Safety, Tolerability and Pharmacokinetics  of a Novel Triaminopyrimidine ZY-19489: A  Randomised Double-blind Placebo-control  Phase-1 Study among Healthy Indian Participants

Kevinkumar A Kansagra; Hardik B Patel; Gaurav A Jansari; Taufik Momin; Ashok Ghoghari; Ajay Barot; Harilal V Patel

Kevinkumar A Kansagra Zydus Research Centre, Clinical R&D, Zydus Lifesciences Limited, Moraiya, Ahmedabad, Gujarat, India
Hardik B Patel Zydus Research Centre, Clinical R&D, Zydus Lifesciences Limited, Moraiya, Ahmedabad, Gujarat, India.
Gaurav A Jansari Zydus Research Centre, Clinical R&D, Zydus Lifesciences Limited, Moraiya, Ahmedabad, Gujarat, India
Taufik Momin Zydus Research Centre, Clinical R&D, Zydus Lifesciences Limited, Moraiya, Ahmedabad, Gujarat, India.
Ashok Ghoghari Zydus Research Centre, Clinical R&D, Zydus Lifesciences Limited, Moraiya, Ahmedabad, Gujarat, India.
Ajay Barot Zydus Research Centre, Clinical R&D, Zydus Lifesciences Limited, Moraiya, Ahmedabad, Gujarat, India.
Harilal V Patel Zydus Research Centre, Clinical R&D, Zydus Lifesciences Limited, Moraiya, Ahmedabad, Gujarat, India

Keywords: ZY19489, Safety, Pharmacokinetic, Healthy Participants, Antimalarial

Abstract

Background: ZY-19489 is a triaminopyrimidine comprising the novel antimalarial class.

Methods: This was a phase-1, two-part double-blind, placebo-controlled study conducted in Ahmedabad, India. Part-1 was a single-dose singlecohort study. Part-2 was a multiple-ascending-dose study. Healthy participants aged 18-55 years were included. The primary objective was to evaluate the safety and tolerability of ZY-19489 in healthy adult Indian participants. This study was registered with CTRI/2021/08/035449 and on clinicaltrials.gov (NCT05206201).

Findings: Eight participants were enrolled in part-1 (450 mg) and 16 participants were enrolled in part-2, a multiple ascending dose part, (two cohorts; 300 and 500 mg once daily for three days). All participants were randomised to a 3:1 ratio (ZY-19489:placebo) within the cohort. The majority of adverse events (AEs) reported were mild in severity. One of six participants in part-1 and one of twelve participants in part-2, exposed to ZY-19489, experienced grade-2 AEs (enteric fever, dengue, and leg pain). One of six participants in part-1 and one of twelve participants in part-2, exposed to ZY-19489, experienced grade-3 AEs (GGT increase and epigastric pain). Following single-dose administration, ZY-19489 displayed slow oral absorption with a median Tmax of 7.5 h and a mean elimination half-life of 90 h. Following multiple dose administration of ZY-19489 for three consecutive days, on day 3, the maximum plasma concentration was achieved at 6.25 h (median Tmax) after dosing.

Conclusion: ZY-19489 was well-tolerated up to 500 mg once a day for three days. It displayed good oral absorption, dose-proportional increase in exposure, and long elimination half-life.

How to cite this article:
Kansagra KA, Patel HB, Jansari GA, Momin T, Ghoghari A, Barot A, Patel HV. Safety, Tolerability and Pharmacokinetics of a Novel Triaminopyrimidine ZY-19489: A Randomised Double-blind Placebo-control Phase-1 Study among Healthy Indian Participants. J Commun Dis. 2023;55(2):53-66.

DOI: https://doi.org/10.24321/0019.5138.202325

References

World Health Organization [Internet]. World Malaria Report 2022; 2022 [cited 2023 Jun 28]. Available

from: https://www.who.int/teams/global-malaria programme/reports/world-malaria-report-2022

[Google Scholar]

Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT, Thanh NV, Jittamala P, Hanboonkunupakarn B,

Chutasmit K, Saelow C, Runjarern R, Kaewmok W, Tripura R, Peto TJ, Yok S, Suon S, Sreng S, Mao S,

Oun S, Yen S, Amaratunga C, Lek D, Huy R, Dhorda M, Chotivanich K, Ashley EA, Mukaka M, Waithira N,

Cheah PY, Maude RJ, Amato R, Pearson RD, Gonçalves S, Jacob CG, Hamilton WL, Fairhurst RM, Tarning J,

Winterberg M, Kwiatkowski DP, Pukrittayakamee S, Hien TT, Day NP, Miotto O, White NJ, Dondorp AM.

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria

in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet

Infect Dis. 2019 Sep;19(9):952-61. [PubMed] [Google Scholar]

Hameed PS, Solapure S, Patil V, Henrich PP, Magistrado PA, Bharath S, Murugan K, Viswanath P, Puttur

J, Srivastava A, Bellale E, Panduga V, Shanbag G, Awasthy D, Landge S, Morayya S, Koushik K, Saralaya

R, Raichurkar A, Rautela N, Choudhury NR, Ambady A, Nandishaiah R, Reddy J, Prabhakar KR, Menasinakai S,

Rudrapatna S, Chatterji M, Jiménez-Díaz MB, Martínez MS, Sanz LM, Coburn-Flynn O, Fidock DA, Lukens AK,

Wirth DF, Bandodkar B, Mukherjee K, McLaughlin RE, Waterson D, Rosenbrier-Ribeiro L, Hickling K,

Balasubramanian V, Warner P, Hosagrahara V, Dudley A, Iyer PS, Narayanan S, Kavanagh S, Sambandamurthy

VK. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun. 2015 Mar

;6(1):6715. [PubMed] [Google Scholar]

Barber BE, Fernandez M, Patel HB, Barcelo C, Woolley SD, Patel H, Llewellyn S, Abd-Rahman AN, Sharma S, Jain

M, Ghoghari A, Resta ID, Fuchs A, Deni I, Yeo T, Mok S, Fidock DA, Chalon S, Möhrle JJ, Parmar D, McCarthy JS,

Kansagra K. Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489:

a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot foodeffect study, and volunteer infection study. Lancet Infect Dis. 2022 Jun;22(6):879-90. [PubMed] [Google Scholar]