Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria

Abstract

Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that could be used to optimize the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated 1,800 blood-stage Plasmodium falciparum parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by qPCR, and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modelling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. Pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semi-mechanistic parasite dynamics model was developed to explain maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with falciparum malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (Emax) function. Treatment simulations (i.e. 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥102 per life cycle (38.8 h) with a duration of action of ≥ 2 weeks. The semi-mechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool to assess and optimize current and new antimalarial drug combinations therapies containing piperaquine, and the impact of these therapies on killing multidrug resistant infections.

Pharmacokinetic considerations in seasonal malaria chemoprevention

“…These indirect MIC calculations might be inaccurate as they depend on several unvalidated assumptions. Controlled human malaria infection (CHMI) studies with subtherapeutic antimalarial doses also provide a method for determining the in vivo MIC values, albeit in the absence of induced host defences [44,45].…”

Asexual stage synchronicity in symptomatic and asymptomatic falciparum malaria

“…The bias to young ring stage parasites in the report by Andrade et al is compounded by selection of the 12 patients with the highest parasite densities: as Fairley showed in his seminal studies, peripheral blood parasitaemia in acute falciparum malaria follows an increasing sine-wave pattern driven by synchronous iterations of schizogony and sequestration [5]. This sine-wave pattern has been demonstrated more recently in human challenge studies [6]. If parasitaemia follows a sine-wave pattern driven by the mean developmental age, it follows that selecting patients with the highest peripheral parasitaemia will select for those with highly synchronous infections following schizogony [7].…”

Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokinetic-pharmacodynamic model

“…A dynamic pharmacokinetic-pharmacodynamic model is needed to capture the interplay between parasite growth, drug exposure, drug-induced parasite clearance, and suppression of parasite regrowth after treatment of the host. While pharmacokinetic-pharmacodynamic models have been shown to be useful for the understanding of other parasitic diseases, such as malaria [25][26][27][28], in vivo parasite replication rates or parasite clearance by VL drugs have not previously been studied and quantified for Leishmania. Longitudinal analysis of repeated blood parasite loads during and after VL treatment will enable characterization of these dynamics [11].…”