Pharmacokinetic studies

Placenta under a microscopeProject Coordinator: Francois Nosten (Thailand)

Principal Collaborators:

Philippe Guerin, Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford (UK); Philippe Brasseur, IRD (France/Sénégal); Rose McGready, Wellcome/Madihol (UK/Thailand); Karen Barnes, University of Capte Town (South Africa); Patrice Piola and Carole Fogg, Epicentre Mbarara (Uganda); Halidou Tinto, Centre Muraz (Burkina Faso); Ishag Adam, New Haifa Hospital (Sudan); Isabela Ribeiro, DNDi (Brazil).

Almost all antimalarials studied have altered kinetic properties during pregnancy. In general the drug levels obtained in the blood of pregnant women are significantly reduced compared to those in non-pregnant women.  It is very likely that these changes in the dispositions of the drugs translate into a lower efficacy in treating and preventing malaria during pregnancy. It is therefore essential to define precisely the correct dose that must be administered to pregnant women both for treatment and in IPTp regimens.

Objectives
Primary: To establish the pharmacokinetic properties of the main antimalarial candidate drugs to be used in pregnancy.
Secondary: To study the pharmacological determinants of the parasitological responses to treatment and the tolerability of the various drug regimens in pregnant women.

General strategy
Formal and population pharmacokinetic studies will be conducted in pregnant patients with uncomplicated and severe falciparum malaria in the second and third trimesters of pregnancy, provided individual fully informed consent and ethical approval from appropriate ERBs has been obtained.

Study design

  1. Formal Pharmacokinetics (formal PK): These studies involve a small number of patients (usually 24 per drug) and frequent venous blood sampling. The timing of the sampling varies with each drug, depending on its pharmacokinetic properties. The patients who fulfil inclusion criteria are admitted for a minimum of three days and the medications (exact doses per body weight) are given under strict supervision. In order to measure the impact of pregnancy, matched non-pregnant women with uncomplicated malaria will be recruited or the same subjects will be restudied three to four months after delivery. A total of 48 subjects are recruited in each study and approximately 1200 (48x25) specimens are required per drug. For drugs used in combination, the number of assays will be doubled in order to study the kinetics of both components. SOPs for the blood sampling and specimens handling is attached. It is essential that the (clock) timing of the sampling is accurate.

  2. Population pharmacokinetics (sparse sampling or “pop PK”): this method uses fewer samples in a larger number of subjects (usually 70-100). The samples (ideally capillary blood provided such an assay has been validated) are taken at random times during each of the pre-determined time-windows after dosing. The analysis of the levels measured involves modelling PK curves for a population, rather than an individual patient, and allows characterization of the sources of inter-patient variance and the determination of pharmacological determinants (of the partner drug in the ACTs) of treatment outcome. The modelling of the data requires that the profile of the drug is first characterized in a formal kinetic study (above). Sparse sampling is being undertaken as part of clinical trials on the efficacy of the various antimalarials where the dosage regimens may have been “modified” based on the differences in the formal kinetic data obtained from pregnant and non pregnant patients. The population PK approach will be particularly useful in establishing the correct dosing for IPT regimens.

 Interventions

Phase I: Rich PK studies have been completed for some of the drugs, as part of work done by DO-MIP (composed of SMRU, Epicentre (Mbarara), IRD Dakar, New Halfa Hospital Sudan, Cape Town University) that started operating in 2004, while some others are on-going or in the planning phase:

Region

AQ

SP

As

DHA Pip

Mfq

AL

As IV

Quinine

Asia/SA 

Analysis ongoing

 

Analysis ongoing

Completed

 

Completed

 

Planned 2010

Thailand

               

India

       

Planned 2010

     

Brazil

       

Planned 2010

     

Bangladesh

           

Planned 2010

 

Other Non-MiPc

Papua (PQ)

Africa 

               

-Uganda

         

Completed

 

Completed

-Senegal

Ongoing

 

Ongoing

         

-Zambia

       

Planned 2010

     

-Sudan

 

Completed

Ongoing

Completed

       

Other Non-MiPc

Mali

DRC

Tanzania

 

Phase II: Pop PK studies. When the drugs involved are ACTs, the studies focus on the partner compounds (not the artemisinins) and capillary samples spotted onto filter paper are preferred when possible to limit the volume of blood taken and the challenge of freezing samples in routine field conditions. For several of these antimalarials (piperaquine and lumefantrine), new filter paper assays have to be developed and/or validated. Each arm has 100 women and the number of arms is determined by the analysis of the rich PK data. During this phase, the kinetics of the drugs used in IPTp will be characterized.

Phase III: As part of the main efficacy trials sparse sampling of antimalarials drug levels and for certain drugs (lumefantrine, mefloquine, piperaquine) a day seven level is collected, in order to determine the PK contribution to treatment outcome. Such samples are collected from all women who are enrolled but analyzed in those who failed treatment and from a random sample of cured women. If we assume that 10% or less of pregnant women treated fail treatment, a total of (estimated 450 depending on the sample size of each trial) additional drug levels will be required to establish the kinetic determinants of the parasitological outcome.