Department of Ambulatory Care and Community Medicine, Lausanne, Switzerland.
Service of Clinical Pharmacology, Lausanne University Hospital, Lausanne, Switzerland.
PLoS One. 2019 Feb 6;14(2):e0210789. doi: 10.1371/journal.pone.0210789. eCollection 2019.
The intermittent preventive treatment in infants (IPTi) trial that took place in Papua New Guinea showed an overall reduction of 29% of the risk of malaria when delivering single-dose sulfadoxine-pyrimethamine (SP) associated to 3 days of amodiaquine (AQ) every three months to children during the first year of life. The aim of the present study was to assess if the last two doses of AQ were truly administered as prescribed by the parents at home based on drug level measurement and PK modelling, which is a good proxy of medication adherence. It provides also important information to discuss the efficacy of the intervention and on feasibility of self-administered preventive malaria treatment.
During the three-arm randomized double-blinded IPTi trial, each child was prescribed one dose of SP (day 0) and 3 doses of either AQ or artesunate (AS) at day 0, 1 & 2 adjusted to weight or placebo. Treatments were given at 3, 6, 9 and 12 months of age. The first day of treatment was delivered by nursing staff (initiation under directly observed treatment (DOT)) and the two last doses of AQ or AS by parents at home without supervision. For this cross-sectional study, 206 consecutive children already involved in the IPTi trial were enrolled over a 2-month period. At the time of the survey, allocation of the children to one of the three arms was not known. Blood samples for drug level measurement were collected from finger pricks one day after the planned last third dose intake. Only children allocated to the SP-AQ arm were included in the present analysis. Indeed, the half-life of AS is too short to assess if drugs were given on not. Because of the short half-life of AQ, desethyl-AQ (metabolite of AQ (DAQ)) measurements were used to investigate AQ medication adherence. Two PK (PK) models from previously published studies in paediatric populations were applied to the dataset using non-linear mixed effect modelling (NONMEM) to estimate the number of doses really given by the parents. The study nurse reported the administration time for the first AQ dose while it was estimated by the parents for the remaining two doses. Out of 206 children, 64 were in the SP-AQ arm. The adjusted dosing history for each individual was identified as the one with the lowest difference between observed and individual predicted concentrations estimated by the two PK models for all the possible adherence schemes. The median (range) blood concentration AQ in AQ arm was 9.3 ng/mL (0-1427.8 ng/mL), (Quartiles 1-3: 2.4 ng/mL -22.2 ng/mL). The median (range) for DAQ was 162.0 ng/mL (0-712 ng/mL), (Quartiles 1-3: 80.4 ng/mL-267.7 ng/mL). Under the assumption of full adherence for all participants, a marked underprediction of concentrations was observed using both PK models. Our results suggest that only 39-50% of children received the three scheduled doses of AQ as prescribed, 33-37% two doses and 17-24% received only the first dose administered by the study nurse. Both models were highly congruent to classify adherence patterns.
Considering the IPTi intervention, our results seem to indicate that medication adherence is low in the ideal trial research setting and is likely to be even lower if given in day-to-day practice, questioning the real impact that this intervention might have. More generally, the estimation of the number of doses truly administered, a proxy measure of adherence and an assessment of the feasibility of the mode of administration, should be more thoroughly studied when discussing the efficacy of the interventions in trials investigating self-administered malaria preventive treatments.
在巴布亚新几内亚进行的婴儿间歇性预防治疗（IPTi）试验表明，在婴儿生命的第一年，每三个月给予一剂磺胺多辛-乙胺嘧啶（SP）联合 3 天阿莫地喹（AQ），可将疟疾风险降低 29%。本研究的目的是评估最后两剂 AQ 是否如父母在家中根据药物水平测量和 PK 建模（这是药物依从性的良好替代指标）所规定的那样真正给药。它还提供了有关干预措施疗效和自我管理预防疟疾治疗可行性的重要信息。
在三臂随机双盲 IPTi 试验中，每个孩子在第 0 天接受一剂 SP，并在第 0、1 和 2 天接受 3 剂 AQ 或青蒿琥酯（AS），根据体重调整或给予安慰剂。治疗在 3、6、9 和 12 个月时给予。第一天的治疗由护理人员（通过直接观察治疗（DOT）开始）给予，最后两剂 AQ 或 AS 由父母在家中无需监督给予。对于这项横断面研究，在两个月的时间内招募了 206 名连续参与 IPTi 试验的儿童。在调查时，儿童被分配到三个手臂之一的情况尚不清楚。在计划的最后一剂摄入后一天，从手指刺取血样进行药物水平测量。仅纳入 SP-AQ 臂的儿童进行本分析。事实上，青蒿琥酯的半衰期太短，无法评估是否给予药物。由于 AQ 的半衰期很短，因此使用去乙基-AQ（AQ 的代谢物（DAQ））测量来研究 AQ 的药物依从性。使用非线性混合效应建模（NONMEM）将之前在儿科人群中发表的两项 PK（PK）模型应用于数据集，以估计父母实际给予的剂量数。研究护士报告了第一剂 AQ 的给药时间，而其余两剂的给药时间则由父母估计。在 206 名儿童中，64 名儿童在 SP-AQ 组。每个个体的调整给药史被确定为与两个 PK 模型估计的所有可能依从性方案的观察浓度和个体预测浓度之间差异最小的方案。AQ 臂中 AQ 的中位数（范围）血浓度为 9.3ng/mL（0-1427.8ng/mL），（四分位距 1-3：2.4ng/mL-22.2ng/mL）。DAQ 的中位数（范围）为 162.0ng/mL（0-712ng/mL），（四分位距 1-3：80.4ng/mL-267.7ng/mL）。在所有参与者完全依从的假设下，两种 PK 模型均观察到浓度明显低估。我们的结果表明，只有 39-50%的儿童按照规定接受了三剂计划的 AQ，33-37%的儿童接受了两剂，17-24%的儿童仅接受了研究护士给予的第一剂。两种模型都高度一致，可以对依从模式进行分类。
考虑到 IPTi 干预措施，我们的结果似乎表明，在理想的试验研究环境中，药物依从性较低，如果在日常实践中给予，药物依从性可能更低，这对该干预措施可能产生的实际影响提出了质疑。更一般地说，在讨论试验中自我管理的疟疾预防治疗干预措施的疗效时，应该更深入地研究实际给予的剂量数，这是依从性的替代指标，以及给药方式的可行性评估。
