Clinical utility of tafenoquine in the prevention of relapse of Plasmodium vivax malaria: a review on the mode of action and emerging trial data

Figures & data

Figure 1 Chemical structure of tafenoquine.

Table 1 List of studies with a primary focus on safety, tolerability, and pharmacokinetics of TQ

Title of publication or clinical trial	Study date	Reference
Assessment of any potential retinal effects of TQ	2016–2017	NCT2658435
Application of the stable isotope label approach in clinical development-supporting dissolution specifications for a commercial tablet product with tafenoquine, a long half-life compound	2016	78
Pharmacokinetic interactions between tafenoquine and dihydroartemisinin-piperaquine or artemether-lumefantrine in healthy adult subjects	2014–2015	55
Hemolytic potential of tafenoquine in female volunteers heterozygous for G6PD deficiency (G6PD mahidol variant) vs G6PD-normal volunteers	2009–2013	49
Tafenoquine at therapeutic concentrations does not prolong fridericia-corrected QT interval in healthy subjects	2011–2012	39
Exposure-response analyses for tafenoquine after administration to patients with Plasmodium vivax malaria	2011–2013	56
Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects	2009	45
Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects	n.i.	54
Gender differences in gastrointestinal disturbances and plasma concentrations of tafenoquine in healthy volunteers after tafenoquine administration for post-exposure vivax malaria prophylaxis	1999	43
Comparative ophthalmic assessment of patients receiving tafenoquine or chloroquine/primaquine in a randomized clinical trial for P. vivax malaria radical cure	1999–2000	41
Plasma concentrations of tafenoquine, a new long-acting antimalarial agent, in Thai soldiers receiving monthly prophylaxis	1998–1999	79
Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers	1998–1999	53
First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial	n.i.	14

Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; n.i., not indicated; TQ, tafenoquine.

Table 2 List of clinical studies focusing on TQ efficacy

	Study drugs	Study type/endpoint(s)	Study period	RC/Pro	Location	No. of participants	Sex/age	Infected on inclusion	Treatment allocation	Status	Phase	Outcome	Reference
1	TQ PQ DHA/PQP	Randomized, active-controlled, double-blind Efficacy/superiority of DHA/PQP+TQ against DHA/PQP for Plasmodium vivax radical cure compared to CQ at 6 months after treatment	2018 – 2019	RC	Timor-Leste	150 planned	Males, females/≥18 years	Yes P. vivax	T1) DHA/PQP+TQ 300 mg (single dose)+ PQ-placebo (for 14 days) T2) DHA/PQP+PQ 15 mg (for 14 days)+TQ-placebo T3) DHA/PQP+PQ-placebo (for 14 days)+TQ placebo	R	III	Study is ongoing	NCT2802501
2	TQ PQ CQa	Active-controlled, double-blind Incidence of hemolysis, safety, and efficacy of TQ vs PQ for P. vivax radical cure at 6 months after treatment	2015 – 2016	RC	Brazil Colombia Ethiopia Peru Thailand Vietnam	251 included	Males, females/≥16 years	Yes P. vivax	T1) CQ + TQ 300 mg (single dose)+PQ-placebo daily for 14 days T2) CQ + TQ placebo+PQ 15 mg daily for 14 days	C	III	Number (%) of recurrence-free participants at 6 months post-treatment: T1) CQ + TQ: 112/166 (76%) T2) CQ + PQ: 60/85 (71%) Overall incidence of clinically relevant hemolysis: T1) CQ + TQ: 2.4% T2) CQ + PQ: 1.2%	NCT2216123 (GATHER), 24
3	TQ PQ CQa	Randomized, active-controlled, double-blind Effectiveness and safety of 300 mg TQ + CQ for P. vivax radical cure compared to CQ at 6 months after treatment	2014 – 2016	RC	Bangladesh Brazil Cambodia Ethiopia India Peru Philippines Thailand	522 included	Males, females/≥16 years	Yes P. vivax	T1) CQ + TQ 300 mg (single dose)+PQ-placebo daily for 14 days T2) CQ + TQ placebo+PQ 15 mg daily for 14 days T3) CQ + TQ placebo+PQ-placebo daily for 14 days	C	III	Number (%) of recurrence-free participants at 6 months post-treatment: T1) CQ + TQ: 155/260 (60%) T2) CQ + PQ: 83/129 (64%) T3) CQ: 35/133 (26%)	NCT1376167 (DETECTIVE, Part 2), 24
4	TQ MQ PQ	Randomized, active-controlled, double-blind Efficacy of TQ for malaria prophylaxis for 6 months and for P. vivax post-exposure prophylaxis 3 months later	2000 – 2001	Pro, RC	Timor-Leste	654 included	Males, females/18–55 years	No	T1) TQ loading dose 200 mg/day for 3 days followed by weekly dose of 200 mg TQ for 26 weeks T2) MQ loading dose 250 mg/day for 3 days followed by weekly dose of 250 mg MQ for 26 weeks Upon return to Australia: T1 received placebo twice a day for 14 days T2 received PQ 15 mg twice a day for 14 days	P	III	Malaria prophylaxis: number (%) of P. vivax uninfected participants at 6 months exposure: T1) 492/492 (100%) T2) 162/162 (100%) Post-exposure prophylaxis, number (%) of P. vivax uninfected participants at 3 months post-exposure: T1) 488/492 (99%) T2) 161/162 (99%)	40, 80
5	(Doxy) TQ PQ	Randomized, open-label, parallel-group Efficacy of TQ for P. vivax post-exposure prophylaxis for 12 months	1999 – 2000	Pro	Papua New Guinea Timor-Leste	1,512 included	Males, females/18–55 years	No	All study participants took doxy during their stay of at least 2 months in a malaria endemic region. The study started after their return and participants were randomized to 4 arms: T1) TQ 400 mg 1× daily for 3 days T2) TQ 200 mg 2× daily for 3 days T3) TQ 200 mg 1× daily for 3 days T4) PQ 7.5 mg 3× daily for 14 days+doxy 100 mg for 14 days	P	II/III	Number (%) of P. vivax uninfected participants at 12 months post-exposure: T1): 223/242 (92%) T2): 156/161 (97%) T3): 386/406 (95%) T4): 429/464 (92%) Most common AEs were GID. Most AEs were mild or moderate	19
6	TQ	Randomized, placebo-controlled, double-blind, Long-term safety	2017 – 2020	Pro	Australia	600 planned	Males, females/18–55 years	NA	T1) TQ 200 mg/day for 3 days followed by TQ 200 mg 1× per week for 51 weeks T2) Placebo daily for 3 days followed by placebo 1× per week for 51 weeks	R	II	Study is ongoing	NCT3320174
7	TQ CQ	Open-label, non-comparative, single arm Pharmacokinetics, safety and efficacy of TQ in pediatric patients for P. vivax radical cure	2017 – 2019	RC	Colombia Thailand Vietnam	60 planned	Males, females/6 months–15 years	Yes P. vivax	T1) CQ + TQ single dose (100–300 mg depending on weight)	R	II	Study is ongoing	NCT2563496
8	TQ CQa PQ	Randomized, double-blind, dose-ranging Optimal TQ dose, safety and tolerability, efficacy of TQ + CQ for P. vivax radical cure compared to CQ at 6 months after treatment	2011 – 2013	RC	Brazil Peru India Thailand	329 included	Males, females/≥16 years	P. vivax	Single dose of each: T1) CQ + TQ 50 mg T2) CQ + TQ 100 mg T3) CQ + TQ 300 mg T4) CQ + TQ 600 mg T5) CQ + PQ 15 mg over 14 days T6) CQ only	P	II	Number (%) of recurrence-free participants at 6 months post-treatment: T1) 29/55 (53%) T2) 29/57 (51%) T3) 48/57 (84%) T4) 43/56 (77%) T5) 34/50 (68%) T6) 21/54 (39%) QT prolongation was the most common SAE: 2% in TQ group 8% in PQ group 4% in CQ alone AEs: Headache (28%), pyrexia (24%) and chills (23%), high incidence of diarrhea in T4	15 Part 1 of DETECTIVE
9	TQ CQ PQ	Randomized, placebo-controlled, double-blind Efficacy and safety of TQ for treatment of P. vivax	2003 – 2005	Treatment and RC	Thailand	70 included	Males, females/20–60 years	Yes P. vivax	T1) TQ 400 mg/day for 3 days+CQ placebo for 3 days, then PQ placebo from day 4 to day 18 T2) CQ 1,000 mg on day 1 and day 2 and CQ 500 mg on day 3, then +TQ placebo on day 1 to day 3, then PQ 15 mg/day from day 4 to day 18	P	II	Number (%) of participants cured at day 28 after T1) TQ: 40/43 (93%) T2) CQ + PQ: 22/22 (100%) Number (%) of recurrence-free participants at 4 months after treatment start: T1) TQ: 35/35 (100%) T2) CQ + PQ: 19/20 (95%) Safety: 5 SAE in TQ group as increased MHb (related to drug)	22
10	TQ MQ	Randomized, placebo-controlled, double-blind Prophylactic efficacy of Plasmodium falciparum infection of TQ compared to MQ within 6 months	2000 – 2003	Pro	Kenya	306 included	Males, females/18–55 years	No	T1) TQ 200 mg/day for 3 days, then TQ 200 mg weekly for 24 weeks T2) MQ 250 mg/day for 3 days, then MQ 250 mg weekly for 24 weeks T3) Placebo for 3 days, then placebo weekly for 24 weeks	C	II	Number (%) of P. falciparum uninfected participants within 6 months after treatment start: T1) TQ: 12/102 (12%) T2) MQ: 7/99 (7%) T3) Placebo: 6/99 (6%)	NCT2488980
11	TQ MQ	Randomized, placebo-controlled, double-blind Prophylactic efficacy against P. falciparum infection of TQ compared to MQ during 17 weeks	1998 – 2003	Pro	Ghana	521 included	Males/18–60 years and Females/50–60 years	No	T1) Placebo/day for 3 days, then placebo weekly for 13 weeks T2) TQ 25 mg/day for 3 days, then TQ 25 mg weekly for 13 weeks T3) TQ 50 mg/day for 3 days, then TQ 50 mg weekly for 13 weeks T4) TQ 100 mg/day for 3 days, then TQ 100 mg weekly for 13 weeks T5) TQ 200 mg/day for 3 days, then TQ 200 mg weekly for 13 weeks T6) MQ 250 mg/day for 3 days, then MQ 250 mg for 13 weeks	P	II	Number (%) of P. falciparum uninfected participants within 17 weeks after treatment start: T1) Placebo: 9/94 (10%) T2) TQ 25 mg: 35/93 (38%) T3) TQ 50 mg: 78/91 (86%) T4) TQ 100 mg: 83/94 (88%) T5) TQ 200 mg: 79/91 (87%) T6) MQ: 40/46 (87%) Safety and tolerability: musculoskeletal, GID and respiratory systems collectively accounted for 52%–70% of the total AEs in each group	50
12	TQ	Randomized, double-blind Prophylactic efficacy against P. falciparum infection and safety of different doses of TQ	1999	Pro	Gabon	417 included	Males, females/12–20 years	P. falciparum	T1) TQ 250 mg/day for 3 days T2) TQ 125 mg/day for 3 days T3) TQ 62.5 mg/day for 3 days T4) TQ 31.25 mg/day for 3 days T5) Placebo/day for 3 days	P	II	Number (%) of P. falciparum uninfected participants at week 11 after treatment start: T1) TQ 250 mg: 84/84 (100%) T2) TQ 125 mg: 78/79 (99%) T3) TQ 62.5 mg: 83/86 (97%) T4) TQ 31.2 mg: 63/79 (80%) T5) Placebo: 68/82 (83%) Abdominal was the most AE reported mainly in the TQ 250 mg group	17
13	TQ	Randomized, placebo-controlled, double-blind Prophylactic efficacy against P. falciparum infection of TQ compared to placebo within 17 weeks	1997 – 1998	Pro	Kenya	235 included	Males, females/18–55 years	No	T1) TQ 400 mg/day for 3 days, then placebo weekly for 13 weeks T2) TQ 200 mg/day for 3 days, then TQ 200 mg weekly for 13 weeks T3) TQ 400 mg/day for 3 days, then TQ 400 mg weekly for 13 weeks T4) Placebo for 3 days, then placebo once weekly for 13 weeks	P	II	Number (%) of P. falciparum uninfected participants within 17 weeks after treatment start: T1) 38/54 (70%) T2) 46/53 (87%) T3) 51/57 (89%) T4) 5/59 (8%) Safety: AEs similar number of volunteers in the 4 treatment groups, GID more common in TQ 400 mg dose, 2 hemolytic events occurred in TQ recipients (G6PD status not been correctly checked)	42
14	TQ CQ*	Randomized, open-label, dose escalation, Safety, tolerability, and efficacy of TQ for P. vivax radical cure compared to CQ at 6 months after treatment	1996 – 1997	RC	Thailand	44 included	Males, females/18–60 years	P. vivax	T1) CQ + TQ 300 mg/day for 7 days T2) CQ + TQ 500 mg/day for 3 days, then 1 week later TQ 500 mg/day for 3 days T3) CQ + TQ 500 mg once T4) CQ only	P	II	Number (%) of recurrence-free participants at 6 months post-treatment: T1) 15/15 (100%) T2) 10/11 (90%) T3) 8/9 (89%) T4) 5/9 (56%) Safety/tolerability: Except of MHb elevations, no clinically important laboratory value abnormalitiesGID were slightly more frequent in the TQ groups than among the CQ group only	21
15	TQ	Randomized, placebo-controlled, double-blind Safety and prophylactic efficacy of TQ against P. vivax and drug-resistant P. falciparum infection	1998	Pro	Thailand	205 included	Males/18–55 years	No	T1) TQ 400 mg/day for 3 days, then 400 mg/month for 5 months T2) Placebo: same dosing schedule	P	II	Number (%) of P. falciparum and P. vivax uninfected participants at 6 months after TQ start treatment start: P. vivax: T1) 103/104 (99%) (1 vivax) T2) 71/101 (70%) (21 vivax, 8 falci, 1, mixed) Safety: GID more common among TQ recipients than among placebo recipientsMost TQ recipients had transient, asymptomatic elevations of MHb	23
16	TQ PQ CQa	Randomized, open-label Safety, tolerability, and efficacy of TQ for P. vivax radical cure	1998 – 1999	RC	Thailand	80 included	Males, females/18–55 years	P. vivax	T1) CQ + TQ 300 mg/day for 7 days T2) CQ + TQ 600 mg/day for 3 days T3) CQ + TQ 600 mg single dose T4) CQ only T5) CQ + PQ 15 mg/day for 14 days	P	II	Number (%) of recurrence-free participants at 6 months post-TQ treatment start: 26/27 (96%) T1) 18/18 (100%) T2) 19/19 (100%) T3) 17/18 (94%) T4) 5/13 (38%) T5) 9/12 (75%) Safety/tolerability: Transient elevations in the MHb, AEs among the treatment groups were mild and transient, higher proportion of GID among TQ recipients, no SAE	20
17	TQ CQ	Open-label Efficacy of TQ for P. vivax radical cure	n.i.	RC	Australia	27 included	Males, females/mean age: 25 years	P. vivax	CQ: 600 mg+300 mg on day 1, 300 mg on day 2 and 300 mg on day 3 to treat acute infections Volunteers who already had ≥1 episode of P. vivax malaria relapse received TQ: TQ: TQ 200 mg/day for 3 days, then TQ 200 mg once/week for 8 weeks	P	II	Number (%) of recurrence-free participants at 6 months post-TQ treatment start: 26/27 (96%) No SAE, TQ was well-tolerated	57
18	TQ	Randomized, placebo-controlled, double-blind, CHMI trial Prophylactic efficacy of TQ against P. falciparum infection by CHMI (blood stage)	2017	Pro	Australia	16 included	Males, females/20–42 years	No	T1) TQ 200 mg/day for 3 days, then TQ 200 mg on day 10. T2) placebo CHMI with 2,800 viable P. falciparum schizonts on day 13	P	I	Number (%) of P. falciparum uninfected participants until day 32 after treatment start: T1) TQ: 12/12 (100%) T2) Placebo: 0/4 (0%)	63
19	TQ	Randomized, placebo-controlled, double-blind, CHMI trial Prophylactic efficacy of TQ against P. falciparum infection by CHMI (blood stage)	n.i.	Pro	USA	6 included	Males, females/median age 25±5 years	No	T1) TQ 600 mg single, oral dose on day 1 T2) placebo on day 1 CHMI with P. falciparum by bites of 5 infected mosquitoes on day 2	P	I	Number (%) of P. falciparum uninfected participants until day 65 after treatment start: T1) TQ: 12/12 (100%) T2) Placebo: 0/2 (0%)	12

Notes: Bold: key studies. Study intervention: TQ, MQ, DHA/PQP, AL, Doxy. Outcome: AEs, SAEs.

a If not otherwise indicated, in these studies CQ was given as an oral dose of 600 mg on day 1, 600 mg on day 2, and 300 mg on day 3.

b Clinical relevant hemolysis was defined as a decrease in Hb of ≥30% or 3 g/dL from baseline or an overall drop in Hb below 6 g/dL.

Abbreviations: AL, artemether+lumefantrine; C, complete; CHMI: controlled human malaria infection with P. falciparum; CQ, chloroquine; DHA/PQP, dihydroartemisinin+piperaquine; Doxy, doxycyclin; FDA, Food and Drug Administration; G6PD, glucose-6-phosphate dehydrogenase; GID, gastrointestinal disturbances; MHb, methemoglobinemia; MQ, mefloquine; NA, not applicable; n.i., not indicated; NR, not yet recruiting; P, peer-review published; PQ, primaquine; R, recruiting; RC/Pro, TQ efficacy investigated for P. vivax radical cure (RC) or for malaria prophylaxis (Pro) (all Plasmodium species); TQ, tafenoquine.