R. Bonn

Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects

In a single-blind, randomized, two-way crossover study with 12 healthy male volunteers, 60 μg of prostaglandin E1 (PGE1) or placebo was administered by intravenous infusion during a 120-min period. PGE1, 13,14-dihydro-PGE1 (PGE0) and 15-keto-PGE0 plasma concentrations were measured by a highly specific and sensitive GC-MS/MS method.Endogenous PGE1 plasma concentrations ranged between 1.2 and 1.8 pg·ml−1. Endogenous PGE0 and 15-keto-PGE0 plasma concentrations varied from 0.8 to 1.3 pg·ml−1 and from 4.2 to 6.0 pg/ml respectively. During intravenous infusion of PGE1, plasma PGE1 concentrations rose to a level twice as high as during the placebo infusion. In contrast, PGE0 plasma concentrations were 8 times higher during PGE1 infusion than during placebo infusion, and 15-keto-PGE0 plasma concentrations were 20 times higher.The new analytical method has thus been useful to describe the pharmacokinetics of PGE1 and its metabolites PGE0 and 15-keto-PGE0, during and after intravenous infusion of PGE1.

No Pharmacokinetic Interaction Between Lacosamide and Valproic Acid in Healthy Volunteers

Two open‐label, randomized, multiple‐dose clinical studies evaluated the potential for pharmacokinetic interaction between the antiepileptic drugs lacosamide and valproic acid. The influence of lacosamide on valproic acid pharmacokinetics (trial A) and valproic acid on lacosamide pharmacokinetics (trial B) was investigated in 32 healthy male volunteers, 16 in each trial. Volunteers in trial A received valproic acid (300 mg bid) with randomization to either early or late addition of lacosamide (200 mg bid). Those in trial B received lacosamide (200 mg bid) with randomization to either early or late addition of valproic acid (300 mg bid). Area under the concentration‐time curve during a 12‐hour dosing interval at steady state (AUCTSS) and maximum steady‐state plasma drug concentration (Cmax, ss) were measured for each drug alone and together and tested for equivalence. The point estimates (90% confidence intervals) for AUCt, ss and Cmax, ss were 104% (99%–109%) and 101% (97%–107%), respectively, for valproic acid and 100% (98%–103%) and 101% (96%–107%), respectively, for lacosamide, which were within the generally accepted equivalence range of 80% to 125%. No changes in the rate or extent of absorption, terminal half‐life, or time to maximum concentration were observed. These results suggest that lacosamide and valproic acid have no relevant pharmacokinetic drug‐drug interaction.

Bioequivalence of Intravenous and Oral Formulations of the Antiepileptic Drug Lacosamide

Background/Aims: To evaluate the bioequivalence of intravenous and oral lacosamide (tablet), an antiepileptic drug. Methods: Two randomized, single-dose (200 mg) trials were conducted: a 2-way trial (study A, 15-min infusion, oral tablet) and a 3-way crossover trial (study B, 30- and 60-min infusions, oral tablet). Twenty four healthy men participated in study A and 27 in study B. Eighteen blood samples were taken before to 72 h after lacosamide administration during each treatment period, followed by a 1-week washout. Safety and the ratio of intravenous/oral lacosamide for AUC0–tz (area under the concentration-time curve from zero up to the last measurable plasma concentration) and Cmax (maximum plasma concentration) were evaluated. Results: For AUC0–tz and Cmax, 90% confidence intervals for the ratio of intravenous/oral lacosamide fell within the predetermined bioequivalence range (80–125%) for 30- and 60-min infusions. In study A, all adverse events (AEs) were mild, with no discontinuations. In study B, 3 volunteers discontinued due to AEs; one serious AE (epiglottitis) was reported. No clinically relevant effects on vital signs, electrocardiograms or laboratory parameters and no AEs relating to infusion site were reported. Conclusion: Intravenous infusions (15, 30 and 60 min) of 200 mg lacosamide are as well tolerated as the oral tablet. Bioequivalence was demonstrated for 30- and 60-min infusions; therefore, direct conversion from oral to intravenous lacosamide, or vice versa, is possible.

Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers.After the sublingual spray Cmax was higher (39.0 ng·ml-1) and tmax was shorter (3.9 min) than after the sublingual (22.8 ng·ml-1 and 13.8 min) and peroral (16.9 ng·ml-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively.The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (emax=130%) and the time to emax (temax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.

Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve

SummaryThe time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAPd) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II–III) with elevated PADd at rest (≥15 mm Hg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAPd, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min.The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAPd, respectively. The mean time courses of the decrease in PAPd and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAPd and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAPd in the individual patient could not be predicted from the changes in a/b-ratio.

Pharmacodynamic and Pharmacokinetic Evaluation of a New Transdermal Delivery System with a Time‐Dependent Release of Glyceryl Trinitrate

The pharmacokinetics of glyceryl trinitrate (GTN) and its main metabolites as well as the hemodynamic effects of a new transdermal delivery system (TDS) were investigated in ten healthy male volunteers using a single blind, placebo‐controlled study design with an application period of active drug of 4 successive days. The adhesive‐type matrix system contains 20‐mg GTN and released about 75% in a time‐dependent manner. The plasma concentrations of GTN and its metabolites 1–2‐ and 1–3 glyceryl dinitrate reflected the time‐dependent release with higher plasma concentrations during the first 12 hours than during the second 12 hours. Continuous administration of the TDS, which released 15 mg GTN/day, caused an accumulation of GTN in the plasma (about 70% greater AUC at the fourth day in comparison with the first day). The total effect per dose on the a/b‐ratio of the digital pulse (height of the peak of the systolic wave divided by the height of the peak of the dicrotic wave) and the reflex tachycardia were diminished by about 50% and 37%, respectively, at the fourth treatment day. The effect on systolic blood pressure measured under orthostatic conditions was blunted already 8 hours after the first application. The effect of sublingually administered GTN on digital pulse was attenuated during administration and also 1 hour after removal of the last TDS. The effect was restored 8 to 12 hours after removal of the TDS. Thus, the discontinuous release of GTN from the new system does not prevent the decline of hemodynamic efficacy during continuous therapy.

Haemodynamic effects of glyceryl trinitrate following repeated application of a transdermal delivery system with a phasic release profile

SummaryThe haemodynamic effects and plasma concentrations of glyceryl trinitrate (GTN) and its dinitrate metabolites were investigated in 8 healthy male volunteers during 5 days of application of a new transdermal delivery system (TDS) with time-dependent release characteristics, which were considered to prevent or to diminish development of nitrate tolerance.On the first and fifth day of administration the following haemodynamic parameters were determined: digital pulse ratio of height of systolic peak to height of dicrotic wave (i.e.a/b-ratio), heart rate and systolic blood pressure under orthostatic conditions.Peak plasma concentrations of GTN were 139 and 155 pg·ml−1 on the first and fifth day of treatment, and the corresponding trough concentrations (i.e. 24 h after administration) were 52.5 and 36.6 pg·ml−1, respectively.Compared to placebo, the area under the effect curve of the a/b-ratio of the digital pulse was increased on the first (25.6%) and fifth day (13%). A significant increase of heart rate and a decrease of systolic blood pressure were seen only on the first day of treatment. The haemodynamic effects of sublingual GTN 0.8 mg were reduced by 69% (a/b-ratio) and 52% (standing heart rate) on the fifth day compared to the pretreatment values.Thus, the phasic release of GTN from the new TDS can be demonstrated by the time course of the plasma concentrations of GTN and its metabolites. Nevertheless, following repeated administration the hemodynamic effects are blunted.

Development of biphasic transdermal nitroglycerin delivery systems

Abstract A number of transdermal systems exist which provide steady nitrate levels over a period of 24 h. Recent investigations have identified the potential for development of nitrate tolerance with these dosage regimes. Therefore, novel delivery systems have been developed to reduce the incidence of tolerance. The design strategy and in vitro testing of such a delivery device is described. In vitro release across hairless mouse and human skin is compared. The data generated from these experiments are used to predict in vivo blood levels. The results are substantiated using computer simulations and experimentally determined in vivo levels.

Evaluation of Bioavailability and Pharmacokinetics of Two Isosorbide‐5‐Mononitrate Preparations in Healthy Volunteers

The objective of this study was to determine both the pharmacokinetic parameters and the bioavailability of two commercial 20‐mg isosorbide‐5‐mononitrate (IS‐5‐MN) preparations (test and reference preparation) after single oral administration. For this purpose, the test and the reference preparation were examined in 24 healthy male volunteers according to a randomized 2‐way cross‐over design, blood samples were withdrawn up to 24 hours postadministration, and plasma concentrations of IS‐5‐MN were quantified by a gas chromatography (GC) method. Both preparations led to peak plasma levels of approximately 360 ng/mL IS‐5‐MN in the mean 0.76 hour (test) and 0.94 hour (reference preparation) after application; the plasma half‐lives were about 5.2 hours, and for the areas under the curve (AUC(0‐∞)), mean values of 2741 (test preparation) and 2742 hour · ng/mL (reference preparation) were found. The statistical comparison (analysis of variance, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both IS‐5‐MN preparations. The undesired side effects/concomitant symptoms observed are known to occur after IS‐5‐MN administration.

Comparison of the Initial Hemodynamic Effects of Immediate‐Release versus Sustained‐Release Isosorbide‐5‐Mononitrate following Single Oral Doses

In this double‐blind, randomized, placebo‐controlled crossover study, the authors investigated the initial time course of effects of isosorbide‐5‐mononitrate (IS‐5‐MN) on hemodynamic parameters in 15 healthy male volunteers after administering a single oral dose of either an immediate‐release formulation (IS‐5‐MN 20 mg) or of a sustained‐release formulation (IS‐5‐MN 50 mg). The latter formulation released 15 mg IS‐5‐MN immediately, while 35 mg of the dose was sustained release. The onset of effect on the a/b‐ratio of the finger pulse curve (20 minutes after administration) and on heart rate following orthostatic challenge (30 minutes) was not different following ingestion of either the immediate‐release or the sustained‐release formulation. Only the systolic blood pressure following orthostatic challenge was affected earlier after ingestion of the immediate‐release form of IS‐5‐MN (10 vs. 30 minutes). There was no statistically significant difference in the maximum effect on the measured hemodynamic parameters between the two formulations. There was no significant difference with respect to the effect per dose between both of the active treatments (i.e., IS‐5‐MN 20 mg immediate release and IS‐5‐MN 50 mg sustained release) within 6 hours after administration. The hemodynamic findings were consistent with the observed rates of the increase of plasma concentrations of IS‐5‐MN following both formulations. Thus, the administration of the sustained‐release formulation of IS‐5‐MN 50 mg caused similar maximum effects when compared with an immediate‐release formulation (20 mg). While the onset of effect of IS‐5‐MN on the a/b‐ratio of the finger pulse curve and on heart rate following orthostasis was similar after administration of either the immediate‐ or the sustained‐release formulation, the onset of effect of the sustained‐release formulation on systolic blood pressure orthostasis was determined slightly later. However, the latter difference seems to be of minor clinical relevance.