Moxidectin: an oral treatment for human onchocerciasis

Figures & data

Figure 1. The observed and modeled skin microfilarial dynamics following a single dose of: (a) ivermectin (150 µg/kg) and (b) moxidectin (8 mg)

The data points (from the phase II clinical trial conducted by [16]) represent the percentage from pre-treatment mean microfilarial (mf) load (four skin snips from each participant) at 8 days and 1, 3, 6, 12, and 18 months after treatment for: (a) 45 ivermectin-treated participants (black triangles); (b) 38 moxidectin-treated participants (black diamonds). By way of model validation, the blue solid line in (a) illustrates the dynamics derived from the equations and parameters presented in [9] rather than re-fitted to the data in [16]. The red solid line in (b) represents the use of the modeling framework of [9] to fit the data in [16]. Error bars show the 95% CIs around the proportional reduction in mean mf counts, illustrating their variability among participants in the two trial arms depicted here. The data points at 8 days and 1, 3, and 6 months post-8 mg moxidectin are narrower than the plotted data and so are not discernible. To enable better visualization of post-treatment data points, the y-axis has been plotted from 0% to 30% (in both panels, the percentage at pre-treatment would be 100%). This figure has been reproduced under the Creative Commons Attribution 4.0 International License (CC BY 4.0) from [45].

Table 1. Summary of adverse events (as a percentage of participants with AEs or SAEs) for ivermectin and moxidectin from phase II and III clinical trials

	Awadzi et al. [16] phase II trial				Opoku et al. [17] phase III trial
AE category or AE	Ivermectin 150 µg/kg	Moxidectin 2 mg	Moxidectin 4 mg	Moxidectin 8 mg	Ivermectin 150 µg/kg	Moxidectin 8 mg
Any AE	100% (45/45)	97.7% (43/44)	100% (45/45)	97.4% (37/38)	–	–
SAEs (any grade)	–	–	–	–	3.4% (17/494)	4.0% (39/978)
Drug-unrelated AEs	93.3% (42/45)	93.2% (41/44)	91.1% (41/45)	94.7% (36/38)	97.8% (483/494)	97.1% (950/978)
Non-Mazzotti AEs	2.2% (1/45)	0% (0/44)	4.4% (2/45)	2.6% (1/38)	0%	0%
Mazzotti AEs (any grade)	95.6% (43/45)	86.4% (38/44)	100% (45/45)	97.4% (37/38)	96.8% (478/494)	98.9% (967/978)
Clinical* Mazzotti reaction (any grade)	–	–	–	–	90.3% (446/494)	96.5% (944/978)
Clinical Mazzotti reaction (grade 4)^†	–	–	–	–	5.1% (25/494)	9.2% (90/978)^#
MAP decrease – SAPH (grade 4)^†	0% (0/45)	6.8% (3/44)	2.2% (1/45)	15.8% (6/38)^#	–	–
MAP decrease – SSPH (grade 4)^†	2.2% (1/45)	2.3% (1/44)	8.9% (4/45)	13.2% (5/38)	–	–

AE: adverse event; SAE: severe adverse event; *Clinical Mazzotti reactions: non-laboratory reactions; MAP: mean arterial pressure; SAPH: severe asymptomatic postural hypotension; SSPH: severe symptomatic postural hypotension; ^†Onchocerciasis Chemotherapy Research Centre grade 4; ^#p < 0.05 for pairwise comparison of moxidectin treatment group vs. ivermectin treatment group.

Table 2. Summary of efficacy on Onchocerca volvulus microfilariae for ivermectin and moxidectin from phase II and III clinical trials

	Awadzi et al. [16] phase II trial				Opoku et al. [17] phase III trial
Time post-treatment (months)	Ivermectin 150 µg/kg	Moxidectin 2 mg	Moxidectin 4 mg	Moxidectin 8 mg	Ivermectin 150 µg/kg	Moxidectin 8 mg
Percentage of participants with undetectable microfilaridermia (by 4 skin snips)
1	54.8% (23/42)	78.6% (33/42)^#	97.8% (44/45)^#	97.3% (36/37)^#	42.3% (208/492)	83.6% (813/973)^#
6	31.0% (13/42)	81.0% (34/42)^#	91.1% (41/45)^#	100% (37/37)^#	11.0% (54/491)	91.6% (881/962)^#
12	19.1% (8/42)	35.7% (15/42)^#	40.0% (18/45)^#	59.5% (22/37)^#	5% (24/480)	46.5% (440/947) ^#
18	14.3% (6/42)	16.7% (7/42)	26.7% (12/45)	35.1% (13/37)^#	4.1% (16/386)	28.1% (215/764)^#
Percentage reduction from pre-treatment skin microfilarial density
1	91.7%	99.8%	100%	100%	93.9%	99.8%
6	92.3%	99.7%	99.9%	100%	90.9%	99.9%
12	84.1%	96.1%	96.1%	98.2%	76.5%	96.8%
18	81.1%	88.3%	89.5%	92.0%	64.0%	89.1%

^#p < 0.05 for pairwise comparison of moxidectin treatment group vs. ivermectin treatment group.

Table 3. Characteristics of ivermectin, moxidectin, and doxycycline

	Ivermectin	Moxidectin	Doxycycline
Drug description
Formula	C48H74O14	C37H53NO8	C22H24N2O8
Molecular mass	875.10 g/mol	639.819 g/mol	444.43 g/mol
Drug family	Avermectin macrocyclic lactone	Milbemycin macrocyclic lactone	Tetracycline antibiotic
Pharmacokinetics*
Dose	150–200 µg/kg (estimated by height)	8 mg	100–200 mg
Treatment course	Single dose	Single dose	Daily for 4–6 weeks
Route of administration	Oral	Oral	Oral
Half-life (t1/2)	18 hours	20–43 days	12–25 hours
Time to peak concentration (Tmax)	3–5 hours	3–4 hours	2.5 hours
Peak concentration (Cmax)	34–55 ng/mL	56.7 ng/mL	3.6 µg/mL
Volume of distribution (Vd)	3–3.5 L/kg	1.2 L/kg	0.7 L/kg
Protein binding	93%	–	>90%
Lipophilicity (LogP)	4.8	6	0.63
Metabolism	Liver	Liver (limited)	Liver, gastro-intestinal tract
Excretion	Feces, breast milk	Feces, breast milk	Feces, urine
Pharmacodynamics
Mechanism of anthelmintic action	Cell hyperpolarization and worm paralysis through opening of ligand-gated chloride channels. Potentially altered worm immunomodulatory protein production	Cell hyperpolarization and worm paralysis through opening of ligand-gated chloride channels. Potentially altered worm immunomodulatory protein production	Depletion of endosymbiotic Wolbachia pipientis bacteria in filarial nematodes [96]
Effect on Onchocerca volvulus	Microfilaricidal [9]	Microfilaricidal [16,17,45]	Non-directly microfilaricidal
	Embryostatic [9]; permanent sterilizing effect (assumed to be cumulative in transmission models [82,83]); partially macrofilaricidal [10]	Assumed embryostatic effect in transmission models [45]	Macrofilaricidal [90–93]; assumed prophylactic in models [93]; retarding L3 development in vectors [94]
Drug distribution modalities in onchocerciasis-endemic areas
Distribution	Community-directed treatment with ivermectin (CDTI); TNT if loiasis co-endemicity	Expected community-directed treatment with moxidectin (CDTM)	TTd
Approved for human use (group)	Yes (≥5 years old)	Yes (≥12 years old)	Yes (≥8 years old), but see [105]
Contraindications	None	None	Hypersensitivity to tetracyclines
Risk in pregnancy	Class C (risk not ruled out); teratogenic in mice, rats, and rabbits at very high doses	Insufficient evidence	Class D (positive evidence of risk); Discoloration of teeth during tooth development, but see [104,105]
Risk in loiasis co-endemicity	Risk of SAEs if ≥20,000 mf/mL of Loa loa [88]	Risk of SAEs anticipated, but see [118]	None [90–92,96,97]

*Pharmacokinetics references [23]: for ivermectin [19–22], for moxidectin, and [115] for doxycycline; mf: microfilariae; SAE: severe adverse event; TNT: test (for loiasis)-and-not-treat (with microfilaricides); TTd: test (for onchocerciasis)-and-treat with doxycycline (macrofilaricide).

Awadzi K, Opoku NO, Attah SK, et al. A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection. PLoS Negl Trop Dis. 2014;8(6):e2953.

 PubMed Web of Science ®Google Scholar

Basáñez MG, Pion SDS, Boakes E, et al. Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis. Lancet Infect Dis. 2008;8(5):310–322.

 PubMed Web of Science ®Google Scholar

Turner HC, Walker M, Attah SK, et al. The potential impact of moxidectin on onchocerciasis elimination in Africa: an economic evaluation based on the Phase II clinical trial data. Parasit Vectors. 2015;8:167.

 PubMed Web of Science ®Google Scholar

Opoku NO, Bakajika DK, Kanza EM, et al. Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial. Lancet. 2018;392(10154):1207–1216.

 PubMed Web of Science ®Google Scholar

Taylor MJ, Bandi C, Hoerauf A. Wolbachia bacterial endosymbionts of filarial nematodes. Adv Parasitol. 2005;60:245–284.

 PubMed Web of Science ®Google Scholar

Turner HC, Churcher TS, Walker M, et al. Uncertainty surrounding projections of the long-term impact of ivermectin treatment on human onchocerciasis. PLoS Negl Trop Dis. 2013;7(4):e2169.

 PubMed Web of Science ®Google Scholar

Stolk WA, Walker M, Coffeng LE, et al. Required duration of mass ivermectin treatment for onchocerciasis elimination in Africa: a comparative modelling analysis. Parasit Vectors. 2015;8(1):552.

 PubMedGoogle Scholar

Walker M, Pion SDS, Fang H, et al. The macrofilaricidal efficacy of repeated doses of ivermectin for the treatment of river blindness. Clin Infect Dis. 2017;65(12):2026–2034.

 PubMed Web of Science ®Google Scholar

Walker M, Specht S, Churcher TS, et al. Therapeutic efficacy and macrofilaricidal activity of doxycycline for the treatment of river blindness. Clin Infect Dis. 2015;60(8):1199–1207.

 PubMed Web of Science ®Google Scholar

Albers A, Esum ME, Tendongfor N, et al. Retarded Onchocerca volvulus L1 to L3 larval development in the Simulium damnosum vector after anti-wolbachial treatment of the human host. Parasit Vectors. 2012;5:12.

 PubMed Web of Science ®Google Scholar

Gaillard T, Briolant S, Madamet M, et al. The end of a dogma: the safety of doxycycline use in young children for malaria treatment. Malar J. 2017;16(1):148.

 PubMedGoogle Scholar

Tan KR, Magill AJ, Parise ME, et al. Doxycycline for malaria chemoprophylaxis and treatment: report from the CDC expert meeting on malaria chemoprophylaxis. Am J Trop Med Hyg. 2011;84(4):517–531.

 PubMed Web of Science ®Google Scholar

Kamgno J, Pion SD, Chesnais CB, et al. A test-and-not-treat strategy for onchocerciasis in Loa loa-endemic areas. N Engl J Med. 2017;377(21):2044–2052.

 PubMed Web of Science ®Google Scholar

US National Library of Medicine. Clinical trial evaluating the safety and efficacy of moxidectin 2 mg ivermectin-controlled in loa loa microfilaremic patients (EOLoa). National institutes of Health; 2019 [cited 2020 June 27]. Available from: https://clinicaltrials.gov/ct2/show/NCT04049851

 Google Scholar

Turner JD, Tendongfor N, Esum M, et al. Macrofilaricidal activity after doxycycline only treatment of Onchocerca volvulus in an area of Loa loa co-endemicity: a randomized controlled trial. PLoS Negl Trop Dis. 2010;4(4):e660.

 PubMed Web of Science ®Google Scholar

González Canga A, Sahagún Prieto AM, Diez Liébana MJ, et al. The pharmacokinetics and interactions of ivermectin in humans–a mini-review. AAPS J. 2008;10(1):42–46.

 PubMed Web of Science ®Google Scholar

Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother. 2006;58(2):256–265.

 PubMed Web of Science ®Google Scholar