PRACTICAL ISSUES AND UPDATES

Schistosomiasis, a common parasitic disease, can changethe pharmacokinetics of certain drugs, thereby affectingclinical outcomes

Adis Medical Writers

� Springer International Publishing Switzerland 2014

Abstract Schistosomiasis is a common, although

neglected, tropical parasitic disease that is endemic in

many parts of the world. The pharmacokinetic profile of

certain drugs may change in patients infected with schis-

tosomiasis, with the degree of change varying depending

on the extent of disease (e.g. stage of fibrosis, with or

without signs and/or symptoms of liver disease). As a

consequence, affected patients may consequently be at risk

of adverse clinical outcomes. In order to optimize out-

comes in patients, it is important to increase awareness

about schistosomiasis and its potential effects on

medications.

Neglected tropical disease that is highly prevalent

Schistosomiasis is a parasitic disease that is highly pre-

valent in endemic areas, such as Africa, the Middle East,

the Caribbean, South America, China and South East Asia

[1, 2]. More than 230 million people are estimated to

require treatment for schistosomiasis each year, but most

affected individuals do not receive treatment [1, 3].

Although it is associated with a high burden of morbidity

and mortality, the condition has not been widely studied,

and is designated as a neglected tropical disease by the

World Health Organization [4].

Caused by trematode worms

Schistosomiasis involves parasitic trematode worms

(schistosomes) that are found in the abdominal veins of

human hosts [2]. The most common species that infect

humans are Schistosoma mansori (prevalent in Africa, the

Middle East, the Caribbean and South America), S. ja-

ponicum (China, the Philippines and Indonesia), S. mekoni

(Cambodia, Lao People’s Democratic Republic), S.

guineensis (Central Africa), S. intercalatum (Central

Africa) and S. haematobium (African and the Middle East)

[1, 2].

Contact with fresh water containing larval forms of the

parasite is the cause of all schistosomiasis infections [2].

Following penetration of human skin, larvae enter the

capillaries and lymphatic system, with the worms eventu-

ally migrating to the hepatoportal venous system for

maturity. Mature, paired adult worms then migrate into

mesenteric venules of the bowel/rectum (most species) or

ureters (S. haematobium), where the female worm begins

egg production (begins 4–6 weeks after infection and

continues for &3–5 years). Eggs pass into adjacent tissues,

with many eggs being shed in feces (most species) or urine

(S. haematobium). Eggs that contaminate fresh water hatch

and infect freshwater snails; eventually larvae are released

from the snails, thereby repeating the cycle [2].

Can cause liver and other complications

Within 1 week of water exposure, patients may present

with a maculopapular eruption at the site of entry [2].

Acute schistosomiasis, which usually occurs 14–84 days

after water contact and begins with the deposition of eggs

into host tissues, is associated with flu-like symptoms (e.g.

fever, headache, myalgias, right upper quadrant pain and

Adis Medical Writers (&)

Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,

North Shore 0754, Auckland, New Zealand

e-mail: dtp@adis.com

Drugs Ther Perspect

DOI 10.1007/s40267-014-0111-y

bloody diarrhoea). The host’s immune response to eggs and

the granulomatous reaction evoked by their secreted anti-

gens results in chronic schistosomiasis. Granulomas are

mostly found in the intestine, liver, and genitourinary tract

[2].

Complications that are associated with most species (i.e.

S. mansori, S. japonicum, S. mekoni, S. guineensis and

S. intercalatum) include liver/periportal fibrosis, portal

hypertension, hepatomegaly, intestinal fibrosis, diarrhoea

and blood in the stool; S. haematobium is associated with

urinary tract fibrosis, bladder cancer and renal failure [1,

2].

Easily treated with praziquantel

Schistosomiasis caused by all major Schistosoma spp. can

generally be treated with a single 1-day course of oral

praziquantel [3]. Patients with S. mansoni, S. haematobium

or S. intercalatum should receive praziquantel 40 mg/kg in

two divided doses for 1 day, and those with S. japonicum

of S. mekongi should receive praziquantel 60 mg/kg in

three divided doses for 1 day [3].

Praziquantel is most effective against the adult worm

and requires the presence of a mature antibody response to

the parasite [3]. For travellers who have contracted the

parasite, the optimum timing of praziquantel treatment is

least 6–8 weeks after the last exposure to potentially con-

taminated freshwater. Although a single course of prazi-

quantel is usually curative, the immune response in lightly

infected patients may be less robust, and praziquantel

treatment may be need to be repeated after 2–4 weeks to

increase effectiveness. If the pre-treatment stool or urine

examination was positive for schistosome eggs, the success

of treatment can be confirmed by conducting a follow-up

examination at 1–2 months post-treatment [3].

Liver problems may change drug pharmacokinetics

Changes in the pharmacokinetics, and thereby the clinical

outcome, of many medications may be caused by patho-

logical involvement of schistosomiasis species [5]. Phar-

macokinetic parameters involving the hepatic system are

especially affected by schistosomiasis (e.g. changes in

hepatic blood flow may affect first-pass metabolism, and

changes in plasma protein synthesis or development of

ascites may affect drug distribution).

It is important to characterize potential pharmacokinetic

changes to improve the clinical efficacy and safety of

medications in regions where the infection is endemic and

to increase the awareness of pharmacokinetic implications

when clinical studies are being designed or interpreted in

populations with a high prevalence of this infection. This

article summarizes a review by Wilby et al. [5] that eval-

uated the published literature reporting pharmacokinetic

parameters of medications in patients with schistosomiasis

and assessed the associated clinical implications.

Data are very limited

A search of the current literature conducted by Wilby et al.

[5] identified only 13 articles (in a total of nine different

medications) that adequately described the pharmacoki-

netics of medications in patients with schistosomiasis [6–

18]. All studies were comparative and non-randomized,

with all but one study [8] including healthy volunteers as a

control group (Table 1). The data are limited by:

• the small numbers of patients included in the studies

(studies may be underpowered to determine differences

between comparator groups);

• the use of a single dose in all but one study [8] (the

effects of schistosomiasis on chronically dosed medi-

cations is not known);

• the high inter-subject variability that was reported

within most studies (difficult to make firm conclusions).

Pharmacokinetic changes occur in individuals infected

with schistosomiasis, but the degree varies depending on

the extent of disease and drug being administered [5].

Some generalizations can be made from the evidence

available on a limited number of drugs [5]:

• Drugs with high hepatic extraction ratio ([0.5) have a

high first-pass effect and low bioavailability, and their

clearance is dependant primarily on hepatic blood flow.

Patients with schistosomiasis had increased clinical

(propranolol) [9] and toxic effects (praziquantel) [8]

(Table 1). This is likely due to increased bioavailabil-

ity, resulting in higher exposure to these drugs.

• Drugs with low hepatic extraction ratio (\0.5) have low

hepatic clearance and their free fraction and intrinsic

clearance is affected primarily by changes in metabolic

rate. The pharmacokinetics of these drugs are largely

unchanged in patients with schistosomiasis, however it

may be affected by advanced liver disease (Table 1).

Pharmacokinetic changes for antipyrine (a low clear-

ance drug commonly used as a probe for hepatic

oxidative metabolic capacity) were shown, but only in

patients presenting with liver disease [11, 12]. There-

fore, schistosomiasis is unlikely to affect these drugs

until patients develop hepatic complications. Patients

with schistosomiasis who are taking low clearance

drugs should be monitored for signs and symptoms of

advancing liver disease, as advanced disease may affect

intrinsic clearance and put patients at risk of adverse

effects.

Table 1 Effects of schistosomiasis on the pharmacokinetics of drugs, as reviewed by Wilby et al. [5]

Druga Comparators (no. of pts) Significant PK and clinical results Study conclusions/comments

Hepatobiliary eliminated agents

Cefoperazone 2 g IV over

15 min [6]

Pts with HSS with marked portal

hypertension (6) vs. healthy

controls (4)

: t� in pts with HSS vs. controls Pts with HSS mild liver disease,

but marked portal hypertension.

have, at most, mild impairment

of cefoperazone excretion

Results may aid clinical decision

making for other cephalosporins

and other short-term agents

eliminated by the hepatobiliary

route

Agents with high (>0.5) hepatic extraction ratios (i.e. CL dependent primarily on hepatic blood flow)

Praziquantel 40 mg/kg [7] Pts with HSS with variable grades

of periportal fibrosis (9) vs.

healthy controls (6)

: t� in pts with HSS vs. controls Drug of choice to treat

schistomomiasis

Small sample size may have

precluded significance with PK

parameters other than t�

Results are unlikely to be clinically

significant, as praziquantel has a

wide therapeutic index

Praziquantel 20 mg/kg (3

doses at 0, 1, and 2 h)

[8]

Pts with Schistosomiasis

japonicum with severe liver

disease (8) vs. moderate liver

disease (9) vs. absent liver

disease (13)

: AUC and : Cmax in pts with

severe and moderate liver disease

vs. those with absent liver

disease

Results may be applicable to other

hepatically cleared drugs with

high extraction ratios (e.g.

verapamil, morphine, and

lidocaine) in pts with advanced

HSS disease and altered hepatic

blood flow

Mild adverse effects associated

with higher ([3.0 lg/mL)

plasma concentrations

The efficacy and safety of

hepatically cleared drugs should

be routinely monitored in pts

with advanced liver disease

Propranolol (long-acting)

160 mg [9]

Pts with HSS with periportal

fibrosis (8) vs. healthy controls

(7)

: AUC12, : Cmax and ; tmax in pts

with HSS vs. controls

HSS influenced both

pharmacokinetic and clinical

outcomes

; systolic and diastolic BP in pts

with HSS vs. controls

Not known if the PK and clinical

effects are maintained,

exaggerated, or dissipated with

long-term use

Agents with low (<0.5) hepatic extraction ratios (i.e. CL dependent primarily on free fraction and intrinsic CL)

Aminophylline 5.6 mg/kg

IV over 20 min [10]

Pts with HSS (12) vs. pts with

cirrhosis (14) vs. healthy controls

(16)

; CL in pts with cirrhosis vs. pts

with HSS and controls

Pts should be monitored for both

efficacy and safety

Antipyrine 300 mg [11] Pts with schistosomiasis without

evidence of hepato-

splenomegaly or liver

involvement (6) vs. pts with

schistosomiasis with evidence of

liver involvement (7) vs. healthy

controls (6)

: AUC, ; CL/F, : t� in pts with

liver involvement vs. healthy

controls; no difference between

pts without liver involvement

and healthy controls

Hepatic microsomal metabolism is

impaired in patients with

advanced hepatosplenic

schistosomiasis but not in those

with milder disease without liver

involvement

Antipyrine 1.2 g [12] Pts with HSS without ascites or

history of hematemesis (10) vs.

healthy controls (11)

; t� in pts with HSS vs. controls Lack of significant differences

may reflect mild disease in the

pts with HSS; ; t� may be due to

chance

Be aware of potential complications

Raising awareness about schistosomiasis and its actual and

potential effects on medications is important for optimizing

outcomes in affected individuals [5]. Although current data

are limited, pharmacokinetic changes may occur in patients

with schistosomiasis and, consequently, these patients may

be at risk of adverse clinical outcomes.

Clinicians should carefully screen patients with schisto-

somiasis for signs and symptoms of liver disease prior to

prescribing, dispensing or administering potentially harmful

medications [5]. For example, a lower initial dose and slow

titration to achieve the desired effect may reduce toxicity in

patients with schistosomiasis who are prescribed propranolol.

The dosage of some drugs may also need to be re-assessed and

adjusted during ongoing treatment with medications affected

by hepatic mechanisms in patients who develop signs or

symptoms of liver disease over time. When possible, clini-

cians should avoid the use of hepatotoxic medications [5].

Future clinical research should include pharmacokinetic

assessments to provide information regarding appropriate

dosing in patients with schistosomiasis and evidence of liver

disease, especially for drugs that primarily undergo metab-

olism, are associated with a risk of significant adverse drug

reactions and are widely used in areas in which schistoso-

miasis is endemic [5]. There is also a need for the develop-

ment of screening tools to help identify patients who have an

increased risk for adverse clinical outcomes [5].

Table 1 continued

Druga Comparators (no. of pts) Significant PK and clinical results Study conclusions/comments

Metronidazole 500 mg

[13]

Pts with HSS with periportal

fibrosis (6) vs. healthy controls

(7) [Study 1] and pts with

cirrhosis (6) vs. healthy controls

(5) [Study 2]

No between-group differences in

PK parameters

Adjustment of metronidazole

dosage is probably not required

in pts with chronic liver disease

provided renal function is

unimpaired, but may be required

in patients with severe liver

disease (Child–Pugh C)

Metronidazole 500 mg IV

over 20 min [14]

HSS with periportal fibrosis (10)

vs. healthy controls (7) and non-

HSS cirrhosis [Child–Pugh A

(14), B (9),C (12)]

: AUC, ; CL and : t� in pts with

HSS vs. control and ; AUC, :CL and ; t� in pts with HSS vs.

Child–Pugh Class C

Impairment of metronidazole

metabolism : as severity of liver

damage : with the consequent

direct effects on metabolic

capacity and intrinsic CL

Oxamniquine 1 g [15] Pts with HSS with periportal

fibrosis (9) vs. healthy controls

(5)

; Cmax in pts with HSS vs.

controls; no correlation between

disease severity and

oxamniquine PK values

Elimination of oxamniquine (drug

formerly used to treat

schistosomiasis) may be non-

linear; higher dosage

requirements for oxamniquine in

the Sudan are unlikely to be due

to lower plasma concentrations

of the drug

Paracetamol

(acetaminophen) 1 g

[16]

Pts with HSS (8) vs. healthy

controls (8) [groups subdivided

based on age; 9–25 and

45–65 years old]

Younger and older pts: : AUC

(paracetamol), ; AUC (toxic

glucuronide metabolite), :urinary excretion, : t�, in pts

with HSS vs. controls

Repeated dosing of paracetamol

may require care in pts with HSS

since the elimination the drug

from plasma is ;

Paracetamol 1.5 g [17] Pts with HSS with various states of

periportal fibrosis (8) vs. healthy

controls (8)

No between-group differences in

PK parameters

Tendency for paracetamol toxicity

may be ; as oxidative capacity

(which is primarily responsible

for production of the toxic

metabolite) is possibly ; in pts

with HSS

Other agents

Ethinyl estradiol

50 lg ? levonorgestrel

1,500 lg [18]

Pts with urinary/intestinal

schistosomiasis without evidence

of liver disease (25) vs. healthy

controls (6)

No between-group differences in

PK parameters; treatment with

praziquantel did not affect

plasma steroid concentrations

No PK reason for withholding oral

contraceptive steroids from pts

with early active schistosomiasis

who are receiving treatment with

praziquantel

AUC area under the concentration-time curve; AUC12 AUC from 0 to 12 h, BP blood pressure, CL clearance, CL/F apparent oral CL, Cmax

maximum concentration, HSS hepatosplenic schistosomiasis, IV intravenous, PK pharmacokinetic, pts patients, t� elimination half-life, tmax time

to Cmax, ; indicates decrease(d), : indicates increase(d)a Unless otherwise indicated, one dose of the drug was administered and the route of administration was oral

Disclosure This article was adapted from Clinical Pharmacokinet-

ics 2013;52(8):647–56 [5]. The preparation of these articles was not

supported by any external funding.

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