Toxicokinetic evaluation of a selegiline transdermal system in the dog.

The toxicology and toxicokinetics of a selegiline transdermal system (STS) were evaluated in a 3 month dog study of daily 24 h applications of placebo 4, 8, or 12 STSs in 32 male and 32 female beagle dogs. Each STS delivered approximately 5 mg selegiline over 24 h. No drug-related signs of toxicity were noted in any group with respect to clinical observations, dermal effects, body weight, food consumption, hematology, urinalysis data, or ophthalmoscopic or electrocardiographic examinations. Clinical chemistry data revealed no consistent adverse effects except for an increase in alanine aminotransferase in dogs receiving 8 and 12 STSs. Histological evaluation of tissues revealed the presence of pigment in the Kupffer cells of dogs treated with 8 and 12 STSs. There were no pathology findings suggestive of hemolysis or cholestasis. The no-effect level (NOEL) was 4 STSs (2.9 mg kg-1 d-1). There were no degenerative or life-threatening toxic effects up to 12 STSs (8.5 mg kg-1 d-1). Gender-related differences in steady-state plasma levels were not observed. Steady-state plasma concentrations were similar to maximum plasma concentrations obtained in single-dose studies, suggesting that drug accumulation was not evident. Simulation of systemic exposure following oral administration of 16.8 mg kg-1 d-1 from previous toxicology studies indicated that selegiline exposure following 12 STSs is sixfold greater while N-desmethylselegiline, L-amphetamine, and L-methamphetamine exposure is 0.5, 0.15, and 0.14 times the exposure in the oral study. The threefold difference in NOEL between oral and transdermal studies in the dog (0.8 versus 2.9 mg kg-1 d-1) is probably related to greater L-amphetamine and L-methamphetamine exposure following oral administration. The reduction in metabolite formation, relative exposure of selegiline in the dog at the NOEL compared to oral toxicology studies, and margin of safety provided, given that the expected clinical dose is less than the dosage of oral Eldepryl (0.15 mg kg-1 d-1), documents the safety of the selegiline drug substance and indicates that additional toxicologic findings with the STS may not be expected.

Pressor response to tyramine after single 24-hour application of a selegiline transdermal system in healthy males.

Orally administered selegiline hydrochloride is a selective monoamine oxidase type B inhibitor at the recommended regimen of 10 mg/day, but it loses selectivity at higher doses. In bypassing first-pass metabolism, a 24-hour application of transdermally administered selegiline (7.8 mg/24 hr) yields fifty times greater systemic exposure than is provided by single oral doses. The current study was designed to demonstrate that, similar to the oral regimen, transdermally administered selegiline is devoid of the pressor effects associated with tyramine and classic monoamine oxidase type A inhibitors. A single-blind, staggered, parallel-group study of pressor response to tyramine during a single 24-hour application of one-quarter, one-half, or one selegiline transdermal system relative to baseline (drug-free) response to tyramine was conducted in three groups, each with five healthy male volunteers. The end point of pressor response was declared if a participant's systolic blood pressure rose by > 30 mmHg, heart rate decreased by > 25 bpm with an associated > 20-mmHg rise in systolic blood pressure, or a clinically significant change was observed in the electrocardiogram. Doses up to 600 mg were administered during the baseline phase and up to 200 mg during the active-treatment phase. Participants received escalating tyramine doses every 4 hours until the maximum or threshold dose was achieved. Doses up to 200 mg were tolerated without apparent increase in sensitivity in participants receiving one-quarter, one-half, or one selegiline transdermal system. All participants completed the trial, and no significant adverse events were reported. Monoamine oxidase type B inhibition was complete (100%) by 12 hours after initial application in all treatment groups while plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) after 24-hour application were unaffected relative to baseline. These results suggest that systemic selegiline levels may not predict the propensity for a hypertensive crisis associated with presumed nonselective doses and that the avoidance of peripheral monoamine oxidase type A inhibition in the gut via the selegiline transdermal system may provide a safe vehicle for administering selegiline at plasma levels beyond that which can be safely obtained after oral administration. These findings will need to be confirmed in a long-term dose setting.

Selegiline percutaneous absorption in various species and metabolism by human skin.

PURPOSE: A Selegiline Transdermal System (STS) is under development for indications which may not be optimally or safely treated with oral selegiline. Studies were conducted to evaluate the in vitro penetration and skin metabolism of selegiline in order to better understand the toxicological findings and the observed plasma levels of selegiline and its metabolites in animals and man. METHODS: In vitro penetration studies were conducted in four different species (male hairless mice, male and female rats, female dog and male Micropig) and compared to human skin. In another study, viable human skin was used to estimate the extent of metabolism of selegiline by human skin using Franz diffusion cells. RESULTS: Results indicated that female dog and male Micropig skin were reasonable animal models for 24 hour in vitro selegiline penetration through human skin. Penetration of selegiline through rat skin and hairless mouse skin was 2-fold and 3-fold higher than through human skin, respectively. Metabolism was negligible in human skin. Selegiline metabolites (L-methamphetamine and N-desmethylselegiline but not L-amphetamine) were detected at all time points but the extent of selegiline metabolism was negligible. The cumulative 24 hour in vitro selegiline permeation from a 1.83 mg/cm2 STS through human skin was 5.0 mg. This was similar to the in vivo permeation in humans as assessed by residual patch analysis. CONCLUSIONS: The similarity of dog and human skin permeation results support the use of the dog as a species for evaluating the toxicology of transdermally-administered selegiline. Selegiline is not metabolized cutaneously and hence the metabolic profile following STS administration is likely due to hepatic metabolism only.

Pharmacokinetics and safety of a selegiline transdermal system relative to single-dose oral administration in the elderly.

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.

Relative bioavailability of commercially available ibuprofen oral dosage forms in humans.

Two human bioavailability studies were conducted to assess the in vivo performances of recently marketed 200-, 300-, and 400-mg ibuprofen capsules relative to the innovator's 300- and 400-mg tablets when administered as single oral 300- or 400-mg doses. An ibuprofen oral solution was also administered in each trial. Within each study, the products were equivalent to each other and to the oral solution with respect to the extent of ibuprofen absorption. Absorption rates, however, differed markedly among the products studied. Ibuprofen was more slowly absorbed from the 300- and 400-mg capsules than from the respective strength tablets. The 200-mg capsule exhibited an absorption rate comparable to the 400-mg tablet but more rapid than the 400-mg capsule. It was concluded that two of the duplicator's 200-mg capsules were bioequivalent to one of the innovator's 400-mg tablet. The duplicator's 300- and 400-mg capsules were bioinequivalent to the innovator's 300- and 400-mg tablets, respectively, due to their slower rates of absorption.

Pharmacokinetics of erythromycin in normal and alcoholic liver disease subjects.

The objective of this study was to compare the pharmacokinetic behavior of erythromycin in normal volunteers with that in subjects with alcoholic liver disease. Six normal volunteers received 500 mg erythromycin as an intravenous infusion or as two 250-mg enteric-coated tablets in a crossover fashion. The pharmacokinetics of erythromycin after intravenous administration was best described as a two-compartment model. The elimination half-life was 1.6 +/- 0.7 hours (mean +/- S.D.) after the intravenous dose and 2.0 +/- 0.7 hours after the oral dose. In patients with alcoholic liver disease the elimination half-life after oral administration of two 250-mg enteric-coated tablets was 3.2 +/- 0.5 hours, significantly different from that in normal subjects, probably due to impaired metabolism. The difference in half-life does not require dosage adjustment in this patient population. The systemic availability of erythromycin was 33.5 per cent (range 10.5 to 79.3 per cent).

Influence of study design in assessing food effects on absorption of erythromycin base and erythromycin stearate.

We performed a series of six single-dose and multiple-dose studies to evaluate the effect of food on the absorption of erythromycin base and erythromycin stearate. When we used a single-dose design, we found that an unprotected erythromycin base preparation was absorbed extensively if a prolonged fast preceded administration of the drug. A shorter faster period (as occurs in clinical settings) dramatically reduced the absorption of unprotected base; however, film-coated tablets seemed to be as well protected as and were absorbed more rapidly than enteric-coated tablets when they were evaluated by single-dose testing procedures. In contrast, when a commercially available film-coated preparation of erythromycin base was evaluated in multidose fashion between meals (fasting), the drug was about 25% less well absorbed than commercially available enteric-coated base tablets. Finally, when commercially available film-coated erythromycin base and stearate formulations were administered with meals, both film-coated preparations were 43 to 59% less well absorbed than the enteric-coated base formulation. Furthermore, the enteric-coated base formulation performed equally well when administered either every 6 h between meals (fasting) or four times a day (immediately after meals and at bedtime). These studies document the need for multidose bioavailability techniques when the bioavailabilities of acid-labile drugs are evaluated.

Reversible metabolism and pharmacokinetics: application to prednisone-prednisolone.

The simplest three pharmacokinetic models which apply in cases of reversible metabolism are described. Area under the curve (AUC) relationships are described which allow one to make a choice of which one of the three models may apply in a particular case. Expressions for clearances and other pharmacokinetic parameters are given. It is shown that biexponential time courses are expected after bolus intravenous administration although distribution is not involved in the models. In some cases dose/AUC or infusion rate/steady-state concentration yield simple clearances, while in other cases they are complex. AUC data obtained following oral administration of 5 mg doses of prednisone and prednisolone to 16 normal volunteers were analyzed with the new concepts and one of the models was found to apply. This new interpretation of such data results in some significant changes from application of classical pharmacokinetics.

Pharmacokinetic interpretation of plasma cortisol and cortisone concentrations following a signle oral administration of cortisone acetate to human subjects.

The pharmacokinetic and biopharmaceutic profiles of a single dose of oral cortisone acetate were developed for 23 healthy normal adult volunteers using cortisone and cortisol plasma concentration data. Cortisone acetate was rapidly absorbed and converted to the therapeutic moiety cortisol. There was a linear increase in plasma concentrations and, therefore, areas under plasma concentration-time curves with increasing doses of 5, 10, and 25 mg. Twenty-five-mg doses given as 1 x 25 mg or 5 x 5 mg were found to be bioequivalent. The increased efficacy of oral over intramuscular cortisone acetate can be attributed to the increased conversion to cortisol as a result of first-pass metabolism following oral dosing.

Comparative bioavailability evaluation of erythromycin base and its salts and esters. I. Erythromycin estolate capsules versus enteric-coated erythromycin base tablets.

A randomized crossover study in 16 healthy volunteers given multiple doses of erythromycin base enteric-coated tablets or erythromycin estolate capsules revealed essentially no difference in the resultant plasma concentration of bioactive erythromycin. This similarity in bioactivity persisted despite the fact that total eryghromycin levels (bioactive erythromycin base plus bioinactive erythromycin propionate) were at least three times higher after administration of the estolate than after administration of the base.

The effect of colestipol hydrochloride on the bioavailability and pharmacokinetics of clofibrate.

Since it has been reported by several authors that colestipol HCl and clofibrate have an additive effect in lowering serum cholesterol levels, it was felt advisable to evaluate the blood levels of clofibrate when given simultaneously with colestipol HCl to see whether there was any evidence for drug interaction between the two products that might dictate a need for separation of their administration time. After concomitant single-dose administration, the serum p-chlorophenoxyisobutyric acid levels, bioavailability parameters, and pharmacokinetic parameters investigated provided no evidence for an interaction and suggested that colestipol and clofibrate can be administered concomitantly or at separated in tervals according to whichever dosage regimen is deemed advisable by the physician.

Double Latin square study to determine variability and relative bioavailability of methylprednisolone.

The variability and relative bioavailability of methylprednisolone tablets were evaluated utilizing a double Latin square crossover design in which each of 20 subjects was given four of five treatments. Three different lots of methylprednisolone tablets exhibited virtually identical absorption, with similar ranges and coefficients of variation of some selected bioavailability parameters indicative of lot-to-lot uniformity in bioavailability. Within-lot and between-lot uniformities in bioavailability also were similar, suggesting that the observed variability in serum methylprednisolone levels was not due to manufacturing process variables. With respect to intra-versus intersubject variability, no differences were found for the absorption rate or terminal half-life. In contrast, between-subject variability associated with extent of absorption was greater than that within subjects. Relative to an aqueous suspension, methylprednisolone tablets were fully bioavailable.

Decreased tetracycline bioavailability caused by a bismuth subsalicylate antidiarrheal mixture.

Oral coadministration of a single 250-mg tetracycline capsule and 60 ml of a bismuth subsalicylate antidiarrheal mixture reduced tetracycline absorption by 34% without appearing to perturb its absorption or disposition rate. A pronounced increase in intersubject tetracycline absorption variability also was noted. Apparently, the reduction in tetracycline bioavailability previously reported with a kaolin-pectin suspension is not peculiar to kaolin-pectin but can be expected with almost any antidiarrheal whose mechanism of action is adsorptive in nature.

Pharmacokinetic evaluation of a drug interaction between kaolin--pectin and clindamycin.

The effect of a kaolin--pectin antidiarrheal suspension on the bioavailability of orally administered clindamycin was evaluated by model-dependent pharmacokinetic techniques. Each subject's serum clindamycin concentration--time data in the absence of the kaolin--pectin suspension were fitted to a one-compartment open model with first-order absorption and lag time. The resulting disposition parameters were used to construct individual Wagner-Nelson absorption profiles, expressed as the cumulative relative fraction of clindamycin absorbed versus time following combined antidiarrheal--antibiotic therapy. For each subject, absorption persisted to varying degrees through 14 hr. On the average, the half-time for absorption was prolonged 20-fold (from about 16 min to more than 300 min). In contrast, extrapolation of the individual time courses of relative absorption to infinity revealed that the antidiarrheal had no effect on the extent of clindamycin absorption.

Influence of kaolin--pectin suspension on digoxin bioavailability.

The effect of a kaolin--pectin suspension on the bioavailability of orally administered digoxin was evaluated when both drugs were given concomitantly and when their time of administration was separated by 2 hr. Coadministration of the antidiarrheal with the cardiac glycoside delayed absorption of the latter and, at the same time, decreased by 62% the amount of drug absorbed. Intersubject variation in digoxin bioavailability also was increased more than twofold. When the kaolin--pectin suspension was given 2 hr before the cardiac glycoside, the digoxin absorption rate was not affected, although its relative extent of absorption was reduced by about 20%. In contrast, when the antidiarrheal was given 2 hr after digoxin, neither the rate nor the extent of absorption of the cardiac glycoside was perturbed. No change in the intersubject variability in digoxin bioavailability was noted whether the antidiarrheal was given 2 hr before or 2 hr after the cardiac glycoside.

Generic propoxyphene: need for clinical bioavailability evaluation.

Plasma level data on two investigational capsule formulations of propoxyphene with similar physicochemical parameters demonstrate that the formulations have different in vivo bioavailabilities. The potential bioavailability problems with water-soluble drugs and the lack of correlation of in vitro and in vivo parameters for equivalent drug formulations are discussed.

The clinical pharmacology of methylprednisolone sodium phosphate. I. Intramuscular route of administration.

Intramuscularly administered methylprednisolone sodium phosphate (Medrol Stabisol) in single doses of 40, 80, or 160 mg (methylprednisolone equivalents) had a similar effect as the same doses of methylprednisolone sodium succinate (Solu-Medrol) with regard to eosinophil suppression, elevation of glucose, white blood count differential shifts (lympholytic effect), urinary excretion of sodium and potassium, and localized (pain) and systemic side effects. The average plasma methylprednisolone concentration was approximately 20% higher after the intramuscular administration of methylprednisolone sodium phosphate than after methylprednisolone sodium succinate. The differences in plasma methylprednisolone levels produced by the two esters suggest that either hydrolysis of the succinate ester occurs more slowly or the succinate ester distributes more extensively. This difference in plasma level, however, is not reflected in any other pharmacologic evaluation of the two esters, e.g., both eosinophil depression and hyperglycemic response were identical. No clinically significant changes in the vital signs, standard hematology, and clinical chemistry parameters evaluated were noted after 21 successive doses (q.i.d. for five days with one dose in the morning of day 6) of 80 mg methylprednisolone sodium phosphate. An increase was noted in the systolic blood pressure from a pretreatment mean of 113 mm Hg to a posttreatment mean of 123 mm Hg and an increase in the body weight from a pretreatment mean of 177 pounds to a posttreatment mean of 183 pounds. No signs of adrenal suppression were found as judged by plasma cortisol and ACTH levels. Six (6/12) subjects of the methylprednisolone sodium phosphate group, one (1/12) subject of the vehicle group, and one (1/12) subject of the placebo (sterile saline) group reported the following systemic side effects: gas in stomach, headaches, anorectal itching, and dryness of itching of the skin. No trend was observed for any side effect reported. In these double-blind, randomized studies, single (40, 80, and 160 mg) and multiple (80 mg) intramuscular doses of methylprednisolone sodium phosphate were tolerated in healthy volunteers as well as the same doses of methylprednisolone sodium succinate and similar volumes of vehicle or placebo.