Project Title

Impact of dolutegravir-based antiretroviral regimen on the pharmacokinetic profile and placental penetration of piperaquine administered for preventive treatment of malaria among pregnant women in Malawi

Project Objectives

The PENETRATE study will determine the impact of dolutegravir based ART on the pharmacokinetic profile and placental penetration of piperaquine administered as DP for intermittent preventive treatment of malaria in pregnant women in Malawi.

Host Organisation

EDCTP Project Call

Career Development Fellowship (CDF)

Study Design

Study design: To address the above stated questions, we propose to conduct a prospective pharmacokinetic (PK) cohort study (PENETRATE study) nested within on-going clinical trials in Malawi. Description of the arms of the parent clinical trials The EDCTP-MRC funded IMPROVE clinical trials are aimed at improving pregnancy outcomes with intermittent preventive treatment in Africa (Trial registration number for IMPROVE I: NCT03208179, IMPROVE II is yet to be registered). The participating countries are Malawi, Kenya and Tanzania. The description and arms of the IMPROVE trials are outlined in the table 1 (see graphic file) IMPROVE I will commence in the first quarter of 2018 and recruitment will be conducted over a period of one and half years and is expected to enrol 4,680 women (1,560 per arm) across the three countries and 1,560 women in Malawi (520 per arm). IMPROVE II will start recruitment in the second quarter of 2018 and will similarly enrol participants over a period of one and half years, with a sample size similar to IMPROVE I. It is expected that Malawi will have adopted use of dolutegravir based ART regimen within the adult population by the start of IMPROVE II (mid-2018). These trials will therefore provide appropriate cohorts in which to conduct pharmacokinetic sub-studies Link between the parent trials and the present PENETRATE study Figure 1 in the graphic file illustrates the link between the parent trial, its pharmacokinetic (PK) sub-study and the present PENETRATE study The main pharmacokinetic-pharmacodynamic sub-study of the parent trials will focus on the potential cardiotoxicity of repeated dosing of DP, with/without azithromycin (AZ), and its relationship with piperaquine concentrations. It will also assess the impact of repeated monthly dosing of DP on the steady state concentration of standard antiretroviral drugs, especially dolutegravir. A sparse sampling approach to to target peak (proxy for safety) and troug

Project Summary

Background: Dihydroartemisinin-piperaquine (DP) has been identified as an effective alternative to sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) in areas where SP resistance is high. In malaria endemic settings in Africa, human immunodeficiency virus (HIV) infection is also highly prevalent and HIV-infected pregnant women are on antiretroviral therapy (ART) and trimethoprim-sulphamethoxazole, to which resistance is increasingly reported. Recent evidence has shown that the current efavirenz based ART reduces exposure below purported efficacious concentrations of piperaquine, the longer acting partner drug of DP, during IPTp, and different dosing regimens for DP have been suggested. Due to safety and drug-interaction concerns of efavirenz based ART, a number of countries in malaria endemic settings are planning to adopt dolutegravir-based ART regimen for first-line treatment. However, there are recent potential concerns of possible dolutegravir associated neural tube defects among children born to women who were on dolutegravir-based ART at the time of conception or were exposed to it during first trimester of pregnancy. This has prompted national HIV programmes to delay rolling out of dolutegravir in women of child bearing potential and for first line ART initiation during pregnancy, with the view of revising this position when more safety data is available. This implies that HIV infected pregnant women would in the near future be on either efavirenz- or dolutegravir-based ART regimens. As countries aim to optimize the new proposed DP regimens for when coadministered with standard ART regimens (whether efavirenz or dolutegravir-based ART), there is a genuine need to understand their impact on the pharmacokinetic profile and placental penetration of the promising IPTp candidate, dihydroartemisinin-piperaquine. Aim:The PENETRATE study will determine the impact of standard ART on the pharmacokinetic profile and placental penetration of piperaquine administered as DP for intermittent preventive treatment of malaria in pregnant women in Malawi. Methods: A pharmacokinetic cohort study, nested within two large on-going EDCTP-MRC funded clinical trials (IMPROVE I & II), will be conducted in two steps among HIV uninfected and matched HIV-infected pregnant women commenced on dolutegravir-based ART in Malawi. In step I, intensive plasma blood samples will be collected over a period of 28 days following intake of DP to compare pharmacokinetic (PK) parameters of piperaquine between the HIV-infected and HIV-uninfected groups. In step II, two similar separate cohorts of women from the IMPROVE trials will have a paired maternal plasma and umbilical cord vein sample collected at delivery to compare the ratio of maternal/umbilical cord piperaquine concentrations between HIV-uninfected and HIV infected pregnant women on standard ART. EDCTP scope: The PENETRATE study will promote the career development of the lead investigator by allowing him to strengthen his basic and clinical pharmacology skills while acquiring skills in applied and clinical pharmacometrics, and establishing himself as an independent scientist in Malawi. Expected impact: Findings of the PENETRATE study will inform accurate dosing of DP when co-administered with standard ART, thereby informing the dosing regimen of dihydroartemisinin-piperaquine in the IMPROVE II clinical trial and contributing to the pool of evidence needed by WHO to recommend use of DP for IPTp among HIV-uninfected and -infected pregnant women on standard ART in Sub-Saharan Africa. Edit...

Current Organisation

Kamuzu University of Health Sciences (formerly University of Malawi's College of Medicine)

Current Job Title

Specialist Clinical Pharmacologist

Biography

Publications