Pharmacokinetics of a novel liquid controlled release codeine formulation

Area of Science:

• Pharmacology
• Pharmaceutics
• Drug Delivery

Background:

• Codeine, an opioid antitussive, has a short half-life necessitating frequent administration.
• Conventional liquid codeine formulations require dosing every 4 hours.
• Controlled-release formulations aim to improve dosing convenience and patient compliance.

Purpose of the Study:

• To evaluate the bioavailability of a novel, non-coated liquid controlled-release codeine formulation.
• To compare the pharmacokinetic profile of the new formulation with immediate-release codeine.
• To establish an in vitro-in vivo correlation for the controlled-release formulation.

Main Methods:

• An open-label, single-center, randomized, steady-state, cross-over study in healthy male volunteers.
• Administration of 69.7 mg controlled-release codeine every 12 hours versus 23.2 mg immediate-release codeine every 4 hours.
• Pharmacokinetic analysis including half-life and AUC, with in vivo release profiles derived via numerical deconvolution.

Main Results:

• The controlled-release formulation significantly protracted the apparent mean half-life of codeine from 3.2 to 8.2 hours.
• Mean area under the curve (AUC(0-12 h)) remained unchanged between formulations.
• An acceptable in vitro-in vivo correlation was demonstrated, validating the predictive power of in vitro testing.

Conclusions:

• The novel liquid controlled-release codeine formulation is bioequivalent to immediate-release codeine at a higher dose and less frequent interval.
• The formulation effectively extends codeine's half-life, offering potential for improved patient adherence.
• The established in vitro-in vivo relationship supports the utility of in vitro methods for predicting pharmacokinetic behavior of such formulations.