Janneke M. Brussee (1,2,3,*), Anna Neodo (1,2,*), Jessica D. Schulz (1,2), Jean T Coulibaly (1,2,4,5), Marc Pfister (3,6), Jennifer Keiser (1,2)
(1) Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. (4) Unité de Formation et de Recherche Biosciences, Université Félix Houphouët–Boigny, Abidjan, Côte d’Ivoire. (5) Centre Suisse de Recherches Scientifiques en Côte d’Ivoire, Abidjan, Côte d’Ivoire. (6) Certara LP, Princeton, NJ, USA. (*) Authors contributed equally.
Introduction: Soil-transmitted helminthiasis is a neglected tropical disease, caused by parasites including hookworms. To treat hookworm infections, monotherapy based on a single drug class (albendazole & mebendazole) has been moderately successful [1], and therefore combination therapies should be considered, which would also offer the advantage to prevent drug resistance. The Chinese drug tribendimidine might serve as a viable alternative treatment [2,3]. Tribendimidine is unstable in the gastro-intestinal tract and degrades into deacetylated amidantel (dADT, primary metabolite), which is subsequently absorbed, and later metabolized to an acetylated form of dADT (adADT, secondary metabolite) [4]. In vitro and in vivo studies describe that tribendimidine and its primary metabolite dADT possess potent anti-hookworm properties, while adADT is considered inactive [5]. Recently, a randomized Phase 2 trial has been conducted comparing the efficacy of combination therapies with tribendimidine in adolescents in Ivory Coast [6], and in a subgroup of the study participants, pharmacokinetic (PK) data was collected.
Objectives: We had four aims:
- (i) to characterize the PK of tribendimidine metabolites dADT and adADT in adolescents,
- (ii) to evaluate possible drug-drug interactions of tribendimidine with ivermectin and oxantel pamoate,
- (iii) to link exposure to response in adolescents receiving tribendimidine monotherapy, or a combination with ivermectin or oxantel pamoate,
- (iv) to ultimately identify a treatment strategy that is associated with >90% cure rates.
Methods: Dried-blood-spot samples were collected from 54 hookworm-positive adolescents, following a dense sampling scheme (8-10 samples/participant), in which concentrations of dADT and adADT were measured using a validated LC/MS-MS method. Based on this data, a population pharmacokinetic model was developed, in which combination therapy was evaluated as a possible covariate. Subsequently, an exposure-response analysis was performed correlating PK outcomes to the response markers cure rate and egg reduction rate, utilizing both linear regression and nonlinear least squares regression. Simulations were performed to identify a treatment strategy that is associated with >90% cure rates.
Results: The developed PK model for dADT and adADT included allometric scaling of clearance and volume of distribution parameters utilizing body weight. No pharmacokinetic drug-drug interaction was identified with ivermectin or oxantel pamoate, and the median dADT exposure (90% confidence interval) was 51.7 (28.3‒160.1) nmol/mL*h.
Linear regression analysis revealed no statistical significant correlation between maximum concentration (Cmax) or exposure (AUC) of the secondary metabolite adADT to outcomes (p > 0.1), while the correlation of the AUC of the primary metabolite dADT to outcomes was significant (p < 0.1). This is in agreement with previously described in vitro and in vivo activity of dADT and adADT against Heligmosomoides bakeri and Ancylostoma ceylanicum, two hookworm laboratory animal models [5]. Utilizing nonlinear least squares regression, an Emax model could describe the correlation between exposure and probability to be cured, with a required exposure to achieve 50% of maximum effect of 59.4, 5.4, and 15.8 nmol/mL*h for monotherapy, and combination with ivermectin or oxantel pamoate, respectively (p < 0.1). Assuming dose-linearity in pharmacokinetics and assuming that the Emax model can be extrapolated to higher exposure ranges, simulations show that a dose of >4000 mg tribendimidine (up to 10-fold the current considered safe dose) would lead to the target probability to be cured of >90%. Combination with ivermectin or oxantel pamoate would lower the minimal required dose of tribendimidine to 400 and 1000 mg, respectively.
Conclusions: To achieve cure rates > 90%, an unrealistically high monotherapy dose of >4000 mg would be required, while combination therapy with ivermectin resulted in higher cure and egg reduction rates, which could be an additive or synergistic effect. Further studies should be launched to enable registration of tribendimidine at a stringent regulatory authority.
References:
[1] Keiser J, Utzinger J. 2010. The drugs we have and the drugs we need against major helminth infections. Adv Parasitol 73:197-230.
[2] Xiao SH, Hui-Ming W, Tanner M, Utzinger J, Chong W. 2005. Tribendimidine: a promising, safe and broad-spectrum anthelmintic agent from China. Acta Trop 94:1-14.
[3] Xiao SH, Utzinger J, Tanner M, Keiser J, Xue J. 2013. Advances with the Chinese anthelminthic drug tribendimidine in clinical trials and laboratory investigations. Acta Trop 126:115-26.
[4] Yuan G, Xu J, Qu T, Wang B, Zhang R, Wei C, Guo R. 2010. Metabolism and disposition of tribendimidine and its metabolites in healthy Chinese volunteers. Drugs R D 10:83-90.
[5] Tritten L, Nwosu U, Vargas M, Keiser J. 2012. In vitro and in vivo efficacy of tribendimidine and its metabolites alone and in combination against the hookworms Heligmosomoides bakeri and Ancylostoma ceylanicum. Acta Trop 122:101-7.
[6] Moser W, Coulibaly JT, Ali SM, Ame SM, Amour AK, Yapi RB, Albonico M, Puchkov M, Huwyler J, Hattendorf J, Keiser J. 2017. Efficacy and safety of tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel pamoate, and albendazole plus oxantel pamoate against hookworm and concomitant soil-transmitted helminth infections in Tanzania and Cote d’Ivoire: a randomised, controlled, single-blinded, non-inferiority trial. Lancet Infect Dis 17:1162-71.
Reference: PAGE () Abstr 9286 [www.page-meeting.org/?abstract=9286]
Poster: Drug/Disease Modelling - Infection