Primaquine

The Mimika district lies on the southern coast of Papua in Eastern Indonesia (Figure 1), covering an area of 21,522 square-kilometres with 12 sub-districts and 85 villages. The area is largely forested with both coastal and mountainous areas. Each year a total of approximately 5.5 metres of rainfall is recorded with peaks in July to September and December (unpublished data). At the last census in 2004, the population in the lowlands was reported as 130,000. One hospital, the Rumah Sakit Mitra Masyarakat (RSMM) in the town of Timika, services the whole district and is the only hospital available for the lowland population. Due to the presence of a local mine, there is economic migration, with the local population increasing by an estimated 16% per year. This has resulted in the diverse ethnic origin of the local population, with highland Papuans, lowland Papuans and non-Papuans all resident in the region. Healthcare for the population is provided by the public clinics of the local ministry of health, the Public Health Malaria Control programme (PHMC) of the mine, the RSMM hospital and the private sector.
Malaria transmission is perennial, but restricted to the lowland area where it is associated with three mosquito vectors: Anopheles koliensis, Anopheles farauti and Anopheles punctulatus [11 (link),12 (link)]. Entomological inoculation rates vary between 1 and 4 infected bites per year (unpublished data). Bed net coverage is estimated to be approximately 40%. In view of the high number of infections in non-immune patients, local protocols recommend that all patients with patent parasitaemia at any level are given antimalarial therapy. At the time of the study local treatment guidelines advocated chloroquine plus sulphadoxine-pyrimethamine for P. falciparum and chloroquine monotherapy for non-falciparum malaria. An assessment of local treatment regimens in 2004 highlighted that the day-28 cure rate of chloroquine monotherapy was less than 35% for patients with P. vivax and that of chloroquine plus sulphadoxine-pyrimethamine was only 52% for patients with P. falciparum [7 (link)]. Local and national guidelines also recommend that patients with P. vivax parasitaemia over 1 years old, receive 14 days unsupervised treatment with primaquine, however adherence to and effectiveness of this regimen in this setting is not known.

The WWARN QA/QC proficiency testing program for pharmacology laboratories assesses the ability of pharmacology laboratories to assay blood or plasma samples for concentrations of antimalarial compounds and their metabolites. Participation in the proficiency testing program is open to all laboratories doing either therapeutic efficacy studies or other research on antimalarial drug exposure. The program currently offers plasma-based samples for eight antimalarial drug compounds and metabolites: chloroquine/desethylchloroquine, mefloquine/carboxymefloquine, primaquine/carboxyprimaquine, amodiaquine/desethylamodiaquine, piperaquine, lumefantrine/desbutyl-lumefantrine, dihydroartemisinin, and artesunate. Commercially obtained and controlled plasma is spiked with accurately weighed certified reference materials. All active ingredients and the plasma are controlled by the manufacturer and reflected in certificates of analysis. Each analyte is sent in a range of concentrations, including the highest and lowest concentrations expected to be found in clinical samples (Table 1), which allows each laboratory to test the limits of its assay.

The study area included 13 clinics and hospitals in and around Laiza city, Kachin State, Myanmar along the China-Myanmar border (Figure 1). Kachin State is a predominately agricultural state and the vast majority of the State’s estimated 1.2 million inhabitants are ethnic Kachin, also known as Jingpo in China. This study includes patients who presented with fever at health centers in this study area between April 2011 and October 2012. Informed consent was obtained from patients prior to being included in this study and the overwhelming majority of patients gave consent (absolute numbers were not recorded). Consenting patients were then interviewed using a face-to-face survey that included questions concerning demographic attributes, occupation, education, mosquito prevention history, and malaria experience in the previous 12 months. After filling out the questionnaire, a blood smear was made and microscopic examination was carried out in the local clinics. Blood smears were further examined at another nearby field station by two experienced microscopists. Any discrepancies were re-evaluated to obtain a final consensus of the diagnoses.
Patients diagnosed with malaria by microscopy were treated according to the standard protocols of the Health Unlimited organization. Adult patients with P. vivax were treated with chloroquine for three days by four tablets as the first dose, two tablets at 24 h and two tablets at 48 h after the first oral administration, and primaquine for eight days by three tablets once per day. Plasmodium falciparum positive adult patients were treated with dihydroartemisinin and piperaquine phosphate tablets for three days, with two tablets as the first dose, two tablets 6 h later, two tablets 24 h later, and two tablets 48 h later.
The study protocol was reviewed and approved by institutional review boards from Pennsylvania State University and Kunming Medical University. There is no Kachin institutional review board, however the field team met with representatives of the Kachin Independence Organization prior to beginning the study and received verbal consent to pursue the research.

In the prospective study, we enrolled travelers who visited the travel clinic between January 2017 and December 2019 for malaria chemoprophylaxis. According to CDC recommendations, travelers could choose one from mefloquine, atovaquone-proguanil, doxycycline, chloroquine, primaquine, and tafenoquine for primary malaria prophylaxis [23 ]. In Taiwan, we have mefloquine, a once weekly regimen, and 2 kinds of a once daily regimen to choose from: doxycycline and atovaquone-proguanil. We interviewed 173 travelers, of whom 7 on atovaquone-proguanil were excluded because of the small sample size, and 5 were excluded because they were lost to follow-up after their trip.
All enrolled 161 travelers were Taiwanese, and we communicated verbally in Chinese; the questionnaire was also written in Chinese. Informed consent was obtained from every participant in the study during the first clinic visit. This study was approved by Kaohsiung Medical University Hospital Institution Review Board, KMUH-IRB-970496.

Data from the previously published article on the clinical efficacy of the three-day artesunate-mefloquine combination in the Thai-Myanmar borders during 2008–2009 were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis [18 ]. All patients were diagnosed with uncomplicated P. falciparum malaria. In brief, 124 patients (aged 16–50 years) were included in the study, 90 and 34 patients with sensitive and recrudescence response, respectively. All received 200 mg of artesunate and 750 mg of mefloquine on day 1, followed by 200 mg of artesunate, and 500 mg of mefloquine on day 2, followed by 30 mg of primaquine on day 3.