Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury.

Plasma concentration profiles of the K+ channel-blocking compound Fampridine were obtained from (1) control subjects (n = 6) following oral administration of doses of 10, 15, 20, and 25 mg and (2) patients with spinal cord injury (SCI) (n = 11) following a single oral dose of 10 mg of an immediate-release formulation. Plasma concentrations were determined using a reversed-phase ion-pair high-performance liquid chromatography (HPLC) assay with ultraviolet light detection employing liquid extraction. The drug was rapidly absorbed with a tmax approximately 1 hour for both groups; tmax was independent of dose. Cmax and AUC0-infinity were linearly related to dose, and t 1/2 was 3 to 4 hours for both groups. There were no obvious differences in the (10-mg) plasma concentration profiles between control subjects and SCI patients. The drug was well tolerated, with only mild and transient side effects of light-headedness, dysesthesias, and dizziness.

A steady-state evaluation of the bioavailability of chronotherapeutic oral drug absorption system verapamil PM after nighttime dosing versus immediate-acting verapamil dosed every eight hours.

To compare the steady state pharmacokinetics of the 200 mg verapamil PM CODAS (chronotherapeutic oral drug absorption system) formulation dosed nightly versus immediate-acting verapamil 80 mg tablets dosed three times daily, an open-label, single-dose, two-treatment, two-period, two-sequence, balanced, randomized crossover study was performed with a 7-day washout between two treatment periods. Twenty-four healthy male subjects completed the study. All subjects received CODAS verapamil PM 200 mg under fasting conditions dosed at nighttime or verapamil 80 mg dosed three times daily at 8-hour intervals in a randomized fashion. CODAS verapamil PM 200 mg dosed at night for 5 days results in a plasma profile with a lag time of approximately 4 hours suitable for nighttime dosing. Significantly lower plasma concentrations of both enantiomers of verapamil and norverapamil resulted in lower peak-to-trough fluctuations and should ensure the safety of the product. Both medications tested in this study were well tolerated by the group of healthy volunteers.

IPDAS: a novel technology brings new benefits when applied to naproxen sodium.

The Intestinal Protective Drug Absorption System (IPDAS) is a new oral drug delivery approach that is applicable to gastrointestinal (GI) irritant drugs, including the nonsteroidal anti-inflammatory drug (NSAID) class. Although naproxen, as the free acid or the sodium salt, has pharmacokinetic characteristics that are consistent with once-daily dosing, the GI irritant and ulcerogenic potential associated with a large bolus dose of naproxen precludes safe use of an immediate-release form. In addition, the desired pharmacodynamic activity of a once-daily dosage form of naproxen requires rapidly available naproxen for a prompt onset of analgesic activity, as well as a prolonged phase of absorption to provide 24-hour analgesic/anti-inflammatory activity. Naprelan (naproxen sodium; Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) controlled-release tablets are a unique dosage form designed to achieve the desired features of such a once-daily presentation. Through a series of in vivo studies, the pharmaceutical design features of the product have been confirmed in humans using a combination of imaging and pharmacokinetic characterization. In addition, the potential for limiting any undesirable GI adverse events has been supported by evaluation of the GI toxicity of Naprelan in specialized animal toxicity studies. Naprelan exhibited in vivo performance characteristics that support the hypothesis that, as a once-daily dosage form, it may demonstrate safety and efficacy advantages in clinical evaluation.

New developments in sustained-release antihypertensive therapy: formulation and pharmacokinetic considerations.

In order to achieve a consistently absorbed form of nifedipine over 24 hours, a novel formulation approach, INDAS, was used to develop a once-daily, sustained-release (SR) form of nifedipine that could provide effective control of blood pressure at a low total daily dose. The pharmacokinetic characteristics of this new formulation of nifedipine-SR were compared with those of divided doses of conventional nifedipine. The SR formulation was shown to achieve a lower peak plasma nifedipine level but with a prolonged plasma profile characterized by an extended time to peak plasma levels (Tmax), a higher trough plasma level, a longer apparent half-life, and a markedly lower peak-to-trough fluctuation in plasma nifedipine concentrations. In a separate study, the gastrointestinal transit parameters and physical characteristics of the SR tablet were evaluated. This study established that the large intestine is the major site of residence and absorption for this dosage form. The physical erosion and disintegration characteristics of the SR formulation are such that a well-maintained absorption of nifedipine is consistently achieved over the 24 hour dosing interval.

Effectiveness of once-daily monotherapy with a new nifedipine sustained release calcium antagonist.

Data from 2 separate multicenter, double-blind clinical studies following the same protocol, except for the selection of doses, were pooled to evaluate the efficacy and tolerability of fixed doses of a new sustained-release (SR) formulation of nifedipine compared with placebo in 388 patients with mild to moderate uncomplicated essential hypertension. After a 3-6 week placebo washout period, the patients were randomized to receive either placebo or nifedipine SR-20 mg (study I only), 50 mg, 100 mg, or 150 mg (study II only). Among the 278 patients who completed 6 weeks of active therapy, mean supine diastolic blood pressure reductions from pretreatment baseline were 5.9, 9.3, 9.2, 11.1, and 13.2 mm Hg in the placebo, 20-, 50-, 100-, and 150-mg groups, respectively. The reductions achieved in each of the nifedipine SR groups were statistically significant versus baseline values (p less than 0.001). All nifedipine-SR doses reduced supine systolic blood pressure significantly more than placebo (p less than 0.001). In addition, there was a significant linear relationship between the log of the dose and the blood pressure reduction (p less than 0.05). Automated ambulatory blood pressure recordings performed in 221 of the patients showed that the blood pressure was lowered evenly through the entire 24-hour dosing period. The doses that were effective and associated with the fewest adverse reactions were 20 mg and 50 mg once daily.

Pharmacokinetic properties and antihypertensive efficacy of once-daily diltiazem.

The pharmacokinetic and clinical characteristics of a once-daily formulation of diltiazem are described. In a 20 subject, 5 day, steady-state pharmacokinetic study, 120 and 240 mg of once-daily diltiazem were bioequivalent on a dose-adjusted basis and were bioequivalent to a conventional reference product administered four times daily. The conventional formulation showed marked diurnal variation in its pharmacokinetics. Plasma concentrations following its administration at 2100 and 0300 h were significantly lower than following administration at 0900 and 1500 h. One hundred forty-four hypertensive patients completed a 16 week placebo-controlled, dose-titrated study examining the effects of once-daily diltiazem at doses of 120, 240, and 360 mg. Blood pressure was measured manually and (in 121 patients) by ambulatory evaluation. Following dose titration, diltiazem given once daily reduced blood pressure with significant effects present at 24 h following drug administration. Ambulatory blood pressures were lower than those measured manually and data from the manual measurements demonstrated a placebo effect suggested to result primarily from investigator bias. The placebo-adjusted reduction in blood pressure 24 h following a dose of diltiazem was approximately 5 mm Hg and was comparable for manual (supine and standing) and ambulatory measurements. Diltiazem was well tolerated. The only significant findings were of tiredness/dizziness (9 patients of 144) or oedema (also 9 of 144). The incidence of headache was not different than placebo. On both pharmacokinetic and pharmacodynamic grounds, the results indicate that diltiazem can be formulated in a manner suitable for once-daily antihypertensive use.

Once-daily verapamil in the treatment of mild-to-moderate hypertension: a double-blind placebo-controlled dose-ranging study.

Supine office blood pressures (SOBP) and 24-hour automated ambulatory blood pressure monitorings (AABPM) showed blood pressure reductions from a stable baseline to active treatment with 120-, 240-, and 480-mg doses of a new verapamil QD capsule (solid-spheroidal-oral once-daily drug-absorption system: (SODAS) in patients with mild-to-moderately severe (diastolic blood pressures 95-119 mm Hg) essential hypertension. Reductions were documented at 24 hours, hourly, and by the 24 hour average, using SOBP and AABPM, after the once-daily verapamil administration. Both SOBP and the 24-hour average by AABPM were significantly reduced from baseline by active verapamil treatment of 120-, 240-, and 480-mg doses. In comparison to verapamil QD (0 mg), blood pressure reductions from baseline to active treatment were significant at the 240- and 480-mg doses but not at the 120-mg dose. There was a significant linear dose response. This verapamil formulation (SODAS) was effective throughout the 24-hour period after once-daily dosing.

Clinical and pharmacokinetic properties of a transdermal nicotine patch.

We examined the pharmacokinetics of a transdermal nicotine patch and evaluated the usefulness of such a patch in a pilot smoking-cessation program. Use of the patch was associated with plasma nicotine concentrations that were comparable to smoking or to the use of other smoking-cessation devices. However, these plasma concentrations were maintained for 24 hours, and the patch appeared to be suitable for use once a day. Its use in a 6-week placebo-controlled double-blind study resulted in a significant degree of smoking cessation or in reduction of smoking activity. The findings suggest that it may be valuable to extend investigations to a larger population and that transdermal nicotine may have a useful role in smoking-cessation therapy.

Pharmacokinetic properties and clinical efficacy of once-daily sustained-release naproxen.

The pharmacokinetics and clinical efficacy of a once-daily sustained-release formulation of naproxen (sodium salt) have been compared with those of conventional-release agents. In a single dose pharmacokinetic study, the rate of absorption of the sustained-release preparation was less than that of a conventional-release preparation but the extent of absorption was the same. As is the case with conventional-release naproxen, food decreased the rate but not the extent of absorption of the sustained-release formulation. On multiple dose administration for 7 days, the AUC and average concentrations of the sustained release preparation (1 g daily) were the same as those for conventional release preparations of naproxen sodium (250 mg four times daily) and naproxen free acid (500 mg daily). The conventional-release sodium salt was absorbed more quickly with no differences in bioavailability. A double-blind clinical comparison in patients with osteoarthritis showed the sustained-release preparation (1 g daily) to be equivalent in efficacy to conventional naproxen capsules (500 mg twice daily) but to have a significantly lower incidence of gastrointestinal side-effects. The results suggest that sustained-release naproxen sodium has potential for use as a once-daily treatment for inflammatory disease.

Transdermal delivery of nicotine in normal human volunteers: a single dose and multiple dose study.

The absorption of nicotine delivered by a transdermal delivery system (TDS) was investigated in two separate studies, (A) a dose proportionality study and (B) a multiple dose study. In the dose range of 15-60 mg nicotine, the AUC and Cmax values were proportional to the dose. The levels achieved were in the same range as reported in smokers, following absorption from nicotine chewing gum. The TDS used in the present study produced sustained levels of nicotine for 24 h. No significant accumulation of nicotine was evident as a result of multiple dose administration using a 30-mg nicotine patch. Absorption of nicotine from the TDS was 80-90% and the rate of delivery was similar during both studies.