Fiona Vanobberghen (1,2), Melissa Penny (1,2), Urs Duthaler (1,2), Peter Odermatt (1,2), Somphou Sayasone (3), Jennifer Keiser (1,2), Joel Tarning (4,5)
(1) Swiss Tropical & Public Health Institute, Basel, Switzerland; (2) University of Basel, Basel, Switzerland; (3) National Institute of Public Health, Vientiane, Lao PDR; (4) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; (5) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Objectives: There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini [1], as there is only one registered drug (praziquantel). Oral tribendimidine is a candidate drug with high efficacy against O. viverrini [2]; its pharmacokinetic (PK) properties are unknown yet essential to inform dosing and drivers of cure [3].
Methods: Two phase IIa trials were conducted in Laos in 68 O. viverrini-infected adults receiving single oral doses of 25-600 mg, with the same methodology but study 1 used 200 mg tablets and study 2 used 50 mg tablets (known different absorption properties). Venous whole-blood, plasma and capillary dried blood spot (DBS) were sampled frequently, and concentrations of the two active tribendimidine metabolites p-(1-dimethylamino ethylimino)aniline (dADT) and acetylated dADT (adADT) were measured. O. viverrini egg burden in stool was assessed at enrolment and 21 days later, with cure being no eggs. The two studies were pooled and population PK were assessed using nonlinear mixed-effects modelling with NONMEM v7. We assumed fixed renal dADT clearance of 35%, with the remainder metabolising into adADT [3]. Values below the quantification limit were treated as missing data. We include body weight with allometric scaling and assessed other covariates by visual inspection and stepwise selection. We used univariable logistic regression to assess the relationship between PK and cure.
Results: A six-transit absorption model followed by a one-compartment disposition model for each metabolite described the data well. 10 year older age was associated with 10% lower dADT clearance. Study 1 had 84% higher mean transit time, 66% higher dADT volume of distribution (VC/F) and 583% higher adADT VC/F than study 2.
For a 200 mg dose, the median dADT maximum concentration (Cmax) was 2,460 nmol/L at median 6.83 hours; median half-life was 4.45 hours and median AUC 22,400 nmol/L. Highest cure rates (≥55% of participants) were observed with doses ≥100 mg. Higher dADT Cmax and AUC were associated with cure (both p=0.003).
Conclusion: We have for the first time described the population PK of tribendimidine. Known differences in the 200 mg versus 50 mg tablet formulations were captured by the covariate modelling. Further studies are needed to validate the structural model and confirm covariate relationships.
References:
[1] Keiser J, Utzinger J. Emerging Foodborne Trematodiasis. Emerg Infect Dis. 2005 Oct;11(10):1507–14.
[2] Soukhathammavong P, Odermatt P, Sayasone S, Vonghachack Y, Vounatsou P, Hatz C, et al. Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, tribendimidine, and praziquantel in patients with Opisthorchis viverrini: a randomised, exploratory, open-label, phase 2 trial. Lancet Infect Dis. 2011 Feb;11(2):110–8.
[3] Yuan G, Xu J, Qu T, Wang B, Zhang R, Wei C, et al. Metabolism and disposition of tribendimidine and its metabolites in healthy Chinese volunteers. Drugs RD. 2010;10(2):83–90.
Reference: PAGE 24 () Abstr 3512 [www.page-meeting.org/?abstract=3512]
Poster: Drug/Disease modeling - Infection