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Al-Quteimat and Laila
γ-aminobutyric acid. The exact mechanism behind its psychotropic effect in treating bipolar disorder is not clear.3
Valproate has a complex pharmacokinetic profile that follows a 3-compartment model and shows nonlinear pharmacokinetic properties due to saturable protein binding.3,4
Valproic acid is typically 90% to 95% bound to plasma protein, mainly albumin. The serum-free (unbound) fraction of
VPA ranges between 6% and 10%. However, it depends on
serum albumin, serum VPA concentration, age, and endorgan failure.2 Other drugs that are highly protein bound can
also displace valproate from albumin and precipitate toxicity
(eg, aspirin).3 Therefore, interpreting the total serum concentration might be misleading sometimes.
The initial dosing is 10 to 15 mg/kg/d usually administered every 8 to 12 hours. Total daily dose can be increased
weekly by 5 to 10 mg/kg/d to a maximum of 60 mg/kg/d with
a target therapeutic range of 50 to 100 mg/L. Valproic acid is
extensively metabolized by liver, mainly by glucuronidation
(40%), β-oxidation, and ω-oxidation (20%). Less than 3% of
drug is excreted unchanged via kidney. Valproic acid is an
enzyme inhibitor which can increase the plasma concentration of some drugs (eg, tricyclic antidepressants, lamotrigine).2,3 Adverse drug reactions (ADRs) of VPA include
dizziness, weight gain, fatigue, and headache, whereas the
most serious ADRs include hepatotoxicity and pancreatitis.1

Carbapenem Antibiotics
Carbapenems (meropenem, doripenem, imipenem, ertapenem, and tebipenem) are a class of antibiotics that belongs to
the β-lactam antibiotics, similar to penicillins and cephalosporins. They differ from the other classes in their exact
chemical structure. The mechanism of action for this class is
similar to penicillins; it works as a cell wall synthesis inhibitor. Carbapenems have a wide spectrum of antimicrobial coverage (gram-positive, gram-negative, and anaerobic bacteria).
The use of carbapenems has increased as a result of the rising
resistance to cephalosporin antibiotics in Enterobacteriaceae
(Escherichia coli, Klebsiella, Enterobacter, and related
genera).5
The spread of extended-spectrum β-lactamase-caused
infections and the proven efficacy of carbapenems against
these organisms have led to its wide use in practice.
Unfortunately, some resistance is emerging due to the carbapenem-destroying β-lactamases ("carbapenemases").
Carbapenem-resistant Enterobacteriaceae are remarkably
resistant organisms and can cause serious infections leaving
providers with limited treatment options. All carbapenems
are administered parenterally except tebipenem (an oral drug
approved only in Japan).5
The pharmacokinetic properties of carbapenems are
relatively similar. Meropenem and doripenem have a linear
pharmacokinetics. Ertapenem has a high plasma protein
binding capacity in therapeutic concentration; however, the
effect on pharmacokinetics is minor and hence near-linear

pharmacokinetics can be assumed. Carbapenems do not
accumulate in patients with normal kidney function.6

VPA-Carbapenem Interaction
Carbapenems have been shown to reduce serum concentration of VPA in case reports and retrospective studies. The
interaction was first reported in the Japanese literature in the
late 1990s. The mechanism behind the interaction is complex
and still has not been fully elucidated. The reduction in serum
VPA concentration induced by carbapenems happens rapidly
within 24 hours of concomitant administration and may lead
to the aggravation of seizures. It is recommended to avoid
the use of these 2 medications concurrently.7

Methods
A literature review for relevant evidence was performed by
searching Medline (through PubMed), Ovid, Embase,
Cochrane library using the following keywords: valproate,
valproic acid, carbapenem, ertapenem, doripenem, meropenem, imipenem, and valproate drug interaction. In addition,
a manual search through major journals for articles referenced PubMed was performed. Related publications from
January 1998 till November 2018 were included in the initial
search. Relevant publications were reviewed and data regarding patients, type of carbapenem used, VPA dosing and level,
interaction severity, and clinical outcome were summarized.
Results, recommendations, and alternative options to manage this interaction were discussed.

Results and Discussion
Search Results
Using Medline search, manual search through major journals, and Cochrane Library database, clinically relevant
results were identified. Many case reports, review articles,
and some pharmacokinetic and retrospective clinical trials
were found relevant to the valproate-carbapenem interaction.
Most of these papers reported a significant reduction in valproate blood concentration in patients receiving concurrent
carbapenem therapy. Cochrane Library database was
reviewed, but no relevant systematic reviews were found.

Clinical Findings
The interaction between VPA and carbapenems has been
investigated in clinical studies with the main focus being on
the decrease in serum VPA concentration and the clinical
manifestation of the interaction.7-11 Some of these studies
reported an increase in seizures during VPA-carbapenem
combination therapy.7,9
A retrospective study has looked at 28 children who
received VPA either orally or intravenously concomitantly

Hospital Pharmacy - June 2020

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