Safety and Pharmacokinetics of PSD502 in Healthy Chinese Male and Female Volunteers: Two Randomized, Double-Blind, Placebo-Controlled, Phase I Trials.
Journal
Clinical drug investigation
ISSN: 1179-1918
Titre abrégé: Clin Drug Investig
Pays: New Zealand
ID NLM: 9504817
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
accepted:
25
05
2023
medline:
31
7
2023
pubmed:
29
6
2023
entrez:
28
6
2023
Statut:
ppublish
Résumé
PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals. Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed. Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration-time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials. PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals.
Sections du résumé
BACKGROUND AND OBJECTIVE
OBJECTIVE
PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals.
METHODS
METHODS
Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed.
RESULTS
RESULTS
Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration-time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials.
CONCLUSIONS
CONCLUSIONS
PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals.
Identifiants
pubmed: 37380910
doi: 10.1007/s40261-023-01277-4
pii: 10.1007/s40261-023-01277-4
doi:
Substances chimiques
Lidocaine
98PI200987
Lidocaine, Prilocaine Drug Combination
0
Prilocaine
046O35D44R
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
503-515Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG, et al. An update of the International Society of Sexual Medicine’s guidelines for the diagnosis and treatment of premature ejaculation (PE). J Sex Med. 2014;11(6):1392–422.
doi: 10.1111/jsm.12504
pubmed: 24848686
Shindel AW, Althof SE, Carrier S, Chou R, McMahon CG, Mulhall JP, et al. Disorders of ejaculation: an AUA/SMSNA guideline. J Urol. 2022;207(3):504–12.
doi: 10.1097/JU.0000000000002392
pubmed: 34961344
Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, Alexander J. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol. 2007;51(3):816–23 (discussion 24).
doi: 10.1016/j.eururo.2006.07.004
pubmed: 16934919
Carson C, Gunn K. Premature ejaculation: definition and prevalence. Int J Impot Res. 2006;18(Suppl 1):S5-13.
doi: 10.1038/sj.ijir.3901507
pubmed: 16953247
Gao J, Zhang X, Su P, Liu J, Xia L, Yang J, et al. Prevalence and factors associated with the complaint of premature ejaculation and the four premature ejaculation syndromes: a large observational study in China. J Sex Med. 2013;10(7):1874–81.
doi: 10.1111/jsm.12180
pubmed: 23651451
Salonia A, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al. European Association of Urology guidelines on sexual and reproductive health-2021 update: male sexual dysfunction. Eur Urol. 2021;80(3):333–57.
doi: 10.1016/j.eururo.2021.06.007
pubmed: 34183196
Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, et al. AUA guideline on the pharmacologic management of premature ejaculation. J Urol. 2004;172(1):290–4.
doi: 10.1097/01.ju.0000132159.61156.ea
pubmed: 15201797
Hellstrom WJ. Update on treatments for premature ejaculation. Int J Clin Pract. 2011;65(1):16–26.
doi: 10.1111/j.1742-1241.2010.02479.x
pubmed: 21155940
Keel CE, Dorsey PJ, Acker W, Hellstrom WJ. New concepts in the diagnosis and treatment of premature ejaculation. Curr Urol Rep. 2010;11(6):414–20.
doi: 10.1007/s11934-010-0144-2
pubmed: 20821354
Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85(1):11–28.
doi: 10.1016/S0163-7258(99)00048-0
pubmed: 10674711
Giuliano F, Clément P. Serotonin and premature ejaculation: from physiology to patient management. Eur Urol. 2006;50(3):454–66.
doi: 10.1016/j.eururo.2006.05.055
pubmed: 16844284
Mirone V, Arcaniolo D, Rivas D, Bull S, Aquilina JW, Verze P. Results from a prospective observational study of men with premature ejaculation treated with dapoxetine or alternative care: the PAUSE study. Eur Urol. 2014;65(4):733–9.
doi: 10.1016/j.eururo.2013.08.018
pubmed: 23993257
Wyllie MG, Hellstrom WJ. The link between penile hypersensitivity and premature ejaculation. BJU Int. 2011;107(3):452–7.
doi: 10.1111/j.1464-410X.2010.09456.x
pubmed: 20553259
Atikeler MK, Gecit I, Senol FA. Optimum usage of prilocaine-lidocaine cream in premature ejaculation. Andrologia. 2002;34(6):356–9.
doi: 10.1046/j.1439-0272.2002.00511.x
pubmed: 12472618
Busato W, Galindo CC. Topical anaesthetic use for treating premature ejaculation: a double-blind, randomized, placebo-controlled study. BJU Int. 2004;93(7):1018–21.
doi: 10.1111/j.1464-410X.2003.04773.x
pubmed: 15142155
Martyn-St James M, Cooper K, Ren K, Kaltenthaler E, Dickinson K, Cantrell A, et al. Topical anaesthetics for premature ejaculation: a systematic review and meta-analysis. Sex Health. 2016;13(2):114–23.
doi: 10.1071/SH15042
pubmed: 26599522
Henry R, Morales A, Wyllie MG. TEMPE: topical eutectic-like mixture for premature ejaculation. Expert Opin Drug Deliv. 2008;5(2):251–61.
doi: 10.1517/17425247.5.2.251
pubmed: 18248322
Dinsmore WW, Hackett G, Goldmeier D, Waldinger M, Dean J, Wright P, et al. Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int. 2007;99(2):369–75.
doi: 10.1111/j.1464-410X.2006.06583.x
pubmed: 17129234
Carson C, Wyllie M. Improved ejaculatory latency, control and sexual satisfaction when PSD502 is applied topically in men with premature ejaculation: results of a phase III, double-blind, placebo-controlled study. J Sex Med. 2010;7(9):3179–89.
doi: 10.1111/j.1743-6109.2010.01913.x
pubmed: 20584124
Dinsmore WW, Wyllie MG. PSD502 improves ejaculatory latency, control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III, multicentre, double-blind, placebo-controlled study. BJU Int. 2009;103(7):940–9.
doi: 10.1111/j.1464-410X.2009.08456.x
pubmed: 19245438
Zhou Q, Yu X, Shu C, Cai Y, Gong W, Wang X, et al. Analysis of CYP3A4 genetic polymorphisms in Han Chinese. J Hum Genet. 2011;56(6):415–22.
doi: 10.1038/jhg.2011.30
pubmed: 21412247
Olafuyi O, Parekh N, Wright J, Koenig J. Inter-ethnic differences in pharmacokinetics: is there more that unites than divides? Pharmacol Res Perspect. 2021;9(6): e00890.
doi: 10.1002/prp2.890
pubmed: 34725944
pmcid: 8561230
Cold CJ, Taylor JR. The prepuce. BJU Int. 1999;83(Suppl. 1):34–44.
pubmed: 10349413
Immerman RS, Mackey WC. A biocultural analysis of circumcision. Soc Biol. 1997;44(3–4):265–75.
pubmed: 9446966
McCoombe SG, Short RV. Potential HIV-1 target cells in the human penis. AIDS. 2006;20(11):1491–5.
doi: 10.1097/01.aids.0000237364.11123.98
pubmed: 16847403
Hellstrom W, Carson C, Wyllie M. 1494 PSD 502 appears to be effective in both circumcised and un-circumcised men with premature ejaculation (PE). J Urology. 2010;183(4S):e576-e.
McMahon CG. Dapoxetine: a new option in the medical management of premature ejaculation. Ther Adv Urol. 2012;4(5):233–51.
doi: 10.1177/1756287212453866
pubmed: 23024705
pmcid: 3441133
McMahon CG. Efficacy of dapoxetine in the treatment of premature ejaculation. Clin Med Insights Reprod Health. 2011;2(5):25–39.
Peng J, Fang D, Li H, Tang Y, Yuan Y, Cui W, et al. Efficacy of dapoxetine treatment in Chinese patients with premature ejaculation and possible factors affecting efficacy in the real-world practice. BMC Urol. 2020;20(1):11.
doi: 10.1186/s12894-020-0580-3
pubmed: 32013958
pmcid: 6998231
Buvat J, Tesfaye F, Rothman M, Rivas DA, Giuliano F. Dapoxetine for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries. Eur Urol. 2009;55(4):957–67.
doi: 10.1016/j.eururo.2009.01.025
pubmed: 19195772
Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62(Suppl. 3):10–21.
McMahon C, Kim SW, Park NC, Chang CP, Rivas D, Tesfaye F, et al. Treatment of premature ejaculation in the Asia-Pacific region: results from a phase III double-blind, parallel-group study of dapoxetine. J Sex Med. 2010;7(1 Pt 1):256–68.
doi: 10.1111/j.1743-6109.2009.01560.x
pubmed: 19878447
EMC. EMLA cream 5% (5g pack). 2017. https://www.medicines.org.uk/emc/product/871/smpc#gref . Accessed 18 May 2023.
Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48(3):143–57.
doi: 10.2165/00003088-200948030-00001
pubmed: 19385708
pmcid: 3644551
Abernethy DR, Greenblatt DJ. Impairment of lidocaine clearance in elderly male subjects. J Cardiovasc Pharmacol. 1983;5(6):1093–6.
doi: 10.1097/00005344-198311000-00027
pubmed: 6196560