model parameters used were derived from an adult population and there were no covariate distribution models for the virtual trial population. Subjects were assumed to be healthy and on valproate monotherapy (31). The simulations assumed that the extended release (ER) formulation was administered once daily and the delayed release (DR) preparation was administered twice daily. Unbound and total valproic acid concentrations were simulated from the time of dose administration to 280 h and the simulations were based on the administration of 1000 mg ER once daily, 500 mg DR twice daily, 2500 mg ER once daily, and 1000 mg DR twice daily. For once-daily regimens, simulation scenarios included doses taken 6, 12, 18, and 24h late from schedule and then two doses taken 24h late (replacement dose for the missed dose). For the twice-daily regimens, doses were simulated 3,6,9, and 12 h later than the scheduled times and then two doses were simulated 12 h later than scheduled to mimic replacement dosing for a missed dose. More extreme cases where two doses are delayed at various times or missed were also simulated. 

Several antiinflammatory compounds have been formulated in lactide/ glycolide polymers (107-111). Methylprednisolone microspheres based on an 85 15 DL-lactide/glycolide copolymer were developed for intra-articulate administration (111). The microspheres, prepared by a solvent evaporation procedure, are 5—20 jam in diameter and are designed to release low levels of the steroid over a extended period in the joint. Controlled experiments in rabbits with induced arthritis showed that the microspheres afforded an antiinflammatory response for up to 5 months following a single injection. 

The recently introduced product Concerta is a once-a-day administration MPH delivery system called OROS (osmotically released). This delivery system creates an ascending plasma level pattern instead of the peak-and-valley pharmacokinetic profile seen in the IR preparations. Similar extended-delivery bead-technology, double-pulse preparations have been introduced for Metadate-CD at 10, 20, and 30 mg (Green-hill et ah, 2002, in press) for the spheroidal technology of Ritalin-EA, and for Adderall-XR preparations (McGough et ah, 2002, in press). Beaded stimulant preparations mix IR and delayed-release beads in a capsule. The patient can swallow the capsule whole or sprinkle the contents in food if pill taking is difficult for the child. 

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