The assessment of antimalarial drug efficacy in vivo

Abstract

Currently recommended methods of assessing the efficacy of uncomplicated falciparum malaria treatment work less well in high-transmission than in low-transmission settings. There is also uncertainty how to assess intermittent preventive therapies and seasonal malaria chemoprevention (SMC), and Plasmodium vivax radical cure. A pharmacometric antimalarial resistance monitoring (PARM) approach is proposed specifically for evaluating slowly eliminated antimalarial drugs in areas of high transmission. In PARM antimalarial drug concentrations at recurrent parasitaemia are measured to identify outliers (i.e., recurrent parasitaemias in the presence of normally suppressive drug concentrations) and to evaluate changes over time. PARM requires characterization of pharmacometric profiles but should be simpler and more sensitive than current molecular genotyping-based methodologies. PARM does not require parasite genotyping and can be applied to the assessment of both prevention and treatment.

Keywords: antimalarial drugs; chemoprevention; malaria; pharmacometric antimalarial resistance monitoring (PARM); pharmacometrics; treatment.

Figure 1. Preventive antimalarial pharmacometrics in a high transmission setting.

The total number of parasites in the body (y axis log scale) of a parasitaemic pregnant woman who starts IPTp are shown as dashed lines [9,11]. She is bitten by sporozoite bearing anopheline mosquitos on average once each week (EIR 50/year). Her second next antenatal clinic visit and second IPTp dose is one month later. The incubation period is 13 days and approximately 30,000 parasites are liberated at hepatic schizogony. The blood concentration profile of the IPT drug is shown in light blue. Drug exposure in the population can be characterized by measuring day 7 concentrations [27]. Sensitive parasites (green dashed lines) are either cleared (infection 1 was patent but asymptomatic, and was present before starting IPT, infection 2 was cleared after emerging from the liver) or they are suppressed (infections 3-5) until the next round of IPT which then clears them. A resistant infection (3R) acquired when IPT started, emerges from the liver 13 days later and soon begins to expand reaching densities which are detectable by PCR, but not by microscopy, before the next round of IPT. Drug levels measured at the time reveal antimalarial drug levels which should have suppressed parasite growth (as in 3S) thereby distinguishing inadequate exposure from drug resistance as a cause of recurrent infection. In practice many women have longer intervals than one month between doses.

Figure 2. Assessing treatment responses in symptomatic malaria.

An increase in severity and malaria parasitaemia or a failure to clear parasitaemia within 7 days constitutes an early treatment failure (red) which results either from failure to take or absorb the antimalarial drug, or high-grade resistance. From 7-14 days reinfection is not possible unless there is a very high level of resistance [–4] Nearly all recurrences in the second week are recrudescences. After 14 days patent reinfection is possible, but this still implies low drug exposure or resistance. In low transmission settings recrudescence is more likely. If drug exposure is adequate this implies a lower level of resistance (yellow) than for earlier treatment failures, whereas in high transmission settings reinfection is more likely, and may preempt recrudescence. Recurrences, whether recrudescences or reinfections, have to grow through the declining concentrations of the slowly eliminated antimalarials. The first reinfections to establish are the most resistant [4].

Figure 3. Detecting antimalarial resistance in vivo.

Example of the pattern of P. falciparum reinfections in an area of high transmission following an ACT for uncomplicated malaria. Weekly follow up for 8 weeks. Finger prick blood samples for PCR were taken in weeks 2, 3, and 4. Blood slides were assessed weekly {4]. Microscopy can detect parasite densities down to around 50/μL, and finger prick capillary blood sample PCR down to 1-5/ μL. As the blood concentrations of the slowly eliminated partner drug decline (light blue shadow shows average drug concentration profile), infections are progressively able to establish and multiply. Some patients present with symptomatic recurrences between the follow-up days. The dashed line shows a boundary to the left of which detectable recurrent parasitaemias may be resistant. This requires definition. It could be defined as 99% of drug sensitive parasites could not reach detectable parasitaemias if exposed to the geometric mean antimalarial drug plasma concentration. Recurrent parasite densities appropriate for sensitive P. falciparum are shown in green. The individual contemporaneously measured drug concentration, and thus the preceding drug exposures, were insufficient to suppress the growth of sensitive parasites. Recurrences associated with low drug concentrations are shown in yellow. Recurrences which are outside the 99 percentile for sensitive P. falciparum for the individual contemporaneously measured drug concentration are shown in red. These parasites have grown in concentrations of antimalarial drug which should have suppressed the growth of sensitive parasites. They are therefore likely to be drug resistant [13, 14]. Pharmacometric studies are required to calibrate these thresholds.

Figure 4. A suggested algorithm for simple pharmacometric evaluation.

D7 levels can be added to the prevention assessment, in which case the only difference with treatment assessment is that weekly follow up is not essential.

Figure 5. Severe malaria trial sample sizes.

Total numbers of patients in relation to the reduction in mortality required in a superiority randomized controlled trial (with 95% confidence) in childhood severe malaria in which the comparator was artesunate (mortality 8.5%) with 1:1 randomisation [43].