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INNOSC Theranostics and
Pharmacological Sciences TDM of imipramine: Correlation and case study

and elimination. Imipramine is available in oral forms such establish a dosing interval, since there may be a lag
as tablets, capsules, oral solutions, and parenteral dosage phase between the onset of clinical response and the
forms. There may be differences in bioavailability between plasma concentration of imipramine. The plateau of
generic and branded formulations, which can lead to a the dose-responsive curve reflects the association of
decrease in plasma concentration. Imipramine has a half- therapeutic response with either a slower equilibrating
life of around 12 – 24 h, is highly protein-bound, and has a deep tissue compartment, or some other biochemical
large volume of distribution. Age, liver function, and drug change, or both. Daily changes in blood levels may not
interactions can affect its pharmacokinetics [6,7] . be important for the therapeutic control of depression
1. Bioavailability (F): The bioavailability of imipramine but could be an issue regarding imipramine’s side
ranges from 20% to 70%. Absorption through the effects [6-8] .
gastrointestinal tract is almost complete, but the drug The wide range of pharmacokinetic parameters for
undergoes first-pass metabolism in the liver, which imipramine can be attributed to two factors: either true
reduces its bioavailability to 50% in most patients. alternation in these parameters, or limitations in estimating
The rate of absorption is variable, and it reached the a drug’s half-life within an individual for the dosing
peak concentrations at 2 – 8 h after a single dose. In interval establishment; it is difficult to determine which
general, different dosage forms of imipramine are of the two factors is responsible for the wide range. As
bioequivalent. Parenteral administration results in imipramine requires 1 – 3 weeks of treatment for apparent
less first-pass metabolism or none at all, which is therapeutic effectiveness, clinicians typically wait at least
important for drugs that produce active metabolites 2 weeks for plasma samples collection, unless overt signs
that have different therapeutic effects. There is little of toxicity were shown in patients. Samples obtained before
information suggesting that drug interactions or food the steady state are inaccurate and not recommended.
alter imipramine absorption [6,7] .
2. Clearance (Cl): Imipramine is cleared exclusively by The determination of trough and peak concentrations of
imipramine within the dosing interval is challenging as the
the liver, with <5% eliminated by the kidney. Active rate of absorption is dependent on individuals. It is often
metabolites of imipramine should be considered inconvenient to collect samples for trough concentration,
when monitoring plasma levels of imipramine. The and collection for peak concentration a few hours after the
estimated clearance for imipramine varies from dose administration is likely inaccurate. Yet, adjustments
3- to 5-fold, with a mean clearance of 10 mL/kg/min in dosing regimens can only be made in proportion to the
(0.6 mL/kg/h). This wide range is due to the intra- and changes in plasma concentrations. Therefore, clinicians
inter-individual variations in hepatic metabolism and standardized the dosing of imipramine at bedtime
drug reactions. Some compounds and liver diseases and sample collection in the morning (approximately
can increase imipramine plasma levels, but it is difficult 12 h after the oral dose). The mid-interval plasma
to estimate the clinical significance of these drug-drug concentrations observed would approximate the steady-
interactions when drugs are added or deleted from the state concentrations of imipramine, and any revisions to
therapy regimen. Differences in intrinsic metabolism pharmacokinetic parameters would focus on estimating
among patients and difficulties in predicting the clearance and bioavailability .
[8]
magnitude of drug interactions are also factors that
should be carefully monitored in patients [6,7] . 4.1. Key parameters
3. Volume of distribution (Vd): Imipramine is widely
distributed throughout the body due to its extensive Key parameters that should be monitored during TDM
binding to plasma proteins and tissues. The estimation of imipramine include the patient’s clinical response to
of imipramine’s Vd varies, but the most common range therapy, serum levels of imipramine, and the occurrence of
is 15 – 20 L/kg. This pharmacokinetic parameter is not any adverse effects. The goal of TDM is to optimize dosing
used clinically since loading doses of imipramine are to achieve therapeutic concentrations while minimizing
not administered. Due to its large Vd and high protein the risk of side effects. Imipramine is available in tablets
binding, it is unlikely for hemodialysis to remove of 10 mg, 25 mg, and 50 mg, as well as capsules of 75 mg,
significant amounts of the drug from the body [6,7] . 100 mg, 125 mg, and 150 mg. Injectable imipramine is
[9]
4. Half-life (t ): Imipramine has an average half-life available in a concentration of 12.5 mg/mL .
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of around 20 h due to its increased Vd and Cl. The key parameters to be considered during TDM of
[9]
However, its half-life ranged widely from 9 to 50 h imipramine are as follows :
depending on the changes in Vd and Cl. It is unclear 1. Therapeutic range: The optimal serum concentration
whether t of imipramine would be used clinically to of imipramine for therapeutic efficacy is typically
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Volume 6 Issue 2 (2023) 3 https://doi.org/10.36922/itps.0505