Determination of piperaquine concentration in human plasma and the correlation of capillary versus venous plasma concentrations

Abstract

BackgroundA considerable challenge in quantification of the antimalarial piperaquine in plasma is carryover of analyte signal between assays. Current intensive pharmacokinetic studies often rely on the merging of venous and capillary sampling. Drug levels in capillary plasma may be different from those in venous plasma, Thus, correlation between capillary and venous drug levels needs to be established. MethodsLiquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to develop the method. Piperaquine was measured in 205 pairs of capillary and venous plasma samples collected simultaneously at �24hr post dose in children, pregnant women and nonpregnant women receiving dihydroartemisinin-piperaquine as malaria chemoprevention. Standard three-dose regimen over three days applied to all participants with three 40mg dihydroartemisinin/320mg PQ tablets per dose for adults and weight-based dose for children. Correlation analysis was performed using the program Stata® SE12.1. Linear regression models were built using concentrations or logarithm transformed concentrations and the final models were selected based on maximal coefficient of determination (R 2 ) and visual check. ResultsAn LC-MS/MS method was developed and validated, utilizing methanol as a protein precipitation agent, a Gemini C 18 column (50x2.0mm, 5μm) eluted with basic mobile phase solvents (ammonium hydroxide as the additive), and ESI + as the ion source. This method had

Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance

“…Each treatment was simulated as a once-daily dose for three consecutive days. Low-and high-dose drug concentrations remain at or below the concentrations observed in patient samples in vivo [48,51,52]. However, it should be noted that the high-dose concentrations are close to peak serum concentrations for PPQ (539 ng/mL, 539 nM) [53] but well below those observed for CQ (376 ng/mL, 1.18 uM) [48].…”

Determination of unbound piperaquine in human plasma by ultra-high performance liquid chromatography tandem mass spectrometry

“…Our previous methods for total PQ determination in plasma were based on HPLC-MS/MS systems [ 9 , 13 ]. To gain more sensitivity, a UHPLC-MS/MS system, consisting of a Waters Acquity UPLC (I Class) and a Sciex TripleQuad 6500 + tandem mass spectrometer was used in this method.…”

“…1 . Based on our previous method [ 13 ], an Evo C 18 (50 × 2.1 mm, 1.7 μm, Phenomenex Inc., Torrance, CA, USA) was used for better stability in the basic mobile phase. Under the optimized conditions, the LLOQ reached 10 pg/mL, and linearity was found from 10–5000 pg/mL when clean PQ standard solutions in MeCN-water (1:9, v/v) with 0.5% FA were analyzed.…”

“…Methods for determination of total (including protein-bound and – unbound) PQ in human plasma have been well-documented [ 8 – 13 ]. The lower limit of quantitation (LLOQ) are ≥ 0.5 ng/mL in these methods.…”

Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children

“…PPQ quantification was conducted by protein precipitation using 25 µL of plasma, followed by liquid chromatography and tandem mass spectrometry. Calibrated standards ranging from 0.5 to 50 ng/mL were used and quality control (QC) samples comprise 1.5, 20, 40 ng/mL for sparse samples and standards from 10 to 1000 ng/mL and QC samples comprised of 30, 200, and 800 were used for the intensive analysis 45 . A coefficient of variation <10% for quality control samples was used.…”