dl-Methylphenidate (MPH) remains the most widely used pharmacological agent in the treatment of attention-deficit/hyperactivity disorder (ADHD). The predominantly dopaminergic mechanism of the psychostimulant actions has become more clearly defined. Neuroimaging and genetic studies are revealing the underlying neuropathology in ADHD. Novel extended-release (ER) MPH formulations now offer drug delivery options to overcome both the short-term actions of immediate-release (IR) MPH and the acute tolerance associated with the first-generation ER-MPH products. These novel MPH products apply proprietary technologies such as OROS (Alza), Diffucaps (Eurand) and SODAS (Elan) to offer both the convenience of once-a-day administration and absorption profiles resembling, to varying degrees, the standard multiple dose schedules of IR-MPH. The pharmacodynamics of the separate MPH enantiomers is in the process of further neuropharmacological characterisation. It is well established that dl-MPH undergoes marked stereoselective metabolism. Although l-MPH exhibits only minimal oral absorption, it may preferentially penetrate the brain, and interacts with ethanol to form the metabolite ethylphenidate. The newly approved resolved enantiomer product d-MPH is now available in an IR formulation, and when administered at one-half the dose to that of the racemate, is purported to produce a longer duration of clinical effect, despite essentially identical pharmacokinetics. A long-acting formulation of d-MPH, which employs the SODAS technology, is in the advanced stages of clinical development.

The multiple-dose pharmacokinetics and safety of ciprofloxacin, a new quinoline carboxylic acid derivative, were evaluated in normal volunteers. The drug was administered orally every 12 h during successive 7-day periods at doses of 250, 500, and 750 mg. Samples of serum, urine, and saliva obtained after the first dose on days 1, 4, and 7 of each dosing period were assayed by microbiological methods. Peak concentrations of ciprofloxacin in serum were achieved generally from 1 to 1.5 h after administration. Mean peak serum levels were 1.35 to 1.42 ,ug/ml after the 250-mg dose, 2.60 to 2.89 ,ug/ml after the 500-mg dose, and 3.41 to 4.21 ,ug/ml after the 750-mg dose. Terminal serum half-lives ranged from 3.8 to 4.3, 4.5 to 4.9, and 3.9 to 6.6 h after the 250-, 500-, and 750-mg doses, respectively. Mean concentrations of ciprofloxacin in urine samples collected 0 to 2 h after dosing were 205 to 261, 255 to 518, and 243 to 846 ,ug/ml after the 250-, 500-, and 750-mg doses, respectively. Between 30 and 45% of the dose was recovered in urine 0 to 12 h after drug administration. Mean concentrations of ciprofloxacin in saliva at 2 h after dosing were 0.43, 1.23, and 1.45 ,Ig/ml after the 250-, 500-, and 750-mg doses, respectively. These levels were 30 to 45% of the peak levels in serum and between 40 and 65% of the levels in serum measured 2 h after dosing. Ciprofloxacin was well tolerated.

The metabolic profile of niacin is influenced by the rate of niacin administration. This study characterizes the effect of administration rate on the pharmacokinetics of niacin and its metabolites. Twelve healthy males were enrolled in an open-label, dose-rate escalation study and received 2000 mg niacin at 3 different dosing rates. Plasma was analyzed for niacin, nicotinuric acid, nicotinamide, and nicotinamide-N-oxide. Urine was analyzed for niacin and the metabolites nicotinuric acid, nicotinamide, nicotinamide-N-oxide, N-methylnicotinamide, and N-methyl-2-pyridone-5-carboxamide. C(max) and AUC(0-t) for niacin and nicotinuric acid increased with an increase in dosing rate. The changes observed in plasma nicotinamide and nicotinamide-N-oxide parameters, however, did not correlate to dosing rate. The total amount of niacin and metabolites excreted in urine was comparable for all 3 treatments. However, with the increase in dosing rate, urine recovery of niacin and nicotinuric acid showed a significant increase, whereas N-methyl-2-pyridone-5-carboxamide and N-methylnicotinamide showed a significant decrease.

Objective The following comprehensive review describes the evolution of stimulant drug formulations used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Emphasis is placed on the basic and clinical pharmacology of the dl-methylphenidate (MPH) transdermal system (MTS). Methods The pharmacokinetic and pharmacodynamic literature pertaining to MPH and amphetamine enantiomers was reviewed in the context of ADHD therapy and MTS as a treatment option. Results MTS incorporates MPH into an adhesive monolithic matrix, using the free base form of the drug to facilitate transdermal absorption. MTS technology minimizes contact dermatitis by eliminating to need for percutaneous penetration enhancers. After a lag time of approximately 2 h, plasma concentrations of the therapeutic d-MPH isomer become detectable, then continuously rise over the course of the recommended 9 h wear time. Concentrations of l-MPH typically attain 40−50% that of d-MPH (vs. 1−2% following oral MPH). Unauthorized MTS removal poses some misuse liability and over 50% of MTS drug content remains in the discarded system. Conclusions While liquid or chewable MPH formulations overcome potential swallowing difficulties, as do sprinkled once-daily extended-release (ER) MPH products, only MTS addresses swallowing difficulties while also offering a flexible individualized MPH exposure time in a once-daily MPH regimen.

Purpose Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Methods Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. Results The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. Conclusion The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.