What is the time to peak plasma concentration (Tmax) of flupenthixol after an oral immediate‑release tablet dose versus after a long‑acting intramuscular depot injection in an average adult without hepatic or renal impairment?

Time to Peak Plasma Concentration of Flupenthixol

Oral immediate-release flupenthixol reaches peak plasma concentration (Tmax) at approximately 3–4 hours, whereas the long-acting intramuscular depot formulation (flupenthixol decanoate) reaches peak concentration on days 4–7 after injection.

Oral Immediate-Release Formulation

• Peak plasma concentration occurs at approximately 3–4 hours after administration of oral immediate-release flupenthixol tablets 1
• The rapid absorption from oral film formulations demonstrates faster kinetics, with enhanced bioavailability (151% relative to standard tablets) due to buccal and sublingual absorption bypassing first-pass metabolism 1

Long-Acting Intramuscular Depot Injection

• Flupenthixol decanoate produces peak plasma concentrations between days 4–7 following a single intramuscular injection 2, 3
• The depot formulation exhibits "flip-flop" kinetics, where the absorption rate constant is slower than the elimination rate constant, making absorption the rate-limiting step 2
• The apparent elimination half-life is approximately 17 days after a single injection, which justifies dosing intervals of 2–3 weeks 2, 3

Clinical Implications of Pharmacokinetic Differences

• The depot formulation is synthesized by esterifying flupenthixol to a long-chain fatty acid (decanoate) and dissolving it in vegetable oil, creating a sustained-release depot at the injection site 2
• Steady-state plasma concentrations require 4–6 weeks (approximately 3–4 half-lives) with repeated depot injections 2
• Plasma concentration variability is substantial, with up to 5-fold variation among individuals receiving identical doses, necessitating individualized dose titration between 10–40 mg every 2 weeks based on clinical response and tolerability 4

Dosing Considerations

• The optimal depot dose range is 20–40 mg every 2 weeks, with the dose-response curve rising steeply between 10–20 mg before plateauing at 80–95% treatment success rates 4
• Two-weekly injection intervals provide the highest trough plasma concentration per dose administered and the lowest peak-to-trough concentration ratio compared to longer intervals 4
• Extrapyramidal side effects occur frequently (12–71% of patients) within the therapeutic dose range of 20–40 mg every 2 weeks 4