Pharmacokinetic predictors for recurrent malaria after dihydroartemisinin-piperaquine treatment of uncomplicated malaria in Ugandan infants

Abstract

Background: Although dihydroartemisinin-piperaquine (DP) is used primarily in children, pharmacokinetic/pharmacodynamic (PK/PD) data on DP use in young children are lacking.

Methods: We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63.

Results: The median capillary piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤ 27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria.

Conclusions: These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlated with an increased risk of recurrent malaria after DP treatment in children receiving TMP-SMX prophylaxis. Interestingly, despite strong associations, infants remained at risk for malaria, even if they had residual levels of piperaquine.

Figures

Figure 1.

Trial profile and pharmacokinetic (PK) sampling scheme. Abbreviation: TCC, Tororo Child Cohort.

Figure 2.

Cumulative risk of recurrent malaria at 63 days. The graph shows the risk of recurrence in participants receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, based on an optimal cutoff of 27.3 ng/mL at day 7.

Figure 3.

Scatterplot of levels of piperaquine in capillary plasma found at the time of diagnosis of recurrent malaria in patients with a previous episode of malaria who were treated with dihydroartemisinin-piperaquine (DP) during the study. A total of 132 episodes in the study had a prior episode of malaria treated with DP. In 13 of 132 episodes, piperaquine was undetectable, and the range of time since the prior episode of malaria was 84 to 213 days. In the remaining 119 episodes, piperaquine levels were still detectable (3 samples were below the lower limit of quantification), with a range of time since the prior episode of malaria of 28 to 126 days. The dotted line represents the median piperaquine level (10 ng/mL) in participants with a detectable level at the time of recurrent malaria. Closed circles represent episodes in children not receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, and open circles represent levels in children receiving TMP-SMX prophylaxis.