**7. Conclusion**

150 Current Topics in Tropical Medicine

In phase I studies of tafenoquine the drug is well tolerated with single doses up to 600mg and with chronic dosing (6 months) at 200mg weekly following a load of 200mg daily for 3 days (Brueckner et al., 1998; Leary et al., 2009) with no dose-limiting adverse events. The most common side effects observed are gastrointestinal, including heartburn, nausea and gas, usually associated with higher (>200mg) dosing. The most significant toxicity associated with tafenoquine is the potential to induce hemolysis in G6PD deficient individuals and methemoglobinemia (Crockett & Kain, 2007). GlaxoSmithKline, in partnership with Medicines for Malaria Venture, are undertaking an ascending-dose safety study of tafenoquine in G6PD heterozygous patients to identify the maximum safe dose in

There have been several placebo-controlled trials evaluating tafenoquine as a causal antimalarial chemoprophylactic drug. In a study of non and semi-immune Thai soldiers, tafenoquine was administered monthly at 400mg, following a 1200mg loading dose (given as 400mg/day for 3 days) for a total of 6 months and demonstrated a protective efficacy 96%

In a dose ranging prophylactic trial of tafenoquine to prevent *P. falciparum* in Gabon semiimmunes, which included children, doses of 25mg, 50mg, 100mg or 200mg/day for three consecutive days were tested. Tafenoquine was given one week following treatment with halofantrine. Subjects were actively followed for positive blood smears at day 56 and day 77 following tafenoquine dosing. Notwithstanding the 25mg dose, which uniformly failed, tafenoquine demonstrated 100% protective efficacy (PE) at all doses of 50mg or greater at day 56 and had PE of 80%, 93% and 100% at day 77 for doses of 50mg, 100mg and 200mg,

In a 13-week prophylactic trial in Kenyan semi-immune adults, tafenoquine was evaluated at weekly doses of 200mg and 400mg followed by a 600mg and 1200mg 3-day load, respectively. A third group consisted of a loading dose (1200mg load), followed by weekly placebo and a fourth group received placebo only throughout the 13-week period. The 200mg and 400mg weekly doses demonstrated PE of 91% and 93%, respectively. The

A large randomized, non-placebo controlled trial of non-immune Australian soldiers evaluated tafenoquine, dosed at 200mg weekly for 6 months following a loading dose (200mg/day for 3 days) while deployed to East Timor. Study participants were randomized 3:1 to receive either tafenoquine (n=492) or mefloquine (n=162) throughout their deployment. Although treatment-emergent adverse events were similar between the two groups and tafenoquine was well-tolerated during the study, there were no cases of malaria in any group. Exposure to malaria could not be assessed and therefore efficacy was not

In a subset of subjects (n=74) in the East Timor study who received tafenoquine, detailed safety assessments were conducted which detected vortex keratopathy. This finding had no effect on visual acuity and was fully resolved within one year following cessation of therapy (Nasveld et al., 2010). More extensive clinical ophthalmic evaluation of tafenoquine in a subsequent phase 1 safety trial further supports the vortex keratopathy seen with

Tafenoquine shows promise as a causal prophylactic drug and is currently being developed for a radical cure indication for *P. vivax* through a joint collaboration between

for *P. vivax* and 100% for multidrug-resistant *P. falciparum* (Walsh et al., 2004).

loading dose only group had a PE of 80% (Shanks et al., 2001).

tafenoquine is not clinically significant (Leary et al., 2009).

GlaxoSmithKline and Medicines for Malaria Venture (MMV, 2011).

this population (MMV, 2011).

respectively (Lell et al., 2000).

established (Nasveld et al., 2010).

Addressing malaria chemoprophylaxis for the international traveler can be challenging and should be done within the context of a comprehensive medical evaluation well before visiting the endemic region. Malaria is a life-threatening illness and requires a multidimensional, individually tailored approach to ensure the most appropriate measures, including non-drug strategies, are taken to prevent infection if the traveler is exposed. Existing chemoprophylactic drugs offer effective options for the international traveler, however emerging resistance, side effect profiles and contraindications limit use in many circumstances. Future effort is needed to identify and develop new effective and safe options for malaria chemoprophylaxis.

The views expressed in this chapter are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Army or Air Force, the Department of Defense, nor the U.S. Government
