What are the pharmacokinetics of haloperidol (antipsychotic medication)?

From the Guidelines

Haloperidol's pharmacokinetics are characterized by good absorption, high distribution volume, extensive hepatic metabolism, and slow elimination, with a half-life of 12-36 hours, mainly due to hepatic metabolism, as seen in other medications with similar properties 1. The absorption of haloperidol is good, with maximum plasma concentration within a short time after administration, similar to other medications with high bioavailability.

• Key characteristics of haloperidol pharmacokinetics include:
  • Good absorption from the gastrointestinal tract
  • High distribution volume, with fast distribution from plasma to the central nervous system
  • High plasma protein binding, with 90%-99% of the drug bound to plasma proteins
  • Extensive hepatic metabolism, with a high first-pass metabolism and genetic polymorphisms affecting the metabolism
  • Slow elimination, with a half-life of 12-36 hours, mainly due to hepatic metabolism
• The metabolism of haloperidol is complex, involving multiple enzyme systems, including cytochrome P-450 and UDP-glucuronosyltransferases, with genetic polymorphisms affecting the metabolism, as mentioned in the context of other medications 1.
• The elimination of haloperidol is slow, with a half-life of 12-36 hours, mainly due to hepatic metabolism, and low renal excretion, with a small effect of renal insufficiency on plasma kinetics, similar to other medications with similar pharmacokinetic properties 1.

From the FDA Drug Label

Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses The pharmacokinetics of haloperidol is not fully described in the provided drug labels.

• The labels do not provide information on absorption, distribution, metabolism, or excretion of haloperidol.
• It is only mentioned that the pharmacokinetics in geriatric patients may require the use of lower doses 2. However, this information is not sufficient to fully describe the pharmacokinetics of haloperidol.

From the Research

Haloperidol Pharmacokinetics

• Haloperidol is a benchmark antipsychotic drug with a complex pharmacokinetic profile 3, 4, 5
• The bioavailability of oral haloperidol ranges from 60 to 65%, with large interindividual variability in plasma concentrations 3
• Haloperidol is metabolized via reduction to reduced haloperidol, which is biologically inactive, and also undergoes glucuronidation and oxidative N-dealkylation 3, 5
• The elimination half-life of haloperidol is approximately 3 weeks for the decanoate formulation, with a time to steady-state of about 3 months 3

Factors Affecting Haloperidol Pharmacokinetics

• Ethnic differences in metabolism and genetically determined polymorphic CYP2D6 activity may influence haloperidol disposition 5
• Concomitant administration of certain drugs, such as carbamazepine, phenytoin, and rifampicin, can affect haloperidol pharmacokinetics 5
• Haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, which can lead to pharmacokinetic interactions with other drugs 5

Clinical Implications

• Monitoring of plasma haloperidol concentrations may be clinically useful, particularly in patients with large interindividual variability in pharmacokinetics 3
• The optimal dose range for haloperidol in the treatment of acute schizophrenia is not well established, but doses above 7.5 mg/day may be associated with increased risk of extrapyramidal adverse effects 6
• Haloperidol decanoate has a flip-flop pharmacokinetic model, with a slower absorption rate constant than elimination rate constant, resulting in a peak plasma concentration on day 7 after intramuscular injection 3, 4