The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects.

INTRODUCTION: A new combination tablet containing sublingual testosterone and oral buspirone (T+B) was developed to benefit a subgroup of women suffering from female sexual interest/arousal disorder, caused by dysfunctionally overactive sexual inhibition. AIM: The aim of this study was to compare the effect of food intake on the pharmacokinetics of buspirone, administered as a dual-route, dual-release combination tablet containing 0.5 mg testosterone (T) and 10 mg buspirone (B). METHODS: 19 healthy women took T+B under fed and fasted conditions during 2 overnight visits. The blood was sampled over a 24-hour period to determine the pharmacokinetics of buspirone and its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP). Total testosterone levels were also assessed, at 5 time points and for quality control purposes only, as sublingual testosterone uptake is not expected to be influenced by prior food intake. MAIN OUTCOME MEASURE: PK profiles of buspirone and 1-PP. RESULTS: For buspirone, the 90% confidence intervals (CIs) of the observed fed/fasted ratios for the plasma area under the curve (AUC)0-last, AUC0-inf, and Cmax after administration of T+B were not contained within the prespecified bounds of 80% and 125%, except for the lower bound of AUC0-inf. However, the 90% CIs of the observed fed/fasted ratios for the plasma AUC0-last, AUC0-inf, and Cmax of 1-PP were contained within the prespecified bounds, with the exception of the upper bound for Cmax. The mean AUCs and Cmax for 1-PP did not differ between fed and fasted conditions. CONCLUSIONS: Administration of T+B after high-caloric food intake increased the bioavailability of buspirone but did not result in differences in Tmax when compared with fasted conditions. Both in fed and fasted conditions, T+B was generally well tolerated and safe. Exposure of 1-PP in fed and fasted conditions was comparable in both conditions. These results demonstrate that T+B can safely and effectively be used in both fed and fasted states. Gerritsen J, Bloemers J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects. J Sex Med 2020;8:186-194.

The Effect of Food on the Pharmacokinetics of Sildenafil after Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects.

INTRODUCTION: Female sexual interest/arousal disorder (FSIAD) affects many women worldwide, but pharmacological treatment options are scarce. A new medicine being developed for FSIAD is an on-demand, dual-route, dual-release drug combination product containing 0.5 mg testosterone (T) and 50 mg sildenafil (S), referred to here as T+S. AIM: The aim of this study was to compare the effect of a fed and a fasted state on the pharmacokinetics of sildenafil following administration of T+S. METHODS: Eighteen healthy women were administered T+S under fed and fasted conditions during 2 separate overnight visits in this randomized, open-label, balanced, 2-period, 2-treatment, 2-sequence crossover study. MAIN OUTCOME MEASURES: The pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil were determined over a 24-hour period. Total testosterone was assessed only at a limited number of time points for quality purposes, as sublingual uptake is not expected to be affected by food intake. RESULTS: The observed geometric mean ratios (GMRs) and 90% confidence intervals of sildenafil were not all contained within the prespecified bounds (0.80, 1.25). The GMR (90% CI) for plasma AUC0-last was 1.2753 (0.9706-1.6755); for AUC0-14h, it was 1.7521 (1.0819-2.8374); and for Cmax, it was 1.5591 (0.8634-2.8153). Only lower limits of the CIs fell within the bounds. For N-desmethyl sildenafil, the GMR (90% CI) for AUC0-last was 0.8437 (0.6738-1.0564); for AUC0-10h, it was 1.0847 (0.7648-1.5383); and for Cmax, it was 1.0083 (0.6638-1.5318). Only the GMRs were contained within bounds. No differences were observed between plasma testosterone Cmax and Tmax under fed and fasted conditions, which is in line with expectations for a sublingual administration. CLINICAL IMPLICATIONS: The T+S combination tablet ruptures too late when taken in a fasted state and should therefore not be taken on an empty stomach. STRENGTHS & LIMITATIONS: This is a well-controlled study that provides important insights into the performance characteristics of the delayed-release coating of the combination tablet. The higher variability of the pharmacokinetic parameters in the fasted state was caused by severely delayed rupture in one-third of the women. A reason for this is proposed but the present data do not explain this phenomenon. CONCLUSION: The pharmacokinetics of sildenafil from this modified-release tablet are more robust under fed conditions as compared to the artificial fasted condition where no food is consumed 10 hours prior to and 4 hours after dosing. The dosing situation under the tested fasting condition does not represent the expected common use of this product. Patients should, however, be instructed not to take the tablet on an empty stomach. Bloemers J, Gerritsen J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Sildenafil After Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects. J Sex Med 2019; 19:1433-1443.

Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation.

AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. RESULTS: Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng ml-1 (CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng ml-1 (coefficient of variability, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 ± 0.7 min after administration of 2.5 mg intravenous midazolam, 7 ± 4.4 min after 2.5 mg Nazolam, and 4 ± 1.8 min after 5 mg Nazolam. Sedation duration was 118 ± 95.6 min for 2.5 mg intravenous midazolam, 76 ± 80.4 min for 2.5 mg Nazolam, and 145 ± 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage. CONCLUSIONS: This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.

In vitro iontophoresis of R-apomorphine across human stratum corneum. Structure-transport relationship of penetration enhancement.

To achieve a therapeutical effect of the anti-Parkinson's drug R-apomorphine via iontophoresis delivery, enhancement strategies in vitro were explored using three structurally related enhancers, lauric acid (LA), dodecyltrimethylammonium bromide (DTAB) and Laureth-3 oxyethylene ether (C(12)EO(3)). Human stratum corneum and shed snake skin were pretreated with 0.15 M each enhancer solution in propylene glycol (PG). Thereafter, passive diffusion, iontophoretic transport and post-iontophoretic passive diffusion were investigated. Compared to the control (PG pretreatment), a slight inhibition on both passive and iontophoretic delivery was observed with cationic surfactant DTAB pretreated stratum corneum. Pretreatment with anionic surfactant LA resulted in a great enhancement on passive delivery, but only a small enhancing effect on the iontophoretic delivery. Unlike the others, the nonionic surfactant C(12)EO(3) substantially increased iontophoretic transport rate of R-apomorphine by 2.3-fold, whereas passive delivery was basically unchanged or slightly affected. The magnitude of enhancing effect of C(12)EO(3) was dependent on the surfactant concentration and the pretreatment duration. Moreover, comparison of transport data through shed snake skin with human stratum corneum indicates that both shunt- and intercellular pathways are involved in the iontophoretic transport of R-apomorphine.