A Systematic Review of the Pharmacokinetic Implications of Schistosomiasis

Wilby KJ1
1College

of Pharmacy, Qatar University, Doha, Qatar

Background
!! Schistosomiasis is a common parasitic disease in the Middle East and elsewhere, with over 230 million people requiring treatment annually !! Worldwide increase of medication access poses risk for patients living in endemic regions due to the potential impact of disease on pharmacokinetic outcomes !! Chronic infection and associated disease commonly causes both intestinal and hepatic fibrosis. !! Calcification of the genitourinary tract may also occur in certain cases !! Altered absorption, distribution, metabolism, and elimination of chronically administered agents may lead to altered efficacy and safety in infected patients !! Clinicians and clinician scientists should be aware of these changes, in order to provide optimal drug therapy to affected patients

Background Contd
Figure 1. Lifecycle of Schistosomiasis with Human Host

The lifecycle of Schistosomes (trematode worms) in the human host leading to schistosomiasis; (1) Mature, paired, adult worms migrate from hepatoportal circulation into mesenteric venules of the bowel/rectum where the female worm begins egg production; (2) Eggs attached to the wall of the lumen are shed in feces or urine and contaminate fresh water; (3) Once in contact with fresh water, free-swimming miracidium infect oncomelania snails (4) and mature into cercarie within the hepatopancreas; (5) Cercarie are expelled daily from the fresh-water snails following circadium rhythm cycles and infect humans via skin barrier penetration.

Results:

Table 1. Summary of Key Pharmacokinetic Findings by Agents Identified in Review

Study Objective
!! To summarize and evaluate the published literature reporting pharmacokinetic parameters of medications in patients with schistosomiasis and to assess associated clinical implications

Medication
Cefoperazone (1 Study) Propranolol (1 Study) Praziquantel (2 Studies) Aminophylline (1 Study) Metronidazole (2 Studies)

Classification of Drug
Hepatobiliary Elimination

Key Pharmacokinetic Findings

" Elimination half-life in patients with hepatosplenic schistosomiasis (HSS) "AUC and Cmax in HSS patients #! Tmax in HSS patients "! Elimination half-life in HSS patients "! AUC and Cmax in those with severe and moderate liver disease # Clearance in patients with non-HSS cirrhosis vs. HSS patients and healthy volunteers "! AUC, elimination half-life in HSS patients vs. controls #! AUC and elimination half-life in HSS patients vs. Child-Pugh Class C "! AUC, urinary excretion, and elimination half-life in HSS patients vs. controls #! CL/F in HSS patients "AUC and elimination half-life in those with liver involvement vs. controls
*2nd study showed decreased elimination half-life in HSS patients vs. controls

Methods
!! Design: !! Systematic Review !! Data Sources: !! MEDLINE (1948-December 2012) !! EMBASE (1980-December 2012) !! International Pharmaceutical Abstracts (1970-December 2012) !! Google Scholar !! Google !! Manual search of references from identified articles !! Search Terms Used: !! Schistosomiasis OR bilharzia with pharmacokinetics, and drug metabolism !! Limits Applied to Results: !! Human, English !! Study Inclusion Criteria: !! The study must have had at least one group that reported at least one pharmacokinetic parameter of interest in schistosomiasis !! Study Exclusion Criteria: !! No pharmacokinetic information reported !! Information Extracted: !! Study design, populations assessed, medication administered (including dose, route, and frequency), clinical outcomes, and pharmacokinetic data !! Only pertinent or significant pharmacokinetic results extracted

High Hepatic Extraction Ratio High Hepatic Extraction Ratio Low Hepatic Extraction Ratio Low Hepatic Extraction Ratio

Acetaminophen (2 Studies) Antipyrine (2 Studies)

Low Hepatic Extraction Ratio Low Hepatic Extraction Ratio

Oxamniquine (1 Study) Ethinyl Estradiol + Levonorgestrel (1 Study)

Low Hepatic Extraction Ratio Other

# Cmax in HSS patients vs. controls

None

Conclusions and Implications

!! Pharmacokinetic changes occur in medications used to treat chronic diseases, as well as prototype medications for hepatic clearance (ie. antipyrine for low hepatic clearance) in those with HSS !! Prescribers and dispensing clinicians practicing in endemic regions need to be aware of the symptoms of liver disease and HSS, in order to ensure optimal doses and regimens are given to these patients. This strategy may optimize safety outcomes in HSS patients. !! Clinicians should also be aware of hepatotoxic medications and avoid use where applicable !! We suggest antihypertensive, antihyperglycemic, and cholesterol-lowering medications be targeted for future research based on increasing use in endemic regions
Acknowledgement: Dr. Samuel Gilchrist for providing an original figure