Pharmacovigilance capacity in East Africa with focus on neglected tropical diseases

Abstract

Pharmacovigilance aims to enhance patient safety in relation to the use of medicines by reducing the incidence and severity of adverse events which includes supporting public health programs by providing information on the safety profile of medicines used by the programs. In Africa, the increased access to medicinal products is not well-matched with the pharmacovigilance capacity to monitor drug safety. The aim of this thesis was to assess the national pharmacovigilance centres and neglected tropical diseases public health programs’ pharmacovigilance capacity and performance, to identify gaps for targeted interventions to strengthen the national pharmacovigilance systems. Additionally, the safety of mass praziquantel (PZQ) co-administered with albendazole for the control of schistosomiasis and soil transmitted helminths was also investigated. Lastly the influence of pharmacogenetics (PG) variations on pharmacokinetics (PK) and safety was investigated as well.

Firstly, in paper I the national pharmacovigilance centres hosted at the national medicine regulatory authorities in Ethiopia, Kenya, Rwanda, and Tanzania were assessed to identify gaps for targeted interventions. Based on our findings, the national pharmacovigilance systems in all four countries were supported with legal framework. Except for Rwanda, all the other countries had systems to receive, process, and communicate suspected adverse event reports in place. However, reporting of suspected medicine-related harm from stakeholders including public health programs was inadequate in all countries. Overall, ≤ 1% of the total number of health facilities per country submitted Individual Case Safety Reports (ICSRs).

In paper II, the pharmacovigilance systems of the neglected tropical diseases public health program in Ethiopia, Kenya, Rwanda, and Tanzania were assessed to identify missing pharmacovigilance components for targeted interventions. All four neglected tropical diseases programs although limited had some elements of pharmacovigilance within their programs; this included having pharmacovigilance components in their strategic masterplans and some mechanisms to disseminate pharmacovigilance information. However, none of the four programs had a specific budget for pharmacovigilance and no ICSRs were submitted to the programs or national pharmacovigilance centres in 2017/2018. Furthermore, the programs had not investigated the safety of the medicines used during mass drug administration (MDA) to prevent, control and eliminate selected neglected tropical diseases, this is especially important because the medicines are given to all at-risk populations.

Therefore, in paper III, the safety of mass PZQ and albendazole administration for the control of schistosomiasis and soil transmitted helminths respectively, was investigated in 8037 school children aged 5–15 years in Rwanda. Adverse events were actively monitored on 1-, 2-, and 7-days post MDA. 20.6% of the children experienced at least one type of transient mild to moderate, and in few cases severe, adverse events. The most reported adverse events were headache (21%), dizziness or fainting (15.2 %), nausea (12.8%) and stomach pain (12.2%). The incidence of adverse events varied significantly between sex and age groups. Females, older children (10-15 years versus 5-9 years), those who had reported symptoms before treatment (pre-MDA), and/or received two or more PZQ tablets had an increased risk of experiencing adverse events. Pharmacovigilance during MDA is recommended for timely detection and management of adverse events.

Lastly, in paper IV the objective was to investigate the effect of PG variations on PZQ plasma drug concentration and treatment associated adverse events. A total of 462 school children who received single dose PZQ co-administered with albendazole were enrolled in this study. Whole blood samples were collected for genotyping of CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3) and CYP2J2*7. Two hours post-dose plasma samples were collected, and PZQ, trans- and cis-4-OH-PZQ concentrations were quantified using LCMS/MS. CYP2C9 and CYP2C19 genotypes were significantly associated with PZQ plasma concentrations and its metabolic ratios. Children who carried CYP2C9 (*2, *3) and CYP2C19 (*2, *3) had significantly higher PZQ concentration and lower trans and cis metabolic ratios compared to those with wildtype. Children who were CYP2C19 (*1/*17 or *17/*17) had the lowest PZQ concentration and highest trans and cis metabolic ratios. CYP3A4 genotype was associated with increased cis PZQ metabolic ratio. There was no significant association between the genotypes and adverse events, but those who experienced adverse events had a significantly lower mean cis-4-OH-PZQ metabolic ratio compared to those who did not.

In conclusion, the pharmacovigilance systems in Ethiopia, Kenya, Rwanda, and Tanzania are supported by laws, regulations, and guidelines. However, other missing key pharmacovigilance indicators makes it challenging for the pharmacovigilance centres and the NTD programs to identify medicine safety issues. The active safety surveillance of mass PZQ and albendazole administration showed that more than one in five children experienced at least one adverse event post MDA, most of which were mild to moderate, but few were severe. Factors associated with experiencing adverse events included age, sex, pre-treatment condition (pre-MDA), type of meal taken before drug intake and increased number of PZQ tablets. PZQ pharmacokinetics is mainly influenced by CYP2C19 genotype, and to lesser extent by CYP2C9 and CYP3A4 genotypes. Although the tested genotypes had no significant effect on and safety outcomes, variation in PZQ PK specifically, cis-4-OH-PZQ/PZQ metabolic ratio is associated with experiencing adverse event. Overall findings from this thesis underscores the need to strengthen the pharmacovigilance systems of the national pharmacovigilance centres and NTD programs, and to monitor the safety of the medicines used in MDA.