Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Côte d'Ivoire

Abstract

Background: A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa.

Methods: In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d'Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants' infection status.

Findings: There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment.

Conclusions: Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis.

Trial registration: ClinicalTrials.gov NCT02845713.

Fig 1. Screening, enrollment, PK study, and one-year follow-up to assess drug efficacy.

Fig 2

Plasma concentration-time profiles of (A) ALB-OX, (B) DEC, and (C) IVM, after a single dose of IVM+DEC+ALB stratified by LF infection status (infected = 32, uninfected = 24). Mean (±SD) are shown.

Fig 3

Distribution of dose adjusted C_max and AUC_0-t of DEC (A and B), IVM (C and D), and ALB-OX (E and F) stratified by LF infection status. The median, 25^th, and 75^th quartiles and 95% CI are shown. Significance was assessed with the Kruskal-Wallis test and all P values were >0.05. There were 32 LF-infected and 24 uninfected participants.

Fig 4

Distribution of dose adjusted C_max and AUC_0-t of DEC (A and B), IVM (C and D), and ALB-OX (E and F) stratified by sex. The median, 25^th, and 75^th quartiles and 95% CI are shown. Significance was determined by using the Kruskal-Wallis test. P values for all comparison were >0.05 except C_max for DEC (P = 0.004). There were 24 women and 32 men.

Fig 5

The efficacy of a single co-administered dose of the triple-drug regimen before and after treatment with respect to (A) Mf counts, (B) circulating filarial antigen levels as determined by mean filarial test strip (FTS) scores at 1 year after treatment, and (C) the number of active worm nests at one-year follow-up. Significance was determined by using the Mann Whitney test for FTS and worm nests (*** <0.001).

Fig 6. Variation in drug levels from the mean AUC_0-inf for all 56 study participants.

DEC is depicted as blue circles, ALB-OX as red triangles, and IVM as black asterisks. Four Mf+ individuals at baseline failed to completely clear Mf at 1 year following triple- drug therapy and are highlighted (ellipses).