Single Dose Comparative Bioavailability Study of Lisdexamfetamine Dimesylate as Oral Solution Versus Reference Hard Capsules in Healthy Volunteers.

Lisdexamfetamine is an inactive prodrug of dexamfetamine that is used for the second-line treatment of attention-deficit/hyperactivity disorder (ADHD) and moderate to severe binge eating disorder (BED). Once in the blood, the prodrug is hydrolyzed in erythrocyte cytosol, thus releasing the active dexamfetamine. We here present a fully validated HPLC-MS/MS analytical method for simultaneous determination of lisdexamfetamine and dexamfetamine in human plasma and the first published comparative bioavailability study of lisdexamfetamine including a GMP finished product formulated as oral solution. The Test (T)/Reference (R) ratios for the geometric means (%) of the primary pharmacokinetic (PK) parameters and their corresponding two-sided 90% confidence intervals (CIs) were contained within the predefined regulatory limits of 80.00-125.00% for both lisdexamfetamine and dexamfetamine. While for the lisdexamfetamine prodrug, PK results for the two formulations were slightly different due to the distinct dissolution state at administration, the PK parameters calculated for dexamfetamine were almost identical. A potential explanation of this phenomenon, already described in literature, is that biotransformation of lisdexamfetamine by red blood cells (rather than its release within the gastrointestinal tract) is the process controlling the rate of dexamfetamine delivery.

Single Dose Study Assessing the Pharmacokinetic and Metabolic Profile of Alverine Citrate in Healthy Volunteers.

Alverine citrate is a spasmolytic commonly prescribed in conditions such as irritable bowel syndrome, painful diverticular disease of the colon, and primary dysmenorrhea. While clinical efficacy data on alverine alone or in combination with simethicone is freely available, surprisingly little information regarding the pharmacokinetics and metabolism of alverine can be found in literature. The first HPLC-MS/MS analytical protocol for determination of alverine parent, 4-hydroxy alverine, N-desethyl alverine and 4-hydroxy alverine glucuronide in human plasma was developed and validated. The two validated methods were used for analyzing plasma samples collected during an open label, non-comparative, single dose, one-period, one-treatment, pharmacokinetic and metabolic profile study of Spasmonal® Forte 120 mg hard capsule, conducted in 12 fasting healthy male and female volunteers of Caucasian descent. The study confirmed previous suspicions that parent alverine is subject to high pharmacokinetic variability and also revealed that the metabolic process most susceptible to outlying performance in Caucasians is hydroxylation to the active metabolite 4-hydroxy alverine. Another interesting observation made is that alverine parent accounts for only 3%, whereas total 4-hydroxy alverine (free and conjugated) accounts for 94% of alverine-related moieties in circulation (based on comparisons of total exposure).

The Effect of Food on the Single-Dose Bioavailability and Tolerability of the Highest Marketed Strength of Duloxetine.

Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor indicated in adults for the treatment of major depressive disorder, diabetic peripheral neuropathic pain, and generalized anxiety disorder. The aim of these studies was to evaluate the effect of food on the pharmacokinetics and safety of duloxetine 60-mg gastroresistant hard capsules following single-dose administration. The data were obtained from 2 phase 1 bioequivalence studies, 1 in a fasting state and the other under fed conditions. Both studies have shown that, when administered as a single dose in the same prandial state, the test and reference duloxetine treatments were bioequivalent and exhibited similar safety profiles. The mean fed and fasting pharmacokinetic parameters and drug-related adverse events from the 2 studies were compared in order to assess the effect of food on the duloxetine bioavailability and respectively, tolerability. Administration of duloxetine in fed conditions increased peak plasma concentration by up to 30% and delayed mean time to peak concentration by an average of 1.15 hours while having an insignificant effect on extent of absorption (area under the plasma concentration-time curve in fed state within ±6% as compared with fasting conditions). Even though peak plasma levels were substantially higher in the fed state, there was no negative impact on the drug's safety profile. Actually, administration with food resulted in a lower average number of adverse events per single dose exposure. The negligible variation in overall systemic exposure suggests that efficacy remains unchanged irrespective of administration conditions; however, a better tolerability of the 60-mg dose is expected when the drug is taken with food.

Single-Dose Pharmacokinetic Properties and Relative Bioavailability of Different Formulations of Posaconazole Oral Suspension in Healthy Volunteers.

The rate and extent of absorption of drugs belonging to Biopharmaceutics Classification System class II are rate-limited by dissolution and highly dependent on the performance of the formulated product. The purpose of the present study was to investigate the potential impact of a surfactant and the particle size of the active substance on the in vitro drug dissolution profiles and in vivo pharmacokinetics of the poorly soluble drug posaconazole. A comparative physicochemical evaluation was conducted, and 3 formulations of posaconazole oral suspension were tested in various dissolution media compared with the reference product. In addition, a comparative bioavailability study was conducted in healthy volunteers under high-fat fed conditions. Bioequivalence was assessed based on plasma concentrations of the parent drug (posaconazole) measured by a validated high-pressure liquid chromatography-tandem mass spectrometry method. The 90% confidence intervals for Cmax and AUC0-72 least-squares mean T/R ratios of all 3 posaconazole formulations were within the bioequivalence acceptance range of 80.00% to 125.00%. The study was useful in the formulation development process and demonstrated that neither surfactant type nor particle size of the active substance within the studied range affected the extent or rate of absorption of posaconazole under the tested fed conditions.