Tolerability and pharmacokinetics of avanafil, a phosphodiesterase type 5 inhibitor: a single- and multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers.

BACKGROUND: Avanafil is a selective phosphodiesterase type 5 inhibitor being developed for the treatment of erectile dysfunction. OBJECTIVE: This study was conducted to meet Korean regulatory requirements for the marketing of avanafil. To this end, tolerability and pharmacokinetic properties of single and multiple oral doses of avanafil in healthy Korean male volunteers were assessed. METHODS: A double-blind, randomized, placebo-controlled, parallel-group, dose-escalation study was conducted at the Asan Medical Center (Seoul, Korea). Subjects were randomized to receive either drug or placebo in blocks according to each dose. Subjects were randomly allocated to receive 50-, 100-, or 200-mg tablets of avanafil or placebo once daily for 7 days (avanafil:placebo, 8:2 in each dose group). Tolerability was assessed by monitoring vital signs and results of laboratory tests, 12-lead ECGs, and color discrimination tests. Blood samples of approximately 6 mL were collected in heparinized tubes before and 0.1, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after drug administration on days 1 and 7. Plasma concentrations of avanafil were measured using LC-MS/MS. Pharmacokinetic parameters of avanafil on days 1 and 7 were determined by noncompartmental analysis and compared among the 3 dose groups. RESULTS: Of the 32 healthy male subjects initially enrolled, 30 completed the study. The mean (SD) age, height, and weight of the participants were 23.4 (1.7) years, 175.0 (5.4) cm, and 70.3 (8.9) kg, respectively. Adverse events were reported by 20 of 25 subjects (80%) taking avanafil and by 4 of 6 (67%) taking placebo. No serious adverse events were reported, and there were no clinically relevant changes in vital signs, ECG recordings, physical examination findings, or color discrimination test results. All the adverse events resolved spontaneously. Avanafil reached a mean T(max) at 0.33 to 0.52 hour after dosing and then declined, with a mean apparent t1/2 of 5.36 to 10.66 hours. AUC and C(max) were proportional to dose, and the mean accumulation index on day 7 after a single daily dose of avanafil was 0.98. CONCLUSION: Avanafil was generally well tolerated and had linear pharmacokinetic properties at daily doses of 50 to 200 mg over 7 days in these healthy Korean male volunteers. Korean National Study Registration Number: 3466.

Synergistic absorption enhancement of salmon calcitonin and reversible mucosal injury by applying a mucolytic agent and a non-ionic surfactant.

The present study investigated the intestinal absorption enhancement of salmon calcitonin (SCT) and the intestinal mucosal damage when a mucolytic agent and a non-ionic surfactant were administered simultaneously to rats. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X -100, TX-100) were chosen as the model mucolytic agent and the non-ionic surfactant, respectively. Dosing solutions containing these agents were administered directly into the rat jejunum, and the bioavailability of SCT up to 2 h was determined. NAC and TX-100, when they were used alone at a dose of 1 mg/head, did not show the apparent enhancement compared to the control. However, simultaneous use of NAC and TX-100 enhanced the intestinal absorption of SCT in a synergistic manner, and absolute bioavailability increased 12.5-fold compared to the control. The effect of NAC and TX-100 on SCT absorption was not dependent on their doses over the range of 0.2-2 mg/head, and the maximum effect was obtained at a dose of 1mg/head. Absorption enhancement of SCT by a combination of NAC and TX-100 was compared to those from the classical absorption enhancers. Absorption-enhancing ability of the combination of NAC and TX-100 was significantly higher than those of sodium deoxycholate, citrate, and the combination of citrate and taurocholate, and was comparable with that of the combination of citrate and taurodeoxycholate. Finally, the intestinal mucosal damage caused by the combination of NAC and TX-100 was assessed using a capsule device. Acute damage on intestinal mucosa was observed when they were exposed into rat intestine, but this morphological damage was found to be reversible. All these results suggest that simultaneous use of a mucolytic agent and a non-ionic surfactant would offer a potentiality for peroral delivery of peptide drugs like SCT.

Twenty-six week carcinogenicity study of ampicillin in CB6F1-TgrasH2 mice.

As a part of the ILSI-HESI Alternative to Carcinogenicity Testing (ACT) program, we performed a 26-week carcinogenetic study of nonmutagenic drug, ampicillin (ABPC) in Tg-rasH2 mice. ABPC was given to Tg-rasH2 mice (0, 350, 1000, 3000 mg/kg, p.o.) and Non-Tg mice (0, 3000 mg/kg, p.o.) daily for 26 weeks. As a positive control, a single dose of MNU was administered once to Tg-rasH2 mice (75 mg/kg, i.p.). In this study, Tg-rasH2 mice did not demonstrate any increases in tumor development in response to ABPC. Thus, ABPC had no carcinogenicity in the 26-week carcinogenesis study in Tg-rasH2 mice or in a 2-year carcinogenesis study in B6C3F1 mice.