Investigating the Pharmacokinetics of Tafenoquine in Healthy Papua New Guinean Children

Safety, Pharmacokinetics, and Preliminary Efficacy of Tafenoquine for the Treatment of Vivax Malaria in Papua New Guinean Children

Plasmodium vivax is the most geographically widespread malaria species and the second largest contributor to symptomatic malaria worldwide. It accounts for half of all malaria cases outside Africa, with an estimated 14.3 million clinical vivax malaria cases reported annually, contributing to an annual cost of US$359 million. Children are most vulnerable to infection, with P. vivax prevalence peaking between 2 to 6 years of age. In Papua New Guinea (PNG), there are >1.5 million suspected P. vivax cases annually, and while P. falciparum infections are the most prevalent, P. vivax transmission is the most intense in the world. P. vivax in PNG provides a unique epidemiological setting in which to assess innovative treatments in children.

The complex biology of P. vivax represents a challenge for malaria control and chemotherapy, especially dormant liver-stage parasites (hypnozoites) which can reactivate (relapse) and cause disease at a time remote from the primary infection. Hypnozoite relapse is the primary cause of vivax malaria in endemic regions and is resistant to most antimalarial drugs. Identifying effective treatments for radical cure, the complete elimination of parasites (both blood- and liver-stage), is therefore a priority. The World Health Organization (WHO) recommends a 14-day radical cure regimen for uncomplicated vivax malaria; comprised of blood stage treatment (chloroquine or artemisinin combination therapy (ACT)) and 14 days of the 8-aminoquinoline drug primaquine (PQ; 0.25-0.5 mg/kg/day) for liver-stage cure. More recently, the 8-aminoquinoline tafenoquine has garnered interest as an alternative radical cure agent to primaquine. However, there is limited data on the pharmacokinetics, tolerability and radical cure efficacy of tafenoquine in children.

The overall aim of the study is to characterise the pharmacokinetic profile of tafenoquine (and primary metabolite) in Papua New Guinean children.

This is an open-label study to evaluate the pharmacokinetic disposition of tafenoquine, with and without coadministration of fat, in healthy Papua New Guinean children. This study represents the first part of a multi-phase evaluation of tafenoquine in PNG children (preliminary efficacy study registered separately).

In this study, healthy PNG children aged 5-12 year will be eligible for inclusion into the study providing they have normal G6PD activity (>70% enzyme activity) and no history of previous hypersensitivity to 8-aminoquinoline drugs. All participants will be admitted to the Alexishafen Health Centre for the first 2-4 days of the study, to facilitate blood sampling and clinical monitoring.

After admission, baseline demographic and medical history will be taken, and the participants will undergo a full clinical assessment to establish baseline safety indices. The 30 participants will then be randomized 1:1 to receive either:

Group A: single dose tafenoquine (10 mg/kg) with water (and cracker biscuits (2% fat), to mitigate gastrointestinal complaints, or Group B: single dose tafenoquine (10 mg/kg) with 250mL of chocolate flavoured mild (9% fat; and cracker biscuits (2% fat)).

For pharmacokinetic analysis, venous blood samples will be collected (via indwelling cannula) at 8 time points within the first 48-hours of drug administration, with further finger prick samples collected on days 3, 4, 7, 14, 28, 42 and 56. Both dried blood spot and plasma samples will be collected at all time points for pharmacokinetic analyses.

Standardised review, including adverse-effect questionnaires, and clinical monitoring (haemoglobin, methaemoglobin, reticulocyte counts, malaria blood films) will be conducted at all daily follow-up time points (Days 0, 1, 2, 3, 4, 7, 14, 28, 42, and 56). Safety testing (hepatorenal function tests (ALT, total bilirubin, creatinine), haemoglobin, urine dipstick analysis and electrocardiogram trace, will be taken at 4, 12, 24 hours and on Days 3, 7 and 28. A standardized clinical taste evaluation survey will be conducted (child or parent response, age dependent) 30 minutes of dosing, which will be repeated on Day 1.

Secondary objectives:

1. To evaluate the role of fat on the bioavailability of tafenoquine
2. To assess the safety of tafenoquine in PNG children
3. To assess the tolerability of tafenoquine in PNG children

The investigators hypothesise that:

1. A single dose of tafenoquine (10 mg/kg) is safe in PNG children
2. Co-administration of tafenoquine with fat will improve drug bioavailability
3. Cut or crushed tablets will not be well tolerated, although tolerability will improve with administration of whole tablets

Inclusion Criteria:

• have a normal glucose-6-phosphate-dehydrogenase (G6PD) activity (>70% enzyme activity) as confirmed by quantitative SD Biosensor
• are Rapid Diagnostic Test negative for malaria
• have not received treatment with any antimalarial in the previous 4-weeks
• have no signs or symptoms of significant morbidity
• have no history of hypersensitivity to primaquine
• are able to attend all scheduled follow-up visits

Exclusion Criteria:

• have G6PD activity <70%
• test positive for malaria by rapid diagnostic test
• have receive treatment with an antimalarial in the previous 4-weeks
• have signs or symptoms of significant morbidities
• have a history of primaquine related hypersensitivity
• cannot, or are not willing, to attend all scheduled follow-up visits